​Hung Van Le*
Biologics & Drug Targets, ProSci LLC, Rockaway, NJ, United States
ORCID
https://orcid.org/0000-0002-6913-2373 (Hung Van Le)

Abstract
 
Chronic hepatitis B remains a major global health challenge despite the success of universal vaccination and the availability of effective nucleos(t)ide analogue therapy. Current standard-of-care treatments suppress viral replication and reduce liver-related complications but rarely achieve functional cure, largely because cccDNA, integrated HBV DNA, and immune exhaustion persist. Recent therapeutic advances have begun to change this outlook. Bulevirtide has introduced a targeted entry-inhibition strategy for patients with HBV/HDV co-infection, while bepirovirsen may provide a broader finite-duration approach capable of increasing HBsAg loss beyond that achieved with standard therapy alone. In parallel, late-stage agents including siRNAs, capsid assembly modulators, neutralizing antibodies, therapeutic vaccines, and checkpoint inhibitors are advancing through Phase 2 and Phase 3 trials. These candidates support a shift toward rational combination regimens that reduce antigen burden, suppress replication, and restore antiviral immunity. Although disease severity and host immune status may limit response, the integration of vaccination, expanded access to care, and improved therapeutics could substantially advance HBV elimination efforts.

Clinical bottom line
 

• Current standard therapy effectively suppresses HBV but rarely cures it.
• Bulevirtide and bepirovirsen represent the first meaningful therapeutic advances beyond standard care.
• The future of HBV treatment lies in rational combination therapy rather than single agents.
• Not all patients are equally likely to achieve functional cure.
• HBV elimination will require both better therapeutics and stronger prevention.

 

Introduction
 
The introduction of the hepatitis B virus (HBV) vaccine more than four decades ago ranks among the greatest achievements in preventive medicine. According to the World Health Organization (WHO) Global Hepatitis Report 2026 [1], the global prevalence of chronic HBV infection among children younger than five years has declined from approximately 5% in the pre-vaccine era to just 0.6% today. More than 80 countries have already met the WHO's 2030 elimination target of reducing childhood HBV prevalence to below 0.1%. Worldwide, the annual incidence of acute HBV infection has fallen by more than 32% since 2015. In countries with longstanding universal infant vaccination programs, including Taiwan, the United States, and many European nations, childhood-acquired chronic HBV infection and its associated pediatric hepatocellular carcinoma have become exceedingly rare.
 
 
Despite this remarkable public health success, hepatitis B remains a major global health challenge, causing more than 1.1 million deaths annually. Approximately 240 million people worldwide continue to live with chronic HBV infection. Most were born before universal infant vaccination was implemented or reside in regions where vaccine coverage remains inadequate. Although completion of the three-dose infant vaccination series is relatively high worldwide, timely administration of the birth-dose vaccine within 24 hours of delivery continues to lag, particularly in low-income countries. In the WHO African Region, only 17% of newborns receive the recommended birth dose, allowing mother-to-child transmission to remain a major driver of the epidemic. Because vaccination prevents new infections but does not eradicate established ones, millions of chronically infected adults remain at risk of progressive liver disease, cirrhosis, and hepatocellular carcinoma. Compounding this problem, fewer than 5% of individuals with chronic HBV infection currently receive antiviral treatment [2,3].
 
Current therapy for chronic hepatitis B (CHB) relies primarily on long-term oral nucleos(t)ide analogues (NAs) and, in selected patients, subcutaneous pegylated interferon-α (PegIFN-α). Although NAs effectively suppress viral replication and markedly reduce the risk of liver disease progression, they rarely achieve a functional cure because they neither eliminate the stable covalently closed circular DNA (cccDNA) reservoir within hepatocyte nuclei nor prevent viral protein expression from integrated HBV DNA. Consequently, functional cure—defined as sustained loss of hepatitis B surface antigen (HBsAg) with undetectable serum HBV DNA for at least 24 weeks after treatment cessation—is achieved only infrequently with NA monotherapy. In most patients, discontinuation of therapy results in virological relapse, necessitating lifelong treatment [4,5].
 
PegIFN-α offers a finite-duration alternative but is limited by its parenteral administration, considerable adverse-effect profile, and suitability for only a carefully selected subset of patients. Functional cure rates following a standard course of PegIFN-α are modest, with cumulative HBsAg loss of approximately 8%–12% after 3–5 years of follow-up. Higher rates of HBsAg loss (15%–25%) have been reported when PegIFN-α is used as an add-on or switch strategy in carefully selected patients who have already achieved long-term viral suppression with NAs, particularly those with low baseline HBsAg levels (<1,000 IU/mL) [6,7]. Nevertheless, these outcomes remain unsatisfactory, underscoring the need for more effective therapeutic strategies capable of producing substantially higher rates of functional cure.
 
Recent advances in the understanding of the HBV life cycle and host immune responses [8] have stimulated the development of multiple novel antiviral and immunomodulatory agents [9]. Although none has yet achieved the long-sought goal of a sterilizing cure, these emerging therapies represent important incremental advances toward higher rates of functional cure. This review summarizes the current therapeutic landscape and highlights the progress, challenges, and future directions in HBV treatment.

Two Promising Direct-Acting Antiviral Approaches: Bulevirtide and Bepirovirsen
 
Bulevirtide: Targeting Viral Entry in HBV/HDV Co-Infection
 
Bulevirtide, developed by Gilead Sciences and marketed as Hepcludex, is approved for chronic hepatitis delta virus (HDV) infection in adults who are serum HDV-RNA positive and have compensated liver disease. The European Medicines Agency approved the drug in July 2020, followed by approvals in Canada in May 2025 and the United States in May 2026 [10]. Because HDV infection occurs only in people with hepatitis B virus (HBV) infection, bulevirtide is most relevant to patients with HBV/HDV co-infection.
 
Bulevirtide is a first-in-class entry inhibitor that binds to and inactivates the sodium taurocholate co-transporting polypeptide (NTCP) receptor on hepatocytes. Both HBV and HDV use NTCP to enter liver cells, so blocking this receptor prevents newly produced viral particles from infecting uninfected hepatocytes. This mechanism is especially important because HDV is an incomplete satellite virus that requires hepatitis B surface antigen (HBsAg) to assemble its envelope and spread [11].
Clinically, this fills a major unmet need. HBV/HDV co-infection is among the most aggressive forms of chronic viral hepatitis and can progress rapidly to cirrhosis and liver failure. Before bulevirtide, treatment options were limited, and finite therapies such as pegylated interferon-α (PegIFN-α) were often ineffective, poorly tolerated, or suitable only for carefully selected patients [12].
 
Administration and combination with nucleos(t)ide analogues
 
Bulevirtide is a 47-amino-acid lipopeptide administered as a daily 2 or 8.5 mg subcutaneous injection depending on EU or US approval, respectively [13, 10]. Treatment is generally long term and continued while clinical benefit is maintained. This prolonged treatment requirement reflects its mechanism of action: as an entry inhibitor, bulevirtide prevents new infection of hepatocytes but does not directly eliminate intrahepatic viral genetic material.
Most clinical practice guidelines, including EASL guidance, and national regulatory bodies such as HAS in France recommend routine co-administration with a nucleos(t)ide analogue (NA), such as tenofovir (TDF/TAF) or entecavir [14]. This approach helps maintain suppression of HBV replication while bulevirtide targets HDV entry.
 
The rationale is based on the interaction between the two viruses. In co-infected patients, HDV can suppress HBV replication, keeping serum HBV DNA low. When bulevirtide reduces HDV RNA, this viral interference may be lifted, potentially allowing HBV replication to rebound. Co-administering an NA reduces that risk by keeping HBV replication suppressed.
 
Potential role with PegIFN-α
 
Bulevirtide has also been studied in combination with PegIFN-α. While bulevirtide plus NA can suppress HDV RNA during treatment, adding PegIFN-α may increase the likelihood of off-treatment sustained virological response (SVR) and HBsAg clearance in selected trial cohorts [12].
 
Bepirovirsen: Toward a Broader Functional-Cure Strategy
 
Bepirovirsen, developed by GSK, is under formal regulatory review by both the US FDA and the European Medicines Agency as a potential first-in-class functional-cure therapy for chronic hepatitis B (CHB). The submissions are supported by two large global Phase 3 registrational trials, B-Well 1 and B-Well 2 [15], which enrolled more than 1,800 patients across 29 countries. The FDA has set a target action date of October 26, 2026, and an EMA opinion is expected in late 2026 or early 2027.
 
In B-Well 1 and B-Well 2, a 24-week course of once-weekly subcutaneous bepirovirsen, given as an add-on to standard NA therapy, produced functional cure in 20% of patients with chronic HBV infection at the 72-week follow-up. This result is comparable to functional-cure rates reported with PegIFN-α add-on strategies in carefully selected patients who have already achieved long-term viral suppression with NAs.
The key advantage of bepirovirsen is its broader potential applicability. Its safety and adverse-event profile appears more localized, manageable, and tolerable than that of PegIFN-α, which could make a similar level of functional-cure efficacy available to a larger cross-section of patients with chronic HBV infection [16].
 
Bepirovirsen may also create new opportunities for combination or sequential approaches. Preliminary studies suggest that PegIFN-α given after a course of bepirovirsen may reduce relapse rates compared with bepirovirsen alone [17]. Further study will be needed to define which patients are most likely to benefit and how best to sequence these therapies.
 
In summary, bulevirtide and bepirovirsen expand the therapeutic landscape for chronic HBV-related disease in complementary ways. Bulevirtide addresses the major unmet need of HBV/HDV co-infection, while bepirovirsen may increase functional-cure rates across a broader population of patients with chronic HBV infection, including those who are not candidates for PegIFN-α. Future combination studies involving these agents, NAs, and PegIFN-α will be important to determine whether relapse can be delayed, sustained responses improved, or functional cure achieved in selected patient groups.

Other Significant Anti-HBV Therapeutics in Late-Stage Phase 2/3 Development
 
Direct-Acting Antivirals (DAAs)
 
Global clinical-development pipelines have shifted away from monotherapy toward combination strategies that pair complementary mechanisms of action to increase the likelihood of functional cure, defined as sustained HBsAg loss with undetectable HBV DNA after treatment cessation, in patients with chronic HBV infection. Based on clinical-trial momentum, robust Phase 2 efficacy data, and expedited regulatory designations, three drug candidates (Table 1) appear most likely to advance toward regulatory submission after bepirovirsen.
 
Elebsiran (VIR-2218) is a small interfering RNA (siRNA) developed by Vir Biotechnology in collaboration with Alnylam and is currently being evaluated in Phase 2b/3 clinical trials. It targets a conserved 3′ region of HBV RNA, promoting degradation of viral transcripts and reducing serum HBsAg levels. Elebsiran is positioned for further development on the basis of encouraging Phase 2 results from studies such as MARCH and SOLSTICE, in which combinations with the neutralizing monoclonal antibody tobevibart and/or pegylated interferon produced off-treatment functional cure rates of 17% to 21% in patients with low baseline HBsAg [18]. In addition, elebsiran is being evaluated with tobevibart in the pivotal Phase 3 ECLIPSE trial for HDV/HBV co-infection, a program that has received FDA Breakthrough Therapy and EMA PRIME designations [19].
 
Another siRNA candidate, Imdusiran (AB-729), developed by Arbutus Biopharma, has reached Phase 2a/2b clinical development and is moving toward Phase 3 planning [20]. It is a subcutaneously delivered N-acetylgalactosamine (GalNAc)-conjugated siRNA designed to suppress HBV transcripts broadly, thereby reducing HBsAg expression and potentially relieving HBV-specific T-cell exhaustion. Clinical data presented at major hepatology conferences, including AASLD, from the IM-PROVE I trial showed that adding a short 24-week course of PegIFN-α to imdusiran plus NA therapy achieved a 25% overall functional cure rate, rising to 50% among patients with baseline HBsAg < 1,000 IU/mL [21]. Imdusiran has also shown strong synergy when paired with therapeutic vaccines, such as VTP-300, and low-dose checkpoint inhibitors, including anti-PD-1 therapy, positioning it as a potential backbone for future finite-duration cure regimens [22].
 
Pevifoscorvir Sodium (ALG-000184) is a capsid assembly modulator (CAM) developed by Aligos Therapeutics and is being evaluated in the Phase 2 B-SUPREME trial. It is a potent oral Class II CAM, or CAM-E, that disrupts capsid formation, blocks pregenomic RNA packaging, and may limit replenishment of intrahepatic cccDNA. Pevifoscorvir sodium is positioned for further development because of two notable advantages. First, it has demonstrated best-in-class potency: unlike earlier-generation CAMs, which showed only modest antiviral activity, ALG-000184 has produced profound multi-log reductions in HBV DNA, HBV RNA, and hepatitis B core-related antigen (HBcrAg) [23,24]. Second, it is orally active and is being directly compared with tenofovir disoproxil fumarate (TDF) in the Phase 2 B-SUPREME trial, offering a potential oral backbone that could replace lifelong NA therapy or be combined with injectable RNAi or antisense oligonucleotide therapies [25].
 
Immunomodulatory Agents and Host-Targeting Strategies
 
Several immunomodulatory and host-targeting agents are in active Phase 2 or Phase 2/3 clinical development. Historically, immunomodulators have faced a major hurdle: when circulating HBsAg levels remain very high, HBV-specific immune cells are profoundly exhausted, limiting the efficacy of therapeutic vaccines or checkpoint inhibitors when used alone. Now that direct-acting agents such as siRNAs and antisense oligonucleotides can reduce serum HBsAg by more than 99%, immunomodulatory therapies are emerging as essential components of combination cure regimens. Four prominent immunomodulatory and host-directed candidates (Table 2) are currently in Phase 2 or Phase 2/3 development.
 
Tobevibart (VIR-3434) is a neutralizing human monoclonal antibody developed by Vir Biotechnology and is being evaluated in Phase 2/3 clinical trials, including ECLIPSE and MARCH [26]. It is engineered to target the conserved S antigen of HBV and serves two complementary functions. First, it binds and neutralizes circulating HBsAg particles, promoting their rapid clearance from the bloodstream [27]. Second, because its Fc region is modified to engage Fc receptors on dendritic cells and promote antigen uptake, it may act as a passive-to-active immune stimulator with a vaccine-like effect [28]. As noted above, tobevibart combined with the siRNA elebsiran has achieved off-treatment HBsAg loss rates of approximately 20% in Phase 2 studies and is advancing toward registration.
 
VTP-300 is an antigen-specific therapeutic vaccine developed by Barinthus Biopharma, formerly Vaccitech, and is being evaluated in Phase 2b clinical trials, including HBV003 and IM-PROVE II. It uses a prime-boost vector strategy, with a ChAdOx1 prime followed by an MVA boost, to deliver HBV antigens, including core, polymerase, and surface proteins, directly to antigen-presenting cells [29]. When administered alone, therapeutic vaccines have limited efficacy in the setting of high viral-antigen burden. However, when VTP-300 is given after siRNA-mediated HBsAg reduction, such as with imdusiran [30], or combined with low-dose anti-PD-1 therapy [31], it can promote sustained T-cell responses and persistent HBsAg declines.
 
BRII-179 (VBI-2601) is a recombinant pre-S1/pre-S2/S therapeutic vaccine developed by Brii Biosciences and VBI Vaccines and is being evaluated in Phase 2b clinical trials. It is a virus-like particle (VLP) recombinant vaccine expressing all three HBV surface antigens—pre-S1, pre-S2, and S—designed to restore both B-cell antibody production and T-cell responses in virally suppressed patients. Phase 2 data suggest that adding BRII-179 to standard care, or to PegIFN-α, may increase the proportion of patients who achieve HBsAg loss and reduce viral rebound after therapy is stopped. It is also being studied as a biomarker tool to identify patients whose immune systems may be amenable to immune re-priming for functional cure [32].
 
Finally, ASC22 (envafolimab, also known as KN035) is a subcutaneous anti-PD-L1 checkpoint inhibitor licensed from Suzhou Alphamab by Ascletis Pharma for development and commercialization in viral diseases, primarily chronic hepatitis B and HIV [33]. The rationale is based on the observation that HBV can promote T-cell exhaustion through upregulation of the PD-1/PD-L1 immune-checkpoint pathway. Blocking PD-L1 is intended to reverse T-cell exhaustion and reactivate HBV-specific CD8+ cytotoxic T cells in the liver. Ascletis advanced ASC22 through a Phase 2b clinical trial [34], demonstrating functional cure rates of 21% to 42% in a subset of patients with very low baseline antigen levels, but limited meaningful HBsAg loss in patients with higher baseline viral loads [35]. Although these results were modest, they support immune checkpoint blockade as a potential pillar of combination cure strategies. They are also noteworthy because several anti-PD-1 and anti-PD-L1 monoclonal antibodies approved for oncology could, in principle, be evaluated in combination with HBV antivirals.

Discussion
 
The therapeutic landscape for hepatitis B remains one of the most dynamic areas of antiviral research, spanning both preclinical discovery and late-stage clinical development. Although current nucleos(t)ide analogue therapy has transformed chronic HBV infection from a rapidly progressive disease into a manageable long-term condition, it rarely produces functional cure and usually requires indefinite treatment. The persistence of cccDNA, the contribution of integrated HBV DNA to HBsAg production, and the profound immune exhaustion associated with chronic antigen exposure continue to make HBV biologically difficult to cure. For this reason, the field has increasingly moved away from single-agent viral suppression and toward finite, mechanism-based combination regimens designed to reduce viral antigen burden, restore antiviral immunity, and prevent relapse after treatment cessation. This strategy is illustrated in Figure 1.
 
Against this background, the introduction of bulevirtide and the anticipated introduction of bepirovirsen represent important incremental advances. Bulevirtide addresses a particularly severe clinical niche: chronic HBV/HDV co-infection, in which therapeutic options have historically been limited and disease progression can be rapid. By blocking NTCP-mediated viral entry, bulevirtide provides a targeted approach for suppressing HDV spread when used with background HBV suppression. Bepirovirsen, by contrast, has broader relevance to chronic HBV infection because it directly reduces HBV RNA transcripts and HBsAg production. Its Phase 3 functional-cure rates of approximately 20% are well above those generally achieved with nucleos(t)ide analogue monotherapy and may offer a finite-treatment option for selected patients, particularly those with lower baseline HBsAg levels. Together, these agents are unlikely to represent a final cure strategy, but they mark a meaningful step beyond the current standard of care.
 
The next decade is likely to bring further progress as multiple agents with diverse mechanisms of action advance through Phase 2 and Phase 3 trials. RNA-targeting agents such as elebsiran and imdusiran can markedly reduce HBsAg levels; capsid assembly modulators such as pevifoscorvir sodium may provide more potent control of viral replication and cccDNA replenishment; neutralizing antibodies such as tobevibart can accelerate clearance of circulating antigen; and therapeutic vaccines or checkpoint inhibitors may help restore exhausted HBV-specific immune responses. The diversity of this pipeline is important because HBV persistence is unlikely to be reversed through a single mechanism. Instead, higher functional-cure rates will probably require rational combinations that pair antigen reduction with immune reactivation and durable suppression of viral replication. If current clinical momentum continues, several of these agents could emerge as approved components of finite combination regimens, raising the possibility that functional-cure rates will move substantially beyond those achieved by today’s therapies.
 
Nevertheless, the upper limit of functional cure may be constrained by disease severity and host factors. Patients with long-standing infection, advanced fibrosis or cirrhosis, high baseline HBsAg levels, impaired innate and adaptive immune responses, or HBV/HDV co-infection may respond less well than individuals with lower antigen burden and preserved immune function. Even when HBsAg loss is achieved, some patients may retain intrahepatic viral reservoirs or integrated HBV sequences that sustain relapse risk or contribute to hepatocarcinogenesis. Thus, future clinical strategies will need to identify the patients most likely to benefit from finite cure regimens, determine whether sequential or combination approaches can overcome poor-response features, and maintain surveillance for liver cancer in those with established advanced liver disease.
 
Ultimately, HBV eradication will require integration of prevention and treatment rather than reliance on therapeutics alone. Universal infant vaccination, timely birth-dose vaccination, maternal screening, antiviral prophylaxis during pregnancy when indicated, expanded testing, and linkage to care remain essential for interrupting transmission. At the same time, the emergence of more effective finite therapies could reduce the pool of chronically infected individuals capable of transmitting infection and progressing to cirrhosis or hepatocellular carcinoma. If highly effective vaccines are deployed equitably and the best emerging therapeutics become accessible beyond high-income settings, the long-term prospect of HBV elimination—and eventually eradication as a public health threat—becomes increasingly realistic. The central challenge will be ensuring that scientific progress is matched by global implementation, affordability, and sustained political commitment.

Conclusion
 
HBV therapy is entering a period of meaningful but still incremental progress. Long-term nucleos(t)ide analogue therapy remains highly effective for viral suppression, yet it rarely produces functional cure. The approval of bulevirtide for HBV/HDV co-infection and the anticipated availability of bepirovirsen for chronic HBV infection signal a transition toward more targeted, finite, and mechanism-based treatment strategies. Even greater gains may come from emerging agents now in Phase 2 and Phase 3 trials, especially when combined to lower antigen burden, intensify viral suppression, and restore exhausted immune responses. However, cure rates are unlikely to improve uniformly across all patients; advanced liver disease, high baseline HBsAg levels, viral reservoirs, and impaired host immunity may continue to constrain outcomes. The long-term goal should therefore be twofold: to develop safer and more effective cure regimens for those already infected, and to strengthen prevention through universal vaccination, timely birth-dose coverage, maternal screening, and equitable access to treatment. Together, these measures could move HBV control from lifelong management toward functional cure and eventual elimination as a public health threat.

Abbreviations
 
ASO: Antisense Oligonucleotide 
CAM: Capsid Assembly Modulator
CHB: Chronic Hepatitis B
cccDNA: covalently closed circular DNA
EMA: Europeam Medicines Agency
EASL: European Association for the Study of the Liver
FDA: Federal Drug Administration
HAS: Haute Autorité de Santé
HBV: Hepatitis B Virus
HDV: Hepatitis Delta Virus
HBcrAg: Hepatitis B core-related Antigen
HBsAg: Hepatitis B surface Antigen
GalNac: N-acetyl Galactosamine
NA: Nucleos(t)ide Analogue
NTCP: sodium taurocholate co-transporting polypeptide
SVR: Sustaine Virological Response
TDF: Tenofovir Disoproxyl Fumarate
TAF: Tenofovir alafenamide
VLP: Virus Like Particle
WHO: World Health Organization

​Table 1. Summary of Emerging Pipeline of Direct-Acting Antivirals

​Table 2. Summary of Emerging Pipeline of immunomodulatory and host-targeting agents

​EMJ Rheumatol. 2026;13[1]:71-85. https://doi.org/10.33590/emjrheumatol/5X6F6HGP

​Hung Van Le*
Biologics & Drug Targets, ProSci LLC, Rockaway, The United States
ORCID
https://orcid.org/0000-0002-6913-2373 (Hung Van Le)

Abstract
This narrative review summarizes key recent clinical findings on the daily use of multivitamin-mineral (MVM) supplements, with emphasis on evidence most relevant to aging and personal health decisions. Recent randomized trials suggest that daily MVM use in older adults may provide modest but clinically meaningful benefits in selected domains, especially global cognition and episodic memory, with less consistent evidence for executive function. Additional findings support a reduction in cataract incidence, a potential benefit for some cancer outcomes, and a possible slowing of biological aging as measured by epigenetic clocks. By contrast, current evidence does not support clear benefits for cardiovascular disease prevention, adjudicated mild cognitive impairment, dementia incidence, or age-related macular degeneration. These findings both complement and contrast with current recommendations from major health agencies, which remain cautious and do not endorse routine MVM use for all adults. The practical implication is not that everyone should take a daily MVM, but that the newer evidence provides a stronger basis for individualized decision-making. Readers may find this information useful when considering their own diet, age, chronic conditions, medications, and family history, and when deciding whether discussion of MVM supplementation with a clinician is warranted as part of a broader strategy to support healthy aging.

Bottom line
 
Current evidence suggests that multivitamin-mineral supplementation in older adults:
 
May help

• Global cognition
• Episodic memory
• Cataract prevention
• Biological aging markers
• Some cancer outcomes

 
Has not been shown to help

• Cardiovascular disease
• Dementia prevention
• Age-related macular degeneration

 
Should not replace

• Healthy diet
• Physical activity
• Smoking cessation
• Blood pressure control
• Vaccination

Introduction
Although the topic may seem trivial and often appears in the news or in everyday conversation, the concerns are legitimate. Vitamin and mineral deficiencies are a worldwide problem, especially in lower-income countries where inadequate nutrition remains widespread. One recent estimate suggests that up to 5 billion of the world’s 8.3 billion people have micronutrient deficiencies, with different effects in males and females [1]. Even in higher-income settings, adequate intake is not guaranteed because diet, lifestyle, health status, cultural factors, and aging all influence nutritional needs.
 
Fortunately, people in higher-income countries have access to abundant, generally clear guidance on meeting micronutrient needs through diet and, when appropriate, supplementation. In the United States, for example, the Centers for Disease Control and Prevention (CDC) provides guidance about micronutrients, the U.S. Preventive Services Task Force (USPSTF) offers its own recommendations, and the National Institutes of Health (NIH) Office of Dietary Supplements provides fact sheets for consumers and health professionals.
 
Despite the guidance provided by health agencies, many people still rely primarily on advice from trusted clinicians when deciding whether to take multivitamin-mineral supplements (MVMs). Others, more skeptical of the medical establishment, related industries, or public health agencies, may follow medical news closely to better understand their health and the implications of new findings. Recent reports that daily MVM use may slow epigenetic clocks [2] are likely to renew interest in a familiar question: whether to take MVMs, and if so, at what stage of life.

Do daily multivitamins slow epigenetic clocks and reduce biological age?
The original study by Li et al. (2026) [3] was a prespecified ancillary analysis of the Cocoa Supplement and Multivitamin Outcomes Study (COSMOS), a large randomized, placebo-controlled trial involving 958 older adults with a mean age of 70 years. Participants received a daily multivitamin-multimineral supplement (Centrum Silver), cocoa extract, both interventions, or placebo. Researchers measured five DNA methylation-based “epigenetic clocks” at baseline and again after two years.
 
The main finding for the multivitamin arm was a statistically significant slowing of biological aging on two of the five clocks studied, especially PCPhenoAge [4] and PCGrimAge [5]. The estimated effect corresponded to roughly 2.5 to 5 fewer months of biological aging over two years. Participants whose biological age exceeded their chronological age at baseline appeared to benefit most. Additional analyses suggested that participants whose clock measures improved also showed lower inflammation and better preservation of cognitive function.
 
Methodologically, this is among the strongest supplement studies conducted to date because it was randomized, placebo-controlled, prospectively planned, and based on a relatively large, well-characterized cohort. The findings are thought-provoking, but by themselves they are unlikely to change clinical practice for prescribing multivitamin-mineral supplements to older adults. That caution is understandable because the study also has important limitations.
 
Most importantly, epigenetic clocks are surrogate end points. They do not show that participants lived longer, avoided disability, prevented fractures, or reduced cardiovascular events. Instead, they reflect changes in biomarkers thought to track biological aging. Whether modest improvements in these clocks translate into meaningful clinical benefits remains uncertain. A biomarker can reach statistical significance without producing clear patient benefit. In addition, the effect size was modest, not all clocks changed, and the study was not designed to identify which components of the multivitamin-multimineral supplement produced the observed effect. Without a stronger mechanistic basis, targeted recommendations would be difficult.
 
The most encouraging aspect of the study is its consistency with earlier COSMOS and Physicians’ Health Studies (PHS) examining the effects of daily multivitamin use on major health outcomes. The new findings on biological age, as measured by epigenetic clocks, should therefore be interpreted in the context of the broader clinical evidence from those large trials.

Effects of daily MVM treatment on cancer incidence
The effects of daily MVM use on cancer incidence were examined in both the PHS and COSMOS trials.
 
In a randomized, double-blind, placebo-controlled trial, Gaziano et al. [6] evaluated daily MVM use in 14,641 U.S. male physicians aged 50 years or older in PHS II, including 1,312 men with a history of cancer at randomization. Median follow-up was 11.2 years (range, 10.7–13.3). Among men with and without a prior cancer history, daily MVM use was associated with a modest reduction in overall cancer incidence. Subgroup analyses further suggested that survivors of epithelial cancers may have benefited the most.
 
A later COSMOS trial, reported by Sesso et al. [7], examined a larger and more heterogeneous cohort of 21,442 U.S. adults (12,666 women aged 65 years or older and 8,776 men aged 60 years or older) who were free of major cardiovascular disease and recently diagnosed cancer at baseline. This randomized, double-blind, placebo-controlled trial had a much shorter median follow-up of 3.6 years. In contrast to PHS II, COSMOS found no statistically significant difference in overall cancer incidence or all-cause mortality between the multivitamin and placebo groups. However, subgroup analyses by cancer site suggested a significant reduction in lung cancer incidence.
 
These results are not necessarily contradictory. PHS II showed a small reduction in total cancer incidence after more than a decade of supplementation in male physicians, whereas COSMOS found no statistically significant reduction during a much shorter follow-up in an older, more heterogeneous population. Given the substantial differences in follow-up duration, demographic composition, and baseline risk, the two trials are best viewed as complementary rather than as directly comparable tests of the same hypothesis.

Effects of daily MVM treatment on cognition, memory, and executive function
Three COSMOS studies reported since 2023 have provided the clearest evidence to date on the cognitive effects of daily MVM supplementation in older adults.
 
In COSMOS-Mind, a randomized, double-blind, placebo-controlled substudy of 2,262 participants (mean age 73 years; 60% women; 89% non-Hispanic White), Baker et al. [8] evaluated the effect of daily MVM use on global cognition after a mean follow-up of three years. Compared with placebo, daily MVM supplementation produced a statistically significant benefit in global cognition, with the largest effect among participants with a history of cardiovascular disease. Benefits were also observed for episodic memory and executive function.
 
In the same year, Yeung et al. [9] analyzed a different COSMOS subgroup, COSMOS-Web, consisting of 3,562 older adults (mean age 71 years; 67% women; 93% non-Hispanic White) followed for up to three years. The primary end point was episodic memory at one year, with three secondary outcomes assessed over three years: episodic memory, performance on novel object recognition tasks, and executive function. Compared with placebo, participants assigned to daily MVM supplementation showed significantly better episodic memory at one year and across the full three-year follow-up. No significant differences were detected for the other two secondary outcomes.
 
The most recent analysis, reported by Vyas et al. [10], drew on all three cognitive COSMOS subgroups: COSMOS-Clinic (573 participants, two years of follow-up), COSMOS-Web (2,472 participants, three years), and COSMOS-Mind (2,158 participants, three years). COSMOS-Clinic was used to assess global cognition as the primary end point, with episodic memory and executive function as secondary outcomes after two years. The study found modest benefits in global cognition and significantly more favorable change in episodic memory, but no benefit for executive function or attention. The authors then performed a meta-analysis across all three COSMOS cognitive subgroups, focusing on global cognition and episodic memory as primary outcomes. Compared with placebo, daily MVM supplementation was associated with significantly more favorable change over time in both domains.
 
Taken together, these three studies suggest that daily MVM supplementation improves global cognition and episodic memory in older adults, whereas evidence for executive function is less consistent. Memory improvement appears to be the most robust and reproducible finding, and improvement in global cognition is reasonably well supported. A benefit for executive function remains plausible but is not yet firmly established. This may reflect greater biological heterogeneity in executive function or the use of measures that are noisier and less statistically powerful.

Effects of daily MVM treatment on cognitive impairment and dementia
Progressive decline in global cognition, memory, and executive function can lead to mild cognitive impairment (MCI) and, eventually, dementia—outcomes that can be formally adjudicated by expert panels. Sachs et al. [11] examined whether daily MVM supplementation, compared with placebo, affected the incidence of adjudicated MCI and all-cause dementia in the COSMOS-Mind cohort of 2,662 participants with a mean age of 73 years. After three years of follow-up, the incidence of neither outcome differed significantly between the MVM and placebo groups. However, among participants adjudicated as having MCI, those assigned to daily MVM performed better on tests of global cognition and executive function when scores at the time of adjudication were compared with scores obtained one year earlier. In the smaller subgroup adjudicated as having dementia, no clear differences were observed in global cognition, executive function, or memory. These latter results should be interpreted cautiously because the dementia subgroup was small and therefore statistically underpowered. Overall, COSMOS-Mind did not show that daily MVM supplementation reduces the incidence of cognitive impairment or dementia over three years, but the favorable cognitive findings within the MCI subgroup are consistent with the broader cognitive benefits reported elsewhere in COSMOS, including by Baker et al. (2023) [8].

Effects of daily MVM treatment on cataract and age-related macular degeneration (AMD)
Cataracts are common in older adults, whereas AMD is less common but remains a major cause of vision loss. Christen et al. [12] evaluated whether long-term daily multivitamin supplementation affected the incidence of cataract and age-related macular degeneration in 14,641 male physicians aged 50 years or older in the Physicians’ Health Study. In this randomized, double-blind, placebo-controlled trial, participants were followed for a mean of 11.2 years. Daily multivitamin use was associated with a modest but statistically significant reduction in cataract risk, but it had no significant effect on visually significant AMD. The cataract finding is consistent with results from two smaller independent trials: Maraini et al. [13], which followed 1,020 participants aged 55 to 75 years for about nine years, and Sperduto et al. [14], which studied 2,141 participants aged 45 to 74 years in a rural Chinese community over five to six years.

Effects of daily MVM treatment on cardiovascular disease
Two large randomized trials—PHS II (Sesso, H. D. et al. [15]) and COSMOS (Sesso, H. D. et al. [7])—found that daily MVM supplementation did not reduce major cardiovascular events, myocardial infarction, stroke, or cardiovascular mortality. Mean treatment and follow-up durations were 11.2 years in PHS II and 3.6 years in COSMOS. The PHS II cohort included 14,641 U.S. male physicians aged 50 years or older, whereas COSMOS enrolled 21,442 U.S. adults, including 12,666 women aged 65 years or older and 8,776 men aged 60 years or older.

Discussion
 
Taken together, the evidence reviewed here suggests that daily multivitamin-mineral (MVM) supplementation has produced several clinically relevant benefits in large randomized trials, although the strength of evidence varies by outcome. The most reproducible benefits have been observed in cognition among older adults, especially for global cognition and episodic memory in the COSMOS substudies, with less consistent evidence for executive function. Table 1 also indicates a modest reduction in overall cancer incidence in PHS II, a possible reduction in epithelial cancer incidence in that trial, a signal for lower lung cancer incidence in COSMOS, and a statistically significant reduction in cataract incidence in long-term follow-up studies. The newer COSMOS-Blood findings add a biologically interesting signal that daily MVM supplementation may modestly slow epigenetic aging, but this result should still be regarded as supportive rather than definitive because biological age is a surrogate marker rather than a hard clinical outcome. By contrast, the evidence does not currently support a reduction in cardiovascular events, mild cognitive impairment incidence, dementia incidence, or age-related macular degeneration.
 
For personal health, these findings are potentially meaningful because they point to benefits in areas that strongly affect independence and quality of life with aging. Even modest preservation of memory or global cognition may matter to older adults who want to maintain functional autonomy, medication management, financial judgment, and social engagement. A small reduction in cancer incidence or cataract risk can also be clinically meaningful when applied over many years, especially because cataracts and cancer are common age-related conditions. At the same time, the significance of these benefits should not be overstated. The demonstrated effects are generally modest, they do not establish that MVMs are a substitute for a healthy diet, and they do not show broad protection across all major chronic diseases. The most reasonable interpretation is that daily MVM supplementation may serve as a low-risk supportive strategy for selected adults, particularly when micronutrient intake may be less reliable because of age, appetite changes, chronic illness, restricted diets, or medication use.
 
These newer findings also create an important tension with current health agency recommendations. The U.S. Preventive Services Task Force (USPSTF) states that evidence remains insufficient to recommend for or against multivitamins for the prevention of cancer or cardiovascular disease in community-dwelling, nonpregnant adults, while specifically recommending against beta carotene and vitamin E for those purposes. That position is understandable because the USPSTF framework focuses on prevention of major clinical end points in generally healthy populations and gives substantial weight to consistency, magnitude of effect, and certainty across trials. Similarly, the NIH Office of Dietary Supplements emphasizes that MVMs do not replace healthy dietary patterns, that formulations vary substantially, and that supplements can help fill nutrient gaps but can also increase the risk of excessive intake of some nutrients. The CDC likewise frames micronutrient sufficiency as important for health but does not treat routine MVM use as a universal preventive intervention for all adults. In other words, the newer trial results do not necessarily overturn existing agency guidance; rather, they suggest that the evidence base for selected benefits of daily MVM supplementation in older adults is becoming stronger than many recommendations currently reflect.
 
A practical way to leverage this information is to think about MVM supplementation through the lens of personal risk rather than as a universal rule. A person with a family history of cognitive decline, memory problems, cataracts, or certain cancers might view the current data as a reason to discuss a standard, age-appropriate MVM with a clinician, especially if dietary intake is inconsistent or if there are risk factors for micronutrient insufficiency such as gastrointestinal disease, vegetarian or highly restrictive eating patterns, low appetite, frailty, polypharmacy, or alcohol overuse. Someone with established cardiovascular disease should recognize that current evidence does not support MVM use as a strategy to prevent heart attack, stroke, or cardiovascular death, even though cognitive benefits may still be relevant in some subgroups. Likewise, a person with a strong family history of dementia should understand that the current evidence is more supportive for slowing cognitive decline than for preventing adjudicated dementia over the short term. This distinction matters because expectations should be realistic: MVMs may help preserve function in some domains, but they should not be presented as a proven way to prevent all age-related diseases.
 
As for timing, the best time to think seriously about MVM supplementation is probably before nutritional vulnerability becomes obvious, but not necessarily in early adulthood for everyone. The clearest trial evidence in this review comes from adults in later life, generally from the early 60s onward, when risks of cognitive decline, cataract, cancer, and subclinical nutritional insufficiency become more relevant. For many people, midlife is therefore a reasonable time to begin considering whether their diet, health conditions, medications, and family history justify supplementation, while older adulthood is the period in which potential benefits may be most actionable. This does not mean that every healthy younger adult should take a daily MVM, nor does it imply that starting later guarantees benefit. Rather, it suggests that MVM use is best approached as part of anticipatory aging care: a decision revisited when diet quality declines, chronic disease accumulates, or family history raises concern about cognitive or age-related outcomes. In that sense, the new evidence is most useful not as a blanket recommendation, but as a prompt for individualized, age-aware decision-making grounded in both personal health context and the limits of the current evidence.

Conclusion
 
Our review summarizes the latest clinical findings on the daily use of multivitamin-mineral (MVM) supplements and shows that the evidence now supports selected benefits more clearly than many people may realize, particularly for global cognition, episodic memory, cataract risk, and possibly biological aging, with a potential benefit for some cancer outcomes, while benefits for cardiovascular disease, dementia, and some other outcomes remain unproven. In that sense, this review both supplements and contrasts current information and recommendations from health agencies, which appropriately remain cautious and do not endorse routine MVM use for all adults. The most useful implication is not a blanket recommendation, but a stronger basis for individualized reflection and action. At different stages of life, especially in midlife and older adulthood, individuals can use this information to consider their diet, health conditions, medications, and family history, discuss the possible role of MVM supplementation with their doctors, and decide whether a standard, age-appropriate product fits their overall preventive health strategy. Used thoughtfully, MVM supplementation may be one small but meaningful part of a broader plan to support healthy aging.

References
 

1. Passarelli, S., Free, C. M., Shepon, A., Beal, T., Batis, C., & Golden, C. D. (2024). Global estimation of dietary micronutrient inadequacies: a modelling analysis. The Lancet Global Health, 12(10), e1590-e1599. DOI: 10.1016/S2214-109X(24)00276-6
2. Belsky, D. W., & Ryan, C. P. (2026). A daily multivitamin slows the ticking of epigenetic clocks. Nature Medicine, 32(3), 810-811. https://doi.org/10.1038/s41591-026-04249-1
3. Li, S., Hamaya, R., Zhu, H., Chen, B. H., Pereira, A. C., Ivey, K. L., ... & Sesso, H. D. (2026). Effects of daily multivitamin–multimineral and cocoa extract supplementation on epigenetic aging clocks in the COSMOS randomized clinical trial. Nature Medicine, 32(3), 1012-1022. https://doi.org/10.1038/s41591-026-04239-3
4. Levine, M. E., Lu, A. T., Quach, A., Chen, B. H., Assimes, T. L., Bandinelli, S., ... & Horvath, S. (2018). An epigenetic biomarker of aging for lifespan and healthspan. Aging (albany NY), 10(4), 573. https://doi.org/10.18632/aging.101414
5. Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., ... & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (albany NY), 11(2), 303. https://doi.org/10.18632/aging.101684
6. Gaziano, J. M., Sesso, H. D., Christen, W. G., Bubes, V., Smith, J. P., MacFadyen, J., ... & Buring, J. E. (2012). Multivitamins in the prevention of cancer in men: the Physicians' Health Study II randomized controlled trial. Jama, 308(18), 1871-1880. doi:10.1001/jama.2012.14641
7. Sesso, H. D., Rist, P. M., Aragaki, A. K., Rautiainen, S., Johnson, L. G., Friedenberg, G., ... & Manson, J. E. (2022). Multivitamins in the prevention of cancer and cardiovascular disease: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial. The American Journal of Clinical Nutrition, 115(6), 1501-1510. https://doi.org/10.1093/ajcn/nqac056
8. Baker, L. D., Manson, J. E., Rapp, S. R., Sesso, H. D., Gaussoin, S. A., Shumaker, S. A., & Espeland, M. A. (2023). Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial. Alzheimer's & Dementia, 19(4), 1308-1319. https://doi.org/10.1002/alz.12767
9. Yeung, L. K., Alschuler, D. M., Wall, M., Luttmann-Gibson, H., Copeland, T., Hale, C., ... & Brickman, A. M. (2023). Multivitamin supplementation improves memory in older adults: A randomized clinical trial. The American journal of clinical nutrition, 118(1), 273-282. https://doi.org/10.1016/j.ajcnut.2023.05.011
10. Vyas, C. M., Manson, J. E., Sesso, H. D., Cook, N. R., Rist, P. M., Weinberg, A., ... & Okereke, O. I. (2024). Effect of multivitamin-mineral supplementation versus placebo on cognitive function: results from the clinic subcohort of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial and meta-analysis of 3 cognitive studies within COSMOS. The American Journal of Clinical Nutrition, 119(3), 692-701. https://doi.org/10.1016/j.ajcnut.2023.12.011
11. Sachs, B. C., Williams, B. J., Gaussoin, S. A., Baker, L. D., Manson, J. E., Espeland, M. A., ... & COSMOS‐Mind Research Group. (2023). Impact of multivitamin‐mineral and cocoa extract on incidence of mild cognitive impairment and dementia: Results from the COcoa Supplement and Multivitamin Outcomes Study for the Mind (COSMOS‐Mind). Alzheimer's & Dementia, 19(11), 4863-4871. https://doi.org/10.1002/alz.13078
12. Christen, W. G., Glynn, R. J., Manson, J. E., MacFadyen, J., Bubes, V., Schvartz, M., ... & Gaziano, J. M. (2014). Effects of multivitamin supplement on cataract and age-related macular degeneration in a randomized trial of male physicians. Ophthalmology, 121(2), 525-534. https://doi.org/10.1016/j.ophtha.2013.09.038
13. Maraini, G., Williams, S. L., Sperduto, R. D., Ferris, F., Milton, R. C., Clemons, T. E., ... & Ferrigno, L. (2008). A randomized, double-masked, placebo-controlled clinical trial of multivitamin supplementation for age-related lens opacities. Clinical trial of nutritional supplements and age-related cataract report no. 3. Ophthalmology, 115(4), 599-607. DOI: 10.1016/j.ophtha.2008.01.005
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15. Sesso, H. D., Christen, W. G., Bubes, V., Smith, J. P., MacFadyen, J., Schvartz, M., ... & Gaziano, J. M. (2012). Multivitamins in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. Jama, 308(17), 1751-1760. DOI: 10.1001/jama.2012.14805

​Hung Van Le*
Biologics & Drug Targets, ProSci LLC, Rockaway, The United States
ORCID
https://orcid.org/0000-0002-6913-2373 (Hung Van Le)

Abstract
 
Post-polio syndrome (PPS) is a progressive neuromuscular disorder that affects a substantial proportion of long-term survivors of poliomyelitis. Traditionally viewed as a consequence of motor unit exhaustion, PPS is increasingly recognized as a multifactorial condition involving neurodegeneration, chronic low-grade inflammation, and, more recently, persistent low-level poliovirus infection. These emerging insights point to a more complex disease model that integrates viral persistence, impaired humoral immunity, and metabolic stress in compensatory motor units.
 
Vitamin D, a pleiotropic secosteroid hormone, has been implicated in several biological processes relevant to PPS, including immune regulation, mitochondrial function, and muscle physiology. Recent findings indicate that vitamin D deficiency is common in PPS patients and may contribute to impaired immune competence and disease progression. While vitamin D does not directly target the primary neurodegenerative process, it may enhance neuromuscular resilience through immunomodulatory and metabolic effects.
 
This review examines the mechanistic intersections between vitamin D signaling and PPS pathophysiology, with particular emphasis on immune function, mitochondrial energetics, and neuromuscular junction stability. It further discusses the clinical role of vitamin D as a supportive intervention and evaluates the potential need for antiviral strategies considering evidence for persistent poliovirus infection. A multimodal therapeutic approach combining antiviral therapy, immune optimization, and metabolic support is proposed as a rational framework for future PPS management.
 
Clinical Bottom Line

• PPS may involve persistent viral and immune-mediated mechanisms in addition to motor neuron exhaustion.
• Vitamin D deficiency is common in PPS and should be corrected, but vitamin D is supportive rather than curative.
• Future PPS management may require a multimodal strategy that includes antiviral therapy, immune optimization, and metabolic support.

 
​
Introduction
 
Post-polio syndrome (PPS) is a late-onset neurological disorder that affects individuals decades after recovery from acute poliomyelitis caused by Poliovirus. Clinically, PPS is characterized by new or progressive muscle weakness, fatigue, pain, and functional decline following a prolonged period of neurological stability. The syndrome typically emerges 15 to 40 years after the initial infection and represents one of the most significant long-term complications of the global poliomyelitis epidemics of the 20th century.
 
Although the incidence of acute poliomyelitis has declined dramatically due to widespread vaccination programs, the population of polio survivors remains substantial. Current estimates suggest that 15–20 million individuals worldwide are living with the sequelae of prior poliovirus infection [1], of whom approximately 20–85% may develop PPS depending on diagnostic criteria [2]. As this population ages, PPS represents an increasing clinical and public health challenge, particularly in regions with historically high poliomyelitis burden.
 
 
Currently, there is no disease-modifying therapy for PPS. Management remains largely supportive and includes physical rehabilitation, with carefully tailored exercise programs to optimize motor unit function while avoiding overuse, symptomatic treatment for pain, fatigue, and sleep disturbances, and orthotic support and assistive devices to improve mobility. Among pharmacological approaches, intravenous immunoglobulin (IVIG) has shown modest benefits in selected patients, particularly in reducing pain and inflammatory markers, although its effects on muscle strength and long-term progression remain limited.
 
In this context of limited therapeutic options, there is increasing interest in interventions that can enhance systemic resilience rather than directly reverse neuronal loss. Vitamin D has attracted attention due to its broad biological activity, including immunomodulatory, metabolic, and neuromuscular effects. Notably, recent studies have identified a high prevalence of vitamin D deficiency in PPS patients, raising the possibility that it may contribute to disease pathophysiology rather than merely reflect lifestyle factors.
 
This review aims to integrate current knowledge on PPS with emerging insights into vitamin D biology and antiviral strategies. By examining the intersections between viral persistence, immune function, and neuromuscular degeneration, it seeks to propose a more comprehensive framework for understanding and managing PPS.

Pathophysiology of Post-Polio Syndrome: from motor unit failure to persistent viral signaling
 
Post-polio syndrome (PPS) is classically explained by progressive failure of enlarged motor units that compensated for the initial loss of anterior horn cells after acute poliomyelitis. Over decades, these metabolically stressed neurons undergo distal degeneration, leading to neuromuscular junction (NMJ) instability and denervation [3]. However, this “purely degenerative” view has been challenged by accumulating immunological data. Studies have demonstrated elevated cytokines in cerebrospinal fluid and blood, suggesting chronic low-grade inflammation [4-8].
 
This inflammatory component is substantially strengthened by recent work from Toniolo et al. [9] who reported evidence consistent with persistent low-level Poliovirus infection in long-term polio survivors with PPS. The evidence came from co-culturing PPS-derived samples, including peripheral blood leukocytes, cerebrospinal fluid, duodenal biopsy specimens, and skeletal muscle fragments, with poliovirus-susceptible cell lines. Poliovirus was then detected by RT-PCR in cell culture supernatants and by immunofluorescence in the cultured cell monolayers. This work was built on earlier studies by Leparc-Goffart et al. [10] and Julien et al. [11], which had identified poliovirus in the CSF of a smaller group of PPS patients using RT-PCR.
 
The observed persistent infection supports a model in which ongoing viral persistence may drive chronic immune activation, rather than inflammation being purely secondary. The authors further described humoral immune deficiencies in PPS patients, altered neutralizing antibody profiles, and a high prevalence of vitamin D deficiency [12]. Together, these findings suggest that PPS may involve a triad of residual viral persistence, inadequate humoral immune control, and chronic low-grade inflammation. The available evidence reframes PPS as a hybrid condition, combining neurodegeneration, immune dysregulation, and possible viral persistence.  

Relevance of Vitamin D in PPS
 
The prevalence of vitamin D deficiency raises questions about its ultimate role in the etiology of PPS. It could simply be a by-product of patients’ lifestyle (poor diet, inadequate mobility and physical activities, and limited sun exposure), or alternatively it could be a bona fide risk factor.  A combination of both could be plausible as well. As an established pleiotropic modulator of multiple pathways [13] vitamin D could be uniquely positioned to affect the development of PPS. How vitamin D signaling intersects with PPS pathways is explored below.
 
Immunomodulation and antiviral defense. Vitamin D signaling suppresses pro-inflammatory T helper 1 responses and reduces IFN-γ production [14]. Beyond dampening inflammation, vitamin D also enhances innate immune responses, supports antimicrobial peptide production, and modulates B cell function. In the context of the finding by Toniolo et al. [9,12], this is particularly relevant since  vitamin D deficiency may exacerbate impaired humoral immunity, potentially allowing persistent poliovirus activity. Thus, vitamin D may not only reduce inflammation but also improve immune competence against residual viral antigenic stimulation.
 
Muscle and mitochondrial energetics. Vitamin D influences skeletal muscle through improved mitochondrial oxidative function [15] and regulation of mitochondrial dynamics and respiration [16]. Given that PPS involves fatigable muscle and metabolically stressed motor units, vitamin D may enhance bioenergetic resilience, even if it does not halt neuronal loss.
 
Neuromuscular junction stability and mitochondrial energetics. The progressive functional decline observed in Post-Polio Syndrome is closely linked to instability of the neuromuscular junction (NMJ), which represents the final common pathway of motor neuron degeneration. In PPS, surviving motor neurons form enlarged motor units that are metabolically overextended. Over time, this leads to distal axonal degeneration, impaired synaptic maintenance, and failure of reinnervation, with NMJ dysfunction preceding overt muscle fiber loss.
 
A critical but often underemphasized aspect of NMJ stability is local energy supply. Maintenance of synaptic transmission, vesicle recycling, and ion homeostasis requires tightly regulated ATP production. This demand is met by mitochondria localized at both pre- and postsynaptic compartments, whose function is essential for sustaining neuromuscular signaling. In aging and neurodegenerative conditions, impairment of mitochondrial function—rather than sheer mitochondrial number—has been implicated as a limiting factor in synaptic resilience.
 
Vitamin D has been shown to influence mitochondrial biology at multiple levels, including enhancement of oxidative phosphorylation, modulation of mitochondrial dynamics, and regulation of transcriptional programs involving PGC-1α [15,16]. Although there is no direct evidence that vitamin D regulates axonal mitochondrial transport or synapse-specific mitochondrial targeting, its effects on mitochondrial efficiency and cellular energetics provide a plausible mechanism for improving NMJ stability under conditions of metabolic stress.
 
In this context, vitamin D may contribute to functional preservation of neuromuscular transmission by improving ATP availability in muscle and possibly nerve terminals, reducing oxidative stress that destabilizes synaptic structures, and supporting the metabolic demands of enlarged motor units. This interpretation aligns with the broader view of PPS as a disorder of metabolic exhaustion of compensatory motor units, where interventions that enhance bioenergetic capacity may delay functional decline.
 
Collectively, these observations indicate that vitamin D may enhance the metabolic stability of existing synapses, thereby slowing functional deterioration.

Clinical positioning: supplementation vs therapeutic dosing
 
This leads to an important clinical consideration: in what context should vitamin D be used in PPS?
 
As a nutritional supplement, maintaining adequate serum 25-hydroxyvitamin D levels (50-125 nmoles/L) is clearly warranted. PPS patients are at increased risk of deficiency due to reduced mobility and sun exposure, and correction of deficiency supports bone health, muscle function, and overall metabolic stability.
 
The use of high-dose vitamin D as a therapeutic intervention remains uncertain. While high-dose regimens (100,000 IU cholecalciferol, every two weeks for 24 months) have shown benefits in Multiple in Sclerosis [17] and potentially in upper respiratory viral infections [18-20], there is currently no direct clinical evidence supporting such an approach in PPS. Moreover, vitamin D exhibits dose-dependent effects, and excessive supplementation may not yield proportional benefit.
 
A more coherent approach is to incorporate vitamin D into a multimodal management strategy, alongside targeted physical therapy to optimize motor unit function, adequate protein and caloric intake, and interventions aimed at preserving mitochondrial and neuromuscular health. The goal here is to remove an exacerbating factor while hoping for disease modifications resulting from a beneficial effect on immune competence, muscle function, and bone health. The role of vitamin D supplementation in PPS is only supportive and there is clearly a need to look beyond seeking curative treatment.

Therapeutic implications: beyond vitamin D 
 
Rationale for antiviral therapy. Evidence of persistent poliovirus infection and defective replication [10,11,9] supports consideration of antiviral therapy in PPS. Combined with physical rehabilitation and the immune and metabolic support potentially provided by vitamin D, an antiviral component could help form a more mechanistically comprehensive treatment strategy. However, no antiviral drugs are currently approved specifically for poliovirus, and historical drug-development efforts were limited in part by the success of global polio vaccination programs.
 
Current development landscape. Momentum in the field has been sustained by the Polio Antivirals Initiative (PAI), which aims to develop therapies that reduce vaccine-derived poliovirus shedding in immunodeficient recipients of oral polio vaccines and mitigate the risk of prolonged excretion in a post-eradication setting. Current discovery efforts focus on four broad approaches: inhibitors of the viral capsid, viral protease, and RNA replication, as well as agents targeting host factors required for replication [21, 22].
 
Capsid inhibitors. Pleconaril and pocapavir are the most advanced candidates, having reached human studies in vaccine-derived poliovirus infection and oral poliovirus vaccine challenge models [23-27]. Pocapavir is also available for compassionate use through its developer, ViroDefense, or via the PAI.
 
RNA-replication inhibitors. Ribavirin, a broad-spectrum inhibitor of viral RNA replication, has been used compassionately in a patient with vaccine-derived poliovirus infection but did not clear the virus [25]. In contrast, remdesivir was associated with viral clearance in that same patient [28]. Remdesivir (Veklury), a nucleoside analog widely used during the COVID-19 pandemic as an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase, therefore represents an intriguing candidate for further study in persistent poliovirus infection.
 
That signal should be interpreted cautiously: the remdesivir evidence is currently limited to a single case report and has not yet been independently replicated. Even so, its availability and established clinical safety profile make it a reasonable high-priority option for off-label compassionate use in carefully selected patients with documented persistent poliovirus infection and shedding.
 
Other inhibitors and future directions. All known poliovirus protease inhibitors and agents targeting host factors remain at the preclinical stage [21,22]. Nevertheless, recent findings on persistent infection, together with renewed progress in antiviral development, provide a strong rationale for reinvigorating this field. From a compassionate-care perspective, such efforts are justified by the potentially large global burden.

Conclusion
 
Vitamin D is best understood as a pleiotropic adjunct in PPS, which may improve immune balance, mitochondrial function, and possibly NMJ resilience. Its deficiency, common in PPS, should be corrected as part of standard care. However, evidence for high-dose therapeutic use remains lacking and its effects are supportive rather than disease-modifying. In light of emerging evidence for persistent poliovirus infection and immune dysregulation, future therapeutic strategies should expand beyond supplementation alone. A combination approach including antiviral therapy, immune optimization, and metabolic support may offer the most rational path forward in PPS management.

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19. Aloia, J. F., & Li-Ng, M. (2007). RE: epidemic influenza and vitamin D epidemiology and infection October 2007, Vol. 135, no. 7, pp. 1095-1098. Epidemiology and infection, 135(7), 1095-1098.
20. Cannell, J. J., Vieth, R., Umhau, J. C., Holick, M. F., Grant, W. B., Madronich, S., ... & Giovannucci, E. (2006). Epidemic influenza and vitamin D. Epidemiology & Infection, 134(6), 1129-1140. DOI: https://doi.org/10.1017/S0950268806007175
21. Xie, H., Rhoden, E. E., Liu, H. M., Ogunsemowo, F., Mainou, B. A., Burke, R. M., & Burns, C. C. (2024). Antiviral development for the polio endgame: current progress and future directions. Pathogens, 13(11), 969.  https://doi.org/10.3390/pathogens13110969
22. Lee, M. F., Tham, S. K., & Poh, C. L. (2025). Antiviral strategies targeting enteroviruses: current advances and future directions. Viruses, 17(9), 1178.  https://doi.org/10.3390/v17091178
23. Romero, J. R., Gross, T., Abromowitch, M., & Jung, L. (1999). Pleconaril treatment of vaccine-acquired poliovirus. Pediatric Research, 45(7), 173-173.
24. Buttinelli, G., Donati, V., Fiore, S., Marturano, J., Plebani, A., Balestri, P., ... & Fiore, L. (2003). Nucleotide variation in Sabin type 2 poliovirus from an immunodeficient patient with poliomyelitis. Journal of General Virology, 84(5), 1215-1221. https://doi.org/10.1099/vir.0.18974-0
25. MacLennan, C., Dunn, G., Huissoon, A. P., Kumararatne, D. S., Martin, J., O'Leary, P., ... & Pillay, D. (2004). Failure to clear persistent vaccine-derived neurovirulent poliovirus infection in an immunodeficient man. The Lancet, 363(9420), 1509-1513. DOI: 10.1016/S0140-6736(04)16150-3
26. Copelyn, J., Hincks, J. R., Wilmshurst, J. M., Petersen, W., Howard, W., Jallow, S., ... & Eley, B. (2020). Clearance of immunodeficiency-associated vaccine-derived poliovirus infection with pocapavir. The Pediatric Infectious Disease Journal, 39(5), 435-437. DOI: 10.1097/INF.0000000000002584
27. Collett, M. S., Hincks, J. R., Benschop, K., Duizer, E., van der Avoort, H., Rhoden, E., ... & Hartford, M. (2017). Antiviral activity of pocapavir in a randomized, blinded, placebo-controlled human oral poliovirus vaccine challenge model. The Journal of infectious diseases, 215(3), 335-343. https://doi.org/10.1093/infdis/jiw542
28. Bermingham, W. H., Canning, B., Wilton, T., Kidd, M., Klapsa, D., Majumdar, M., ... & Huissoon, A. P. (2023). Case report: Clearance of longstanding, immune-deficiency-associated, vaccine-derived polio virus infection following remdesivir therapy for chronic SARS-CoV-2 infection. Frontiers in immunology, 14, 1135834. https://doi.org/10.3389/fimmu.2023.1135834

 
Acknowledgment: Dr. NhuCo Lethi provided the initial inspiration for this article on PPS.

 Abstract
 
Advances in geroscience have identified biological mechanisms that drive aging and age-related diseases, raising the possibility that aging itself may become a therapeutic target. Several FDA-approved medications, including metformin, rapamycin, acarbose, SGLT2 inhibitors, GLP-1 receptor agonists, and bisphosphonates, have emerged as leading gerotherapeutic candidates based on evidence from animal studies, epidemiologic observations, and mechanistic research. Although none are currently approved specifically for aging, growing interest in longevity medicine has increased demand for their off-label use. This article examines the scientific rationale, ethical considerations, and practical challenges surrounding lifespan-enhancing prescriptions. Particular attention is given to the concept of “borderline” clinical conditions, such as prediabetes, early cardiometabolic disease, osteopenia, and obesity, where these therapies may be prescribed for recognized medical indications while potentially conferring healthspan benefits. Until definitive human trials establish their efficacy for extending lifespan, gerotherapeutics are best viewed as tools for proactive risk reduction and healthy aging rather than as prescriptions for longevity itself.

Introduction

The idea that aging itself might be modifiable is no longer confined to science fiction. A growing field known as geroscience has identified multiple biological pathways (Figure 1) that appear to drive aging and age-related disease [1,2]. Drugs that target these pathways are often referred to as gerotherapeutics.
Once purely experimental, gerotherapeutics are now “coming of age.” Several existing medications originally developed for diabetes, osteoporosis, or transplantation, have been shown to either extend lifespan or improve healthspan in animal models and, in some cases, human observational studies [3,4]. While these therapies are not formally approved for “aging,” they are already being accessed by a small but growing group of individuals through specialized longevity clinics [5].
This raises an important question: Can the average patient access these therapies through their primary care physician—and should they? This article explores the science, the ethical and legal landscape, and the practical realities of lifespan-enhancing prescriptions.

Commonly Discussed Gerotherapeutics
 
All were originally FDA-approved for specific metabolic or immune conditions but were not designed to extend lifespan. Their gerotherapeutic potential emerged through:

• Animal studies demonstrating lifespan extension
• Epidemiological observations showing reduced mortality
• Mechanistic insights linking drug targets to aging pathways

This convergence of evidence has led researchers to consider them as candidates for targeting aging itself. The following discussion will consider 6 key classes of gerotherapeutics:

• Metformin
• Rapamycin (Sirolimus)
• Acarbose
• SGLT2 Inhibitors (e.g., Empagliflozin, Canagliflozin)
• GLP-1 Receptor Agonists (e.g., Semaglutide, Tirzepatide)
• Bisphosphonates (e.g. Alendronate, Zoledronate)

They all scored 9 points or better out of 12, based on the ranking scheme developed by Leone, M. & Barzilai, N. [3]. The scheme assigned points according to available preclinical and clinical evidence, including rodent lifespan and healthspan, hallmarks of aging, human mortality and health span. Details about their original FDA-approved indications, relevance to geroscience, and evidence for classification as geretherapeutics, can be found in the Appendix.

Legal and Ethical Considerations
 
Patients and their primary care physician (PCP) will essentially have to walk the tightrope in this area since the path to a longevity prescription is paved with complex legal and ethical questions. Legally, once a drug is FDA-approved for one condition, a doctor can prescribe it for another. However, because "aging" is not currently recognized as a disease by the FDA, any prescription for the sole purpose of life extension is considered off-label. While legal, this often means insurance will not cover the cost, and the doctor assumes a higher degree of professional liability if side effects occur in a "healthy" patient.
In addition, legality does not guarantee ethical appropriateness. Prescribing gerotherapeutics to otherwise healthy individuals raises at least four ethical concerns:
 
1. Evidence Gap
While animal data are compelling, definitive human trials demonstrating lifespan extension are still lacking. The proposed TAME (Targeting Aging with Metformin) trial aims to address this gap [17].
 
2. Risk vs. Benefit
All medications carry risks:

• Metformin: gastrointestinal effects, vitamin B12 deficiency
• Rapamycin: immunosuppression, lipid abnormalities
• SGLT2 inhibitors: infections, rare ketoacidosis
• GLP-1 agonists: gastrointestinal symptoms
• Bisphosphonates: rare, atypical fractures, osteonecrosis of the jaw

In healthy individuals, even small risks may outweigh uncertain benefits.
 
3. Professional Guidelines
Medical organizations emphasize:

• Evidence-based practice
• Patient safety
• Clear therapeutic intent

Since aging is not classified as a disease, prescribing purely for lifespan extension falls outside standard care.
 
4. Equity and Access
Longevity therapies are currently more accessible to affluent individuals, raising concerns about widening health disparities.
 
Considering the above, most physicians will not feel ethically compelled to prescribe gerotherapeutics to perfectly healthy individuals seeking life span extension. However, in this age of advanced molecular diagnostics and imaging, and affordable whole genome sequencing, how many could claim perfect health? Perhaps very few, while most might exhibit borderline conditions that could benefit from early interventions with gerotherapeutics within legal and ethical boundaries.

​The "Borderline" Path to Access

The most ethically and clinically defensible pathway is not treating “aging,” but addressing early or borderline disease states. For the average person, the most viable way to access these drugs is through co-morbidity management. A primary care doctor is far more likely to prescribe a gerotherapeutic if the patient also has a "borderline" medical condition where the drug provides an immediate, approved clinical benefit. In other words, a prescription becomes more justifiable when:

• There is measurable physiological deviation
• The drug has proven benefit in related conditions
• The goal is risk reduction, not enhancement

 
The following are examples of strategic clinical entry points to gerotherapeutics. If you already know you have one or more of the following risk factors or borderline conditions, the table below may be directly relevant to a conversation with your doctor. If you're currently healthy with no known risk factors, a brief scan is sufficient — the closing summary table offers the clearest overview.
 
1. Prediabetes / Insulin Resistance Spectrum
Relevant drug: Metformin, Acarbose
This is probably the strongest and most widely accepted gray-zone indication.
Clinical scenarios:

• HbA1c: 5.7–6.4%
• Elevated fasting insulin
• History of gestational diabetes
• Visceral adiposity with normal glucose

Why it’s defensible:

• American Diabetes Association (ADA) guidelines already allow metformin in high-risk prediabetes
• Diabetes Prevention Program (DPP) supports risk reduction
• Acarbose has evidence for delaying diabetes onset

Here, “longevity” becomes secondary to metabolic risk modification
 
2. Early Cardiometabolic Syndrome (Even Without Diabetes)
Relevant drug: SGLT2 inhibitors
Clinical scenarios:

• Central obesity + mild hypertension + dyslipidemia
• Elevated triglyceride/HDL ratio
• Early fatty liver

Why it’s defensible:

• SGLT2 inhibitors have cardio-renal protective effects independent of glucose
• Trials show benefit even in non-diabetics (e.g., heart failure populations)

This is shifting toward organ protection rather than glucose control
 
3. Stage 1 Chronic Kidney Disease (CKD) or Hyperfiltration
Relevant drug: SGLT2 inhibitors
Clinical scenarios:

• Estimated glomerular filtration rate (eGFR) still “normal” but declining
• Microalbuminuria
• Hyperfiltration (common in early metabolic disease)

Why it’s defensible:

• Strong evidence from randomly controlled trials (RCT) for renal protection—even in non-diabetics
• Increasingly used earlier in disease progression

This is one of the most medically accepted “early intervention” uses today
 
4. Early Heart Failure Risk / Subclinical Cardiac Dysfunction
Relevant drug: SGLT2 inhibitors
Clinical scenarios:

• Diastolic dysfunction
• Elevated B-type natriuretic peptide (BNP) but no overt heart failure
• Long-standing hypertension with left ventricular hypertrophy

Why it’s defensible:

• SGLT2 inhibitors reduce hospitalization and mortality in HF (including non-diabetics)
• Cardiologists are increasingly prescribing them earlier

Again, reframed as cardioprotection, not longevity
 
5. Post-Transplant or Immune Dysregulation Contexts
Relevant drug: Rapamycin
Clinical scenarios:

• Organ transplant (already standard use)
• Rare immune dysregulation disorders
• Certain dermatologic or oncologic indications (off-label)

Why it’s relevant to gerotherapeutics:

• These patients already receive rapamycin
• Observationally, some show reduced cancer incidence and age-related pathology

Not a justification for healthy individuals—but a natural experiment in humans
 
6. Severe Postprandial Hyperglycemia with Normal Fasting Glucose
Relevant drug: Acarbose
Clinical scenarios:

• Normal HbA1c but large glucose spikes after meals
• Continuous glucose monitoring (CGM) reveals excursions >160–180 mg/dL

Why it’s defensible:

• Postprandial spikes are linked to:
  • Oxidative stress
  • Endothelial dysfunction
• Acarbose specifically targets this mechanism

This is a very “geroscience-aligned” phenotype
 
7. Polycystic Ovary Syndrome (PCOS) with Mild Metabolic Dysfunction
Relevant drug: Metformin
Clinical scenarios:

• Insulin resistance without overt diabetes
• Irregular cycles, hyperandrogenism

Why it’s defensible:

• Metformin is already widely used in PCOS
• Improves insulin sensitivity and metabolic profile

Another case where longevity effects are incidental, not primary
 
8. Non-Alcoholic Fatty Liver Disease
Relevant drugs:

• Metformin (limited effect)
• SGLT2 inhibitors (more promising)

Clinical scenarios:

• Elevated ALT/AST
• Imaging-confirmed fatty liver

Why it’s defensible:

• Strong overlap with metabolic aging pathways
• SGLT2 inhibitors show improvements in liver fat

 
9. Obesity with Early Metabolic Drift (But No Disease Yet)
Relevant drugs:

• Metformin
• SGLT2 inhibitors

Clinical scenarios:

• BMI >30 with subtle lab abnormalities
• Rising fasting insulin, borderline lipids

Why it’s defensible:

• Obesity itself is increasingly treated as a disease
• These drugs may reduce downstream risk

 
10. Osteopenia (Not Yet Osteoporosis)
Relevant drug: Bisphosphonates
Clinical scenario:

• T-score: −1.0 to −2.5 (osteopenia)
• No fragility fractures yet
• Possibly additional risk factors (age, steroid exposure, family history)

Why this is a strong borderline case:

• Many guidelines already allow treatment if fracture risk (e.g., FRAX) is elevated
• Observational data suggests bisphosphonates may:
  • Reduce mortality
  • Affect systemic aging processes (possibly via bone–immune signaling)

This is one of the cleanest “pre-disease → intervention” pathways in medicine
 
11. “Normal Weight” but High Visceral Adiposity
Relevant drug: GLP-1 receptor agonists
Clinical scenario:

• Body Mass Index (BMI) in normal or slightly overweight range
• High visceral fat (waist circumference, imaging)
• Early insulin resistance or dyslipidemia

Why it’s defensible:

• GLP-1 agonists improve:
  • Insulin sensitivity
  • Weight distribution
  • Inflammation markers
• Cardiovascular outcome trials show benefit beyond glucose lowering

This reframes treatment as metabolic risk reduction, not cosmetic weight loss
 
12. “Pre-Frailty” or Early Functional Decline
Relevant drug: Bisphosphonates
Clinical scenario:

• Mild sarcopenia
• Slower gait speed
• Reduced grip strength
• No fractures yet

Why it is interesting:

• Bone and muscle aging are tightly linked
• Preventing micro-fractures and bone turnover may:
  • Preserve mobility
  • Reduce downstream morbidity

This is very aligned with geroscience, though still emerging and debated
 
13. Obesity (Now Explicitly a Disease)
Relevant drugs:

• GLP-1 receptor agonists
• (also overlaps with metformin and SGLT2i)

Clinical scenario:

• Body Mass Index (BMI) ≥30 (or ≥27 with comorbidities)

Why this is no longer really “borderline”:

• Obesity is now widely recognized as a chronic disease
• GLP-1 agonists (e.g., semaglutide class) are FDA-approved for weight management

Why it matters for gerotherapeutics:

• These drugs:
  • Reduce cardiovascular events
  • Improve Metabolic Health
  • Likely influence aging pathways (inflammation, nutrient sensing)

This is currently the most socially accepted “longevity-adjacent” prescribing
 
14. Early Atherosclerotic Risk Without Overt Disease
Relevant drugs:

• GLP-1 receptor agonists
• SGLT2 inhibitors

Clinical scenario:

• Elevated coronary artery calcium (CAC)
• Borderline lipid abnormalities
• Family history of premature cardiovascular disease (CVD)

Why it’s defensible:

• GLP-1 agonists reduce major adverse cardiovascular events
• Effects extend beyond glycemic control

This becomes vascular aging prevention, not just diabetes care
 
15. Weight Regain After Lifestyle Intervention
Relevant drug: GLP-1 receptor agonists
Clinical scenario:

• Patient successfully loses weight
• Then begins regaining despite adherence

Why it’s defensible:

• Obesity is increasingly treated as a relapsing neuroendocrine condition
• GLP-1 agents help maintain weight loss

Ethically framed as chronic disease management, not enhancement
 
16. High Bone Turnover Without Low bone mineral density (BMD) Yet
Relevant drug: Bisphosphonates
Clinical scenario:

• Normal BMD but elevated bone turnover markers
• Perimenopausal or early postmenopausal state

Why it’s a gray zone:

• Not standard practice yet
• But mechanistically:
  • High turnover → microarchitectural decline → future fracture risk

A forward-looking, risk-based approach, but still controversial
 
17. Metabolic Syndrome with Inflammatory Phenotype
Relevant drugs:

• GLP-1 receptor agonists
• Metformin

Clinical scenario:

• Elevated CRP
• Central obesity, in this context may not be clinically obvious and can occur in individuals with a normal BMI, making this phenotype easy to overlook
• Borderline glucose and lipids

Why it’s compelling:

• GLP-1 agonists reduce systemic inflammation
• Inflammation is a core aging pathway

 
18. High-Normal Uric Acid (Hyperuricemia)
Relevant Drug:

• SGLT2 Inhibitors

Clinical scenario:

• Borderline high blood pressure
• Elevated uric acid levels (a risk for gout and kidney stones).

Why it’s compelling:

• SGLT2i's are "calorie restriction mimetics"
• SGLT2i's have a side effect of lowering serum uric acid
• They are increasingly used in cardiology and nephrology for "organ protection" rather than just glucose management.

 
19. Chronic "Inflammaging" (High-Sensitivity C-reactive protein (hs-CRP))
Relevant Drug:

• Low-Dose Rapamycin

Clinical scenario:

• High hs-CRP (a marker of systemic inflammation)
• No specific autoimmune disease.

Why it’s compelling:

• Rapamycin is immunosuppressive at standard dose
• Improve immune function in the elderly
• Extend life span in animal model at low dose

This remains the most difficult for a general practitioner to justify. It is usually handled by "Longevity Clinics" that use it to treat the biological process of aging itself, often supported by the 2014 Mannick study showing improved immune response in seniors on low dose rapalogs [18].
 
In summary, the ease of getting a prescription for life span extension varies proportionally with the ethical barrier. The rank order is shown in the following Table for all six classes of gerotherapeutics:

Conclusion

Gerotherapeutics represents a fascinating and rapidly evolving frontier in medicine. They represent a change in thinking about patient management, moving from a "reactive" model (fixing what is broken) to a "proactive" model (slowing the rate of decay). While science suggests that targeting aging biology is possible, clinical practice has not yet fully caught up. For now, these drugs are legally accessible through off-label prescribing although their use purely for longevity remains ethically debated.
 
The most practical pathway towards gerotherapeutics is through existing or early-stage medical conditions. Patients interested in these therapies should engage in informed discussions with their physicians, focusing on individual risk factors rather than abstract longevity goals. As research advances and clinical trials mature, the boundary between prevention and enhancement may continue to blur. Until then, lifespan-enhancing prescriptions remain less about chasing immortality and more about thoughtfully managing the biology of aging as it begins to unfold.
 
The most practical takeaway for an apparently healthy individual is this: don't settle for a cursory annual check-up. A more proactive approach — one that includes a detailed family history, targeted lab work, and relevant imaging — is far more likely to reveal the borderline conditions described above. If risk factors emerge, that becomes the opening for an informed conversation with your doctor about medications that address those risks while also supporting long-term healthspan. The goal isn't to ask for a longevity prescription. It's to ask the right questions about where your biology actually stands.

Appendix

6 classes of gerotherapeutics, their original FDA-approved indications, relevance to geroscience, and evidence as gerotherapeutics.
 
Metformin

• Indication: Traditionally a first-line defense against Type 2 diabetes
• Geroscience relevance: Inhibits Mitochondrial Complex I and activates AMPK (a metabolic master switch), which reduces oxidative stress, mimics the life-extending effects of caloric restriction, improves insulin sensitivity, and reduces inflammation [6]
• Evidence: Observational studies suggest reduced mortality in diabetics; supported by the Diabetes Prevention Program [7]

 
Rapamycin (Sirolimus)

• Indication: Originally an immunosuppressant for organ transplants
• Geroscience relevance: Inhibits the mTOR pathway, triggering autophagy, the body’s cellular "recycling" system that clears out damaged proteins, and extends life span. Rapamycin is the most contoversial among gerotherapeutics. Despite the high level of enthusiasm in the longevity community, mainstream medicine remains cautious considering side effects like immunosuppression and lipid abnormalities
• Evidence: Robust lifespan extension in multiple animal species [8].

 
Acarbose

• Indication: Type 2 diabetes
• Geroscience relevance: An alpha-glucosidase inhibitor used to manage blood sugar spikes. By delaying carbohydrate absorption, it modulates IGF-1 signaling and shifts the gut microbiome toward producing beneficial short-chain fatty acids (SCFAs), effectively slowing the biological clock
• Evidence: Extends lifespan in mice, particularly males [9]

 
SGLT2 Inhibitors (e.g., Empagliflozin, Canagliflozin)

• Indication: Type 2 diabetes, heart failure, chronic kidney disease
• Geroscience relevance: These drugs help the kidneys clear glucose via urine. Beyond blood sugar, they seem to mimic the effects of caloric restriction and have shown significant lifespan extension in the National Institute on Aging’s Interventions Testing Program (ITP) in mice.
• Evidence: Large, randomized trials show that SGLT2 inhibitors reduced mortality and they are increasingly recognized for their "organ-protective" effects on the heart and kidneys, which are primary drivers of age-related decline [10,11].

 
GLP-1 Receptor Agonists (e.g., Semaglutide, Tirzepatide)

• Indication: Type 2 diabetes, weight management
• Geroscience relevance: These drugs mimic caloric restriction by suppressing appetite, increasing insulin secretion while suppressing glucagon release and slowing digestion. The overall effect is an increase in both health and life span demonstrated experimentally and clinically [12]
• Evidence: Cardiovascular outcome trials demonstrate reduced major adverse events [13]

 
Bisphosphonates (e.g. Alendronate, Zoledronate)

• Indication: Osteoporosis
• Geroscience relevance: They are drugs normally taken by senior citizens for brittle bones but surprisingly might have an anti aging effects. They exert these anti aging effects by inducing apoptosis in senescent cells and reducing inflammation. They improve mitochondrial structure and function and reduce muscle decline associated with aging. In animal studies, these drugs shifted the cellular composition of tissues toward those of younger counterparts [14,15].
• Evidence: Observational studies suggest reduced mortality independent of fracture prevention, with lower incidence of cancer and cardiovascular issues in patients using these drugs [16].

Most people do not ignore their health on purpose. They notice the fatigue that will not lift, the sleep that keeps breaking, the low-grade tension that never fully resolves, and they mean to do something about it. But between the noise of conflicting advice and the pressure of daily life, "doing something" stays perpetually on the list.
Effective health monitoring does not require a complicated system or a shelf full of devices. It requires knowing which signals matter, what they mean over time, and when to act. That clarity, not more data, is what turns good intentions into better health.

Track Patterns, Not Moments
The single most important principle in health monitoring is this: one reading rarely tells you anything useful. Your body fluctuates naturally from day to day based on sleep, stress, hydration, and dozens of other factors. What matters is what happens consistently over days and weeks.
This applies to everything from blood pressure to energy levels. A blood pressure reading of 135/82 on a stressful Monday morning is different from readings that consistently hover above 130/80 over two weeks. The first might be noise. The second is a pattern worth discussing with your doctor.
Start by choosing two or three signals to track, not 10. Sleep quality, energy level, and one physical metric relevant to your health history is a reasonable starting point for most adults. Add complexity only when a simpler system is already working.

The Daily Check-In: Two Minutes, High Value
A daily health check-in does not need to be elaborate. A simple note, like how you slept, your energy level, or any recurring symptom, takes about two minutes and builds the kind of longitudinal picture that even a thorough doctor's visit cannot fully capture.
Over weeks, patterns emerge that would otherwise go unnoticed. Fatigue that worsens mid-week. Sleep deteriorates after certain foods or stressful periods. Energy improves after consistent morning movement. These are not dramatic revelations, but they are the kind of insights that lead to meaningful, sustainable changes.
Keep your check-in in the same place every day: a notes app, a small journal, a simple spreadsheet. Consistency of format matters as much as consistency of habit.

Vital Signs: What to Measure and What It Means
For adults managing or monitoring specific health conditions, at-home vital sign tracking adds a valuable layer of awareness. The most commonly useful metrics are resting heart rate, blood pressure, and body weight, but each requires context to be meaningful.

• Resting heart rate is best measured first thing in the morning before getting out of bed. A gradual upward trend over several days can reflect accumulated stress, poor sleep, or early illness, even before you feel noticeably unwell. A sudden spike warrants attention; a slow climb over two weeks warrants a conversation with your provider.
  
  
• Blood pressure should be measured at the same time each day, after five minutes of rest, and never immediately after exercise, caffeine, or stress. The American Heart Association recommends using the average of two readings taken a minute apart. Isolated high readings are common and often benign. Consistently elevated readings, particularly above 130/80 mmHg over multiple days, are worth following up on.
  
  
• Body weight fluctuates by several pounds daily based on fluid, food, and activity. Weekly weigh-ins at the same time of day are more informative than daily ones for most people. Gradual, unexplained changes over weeks are more meaningful than day-to-day movement.

The goal in each case is the same: build a reliable baseline so that genuine changes are recognizable.

Preventive Screenings
Daily habits are only part of the picture. Preventive screenings, such as cholesterol checks, cancer screenings, blood glucose, vaccinations, and routine lab work, catch what home monitoring cannot. The U.S. Preventive Services Task Force (USPSTF) publishes evidence-based screening recommendations by age and risk factor, and they are a practical starting point for anyone unsure why they are due.
If you have not reviewed your screening history recently, your annual physical is the right moment to do it. Bring a list of what you have done and when and ask your provider what is next.

Surround Yourself with What Supports You
Environment shapes behavior more than motivation does. If your surroundings quietly reinforce poor habits, even strong intentions tend to erode. One underrated strategy is making your wellness goals visible.
One simple and often overlooked strategy is making your goals visible in your physical space. A quote that genuinely resonates with you when printed and placed where you start your morning does something a phone notification cannot. It is a quiet, consistent prompt that does not require willpower to notice. You can design and print posters tailored to whatever keeps you motivated, using an app that lets you customize templates and print something worth hanging on a wall.

Bring Your Data to Your Doctor
One of the most underused benefits of health tracking is what it makes possible in a clinical setting. A doctor seeing you for 15 minutes works from snapshots. You have weeks of context they do not.
Before your next appointment, take five minutes to summarize what you have noticed, not raw numbers, but patterns and changes. "My resting heart rate has been trending up for the past three weeks" is more useful than a list of daily readings. "I've had consistent fatigue every afternoon for the past month, regardless of sleep" gives your provider something specific to work with.
This kind of preparation helps your concerns be taken seriously, speeds up the diagnostic process, and puts you in a genuinely collaborative role in your own care.
​
Start With One Habit for 30 Days
The most effective health monitoring routine is the one you will maintain. Start with a single habit and keep it going for 30 days before adding anything else.
Consistency, not comprehensiveness, is what turns monitoring into meaningful health insight. Over time, a simple, reliable system gives you something far more valuable than data: it gives you clarity about your own body, and the confidence to act on what you find.

Abstract
 
Meditation has long been recognized for its psychological and stress-reduction benefits, but growing evidence suggests it may also influence biological aging. This article reviews current research examining the effects of mindfulness meditation, particularly Zen practice, on biological clocks such as DNA methylation age and telomere dynamics. Several studies report that long-term meditators exhibit slower epigenetic age acceleration, reduced DNA methylation age, and favorable telomere-related biomarkers, potentially reflecting improved regulation of stress, inflammation, and metabolic pathways. Meditation has also been associated with short-term molecular changes involving gene expression, cortisol rhythms, and epigenetic regulation. However, important limitations, including small sample sizes, heterogeneous meditation practices, selection bias, and short study durations, make it difficult to establish a definitive causal relationship between meditation and longevity. Current evidence suggests that meditation may not reverse aging but could help slow biological aging and improve healthspan, resilience, and overall quality of life.

Bottom Line
 

• Meditation may influence biological aging: Long-term mindfulness practice has been associated with slower epigenetic aging and more favorable telomere-related biomarkers.
• Stress reduction appears central: Lower chronic stress, reduced cortisol exposure, and improved emotional regulation may be key mechanisms linking meditation to healthier aging.
• Effects are more consistent for epigenetic clocks than telomere length: Evidence for slower DNA methylation aging is generally stronger than evidence for telomere preservation.
• Meditation likely affects upstream aging pathways: Changes in inflammation, gene expression, autonomic balance, and metabolic regulation may contribute to observed benefits.
• Proof of lifespan extension is lacking: Current studies suggest potential improvements in biological age and healthspan, but there is no definitive evidence that meditation extends human lifespan.
• A low-risk intervention with broad benefits: Regardless of its ultimate effect on longevity, meditation remains one of the safest and most accessible practices for enhancing mental, emotional, and physiological well-being. 

Introduction
 
Modern medicine has made remarkable progress in extending human lifespan, yet much of this extension has been driven by pharmaceuticals and technological interventions that often come with trade-offs. At the same time, there is growing scientific interest in whether behavioral practices—particularly meditation—can influence the rate of biological aging itself. Among these practices, Zen mindfulness meditation has gained attention not only for its neurological and psychological benefits, but also for its potential role in modulating biological clocks such as DNA methylation age and telomere dynamics.
 
While early neuroimaging studies focused on structural and functional brain changes, more recent research has shifted toward deeper biological markers of aging. These include epigenetic clocks, which estimate biological age based on DNA methylation patterns, and telomeres, which shorten with cellular replication and stress. This blog examines the current evidence linking meditation—especially long-term mindfulness practices—to these aging markers, while also addressing the significant methodological challenges that complicate efforts to prove a causal relationship.

One of the most compelling lines of research involves epigenetic clocks, particularly the Horvath DNA methylation clock. These clocks are considered among the most robust biomarkers of biological aging.
​
A landmark study by Chaix et al. (2017) [1] in Psychoneuroendocrinology investigated long-term meditators and found that while their overall epigenetic age did not differ significantly from controls, age-related acceleration of the epigenetic clock was absent in experienced meditators. Moreover, years of meditation practice were inversely correlated with epigenetic age acceleration, suggesting a cumulative protective effect.

​Similarly, Pavanello et al. (2019) [2] reported that a meditation-based intervention was associated with reductions in DNA methylation age over a relatively short period (~60 days). More recent work in 2023 by Dasanayaka et al.[3] further supports the idea that meditation may slow epigenetic aging trajectories, particularly in older adults.
 
These findings align with the hypothesis that mindfulness practices may influence gene regulation pathways associated with inflammation, stress response, and metabolic function—key drivers of biological aging.

​Another major biological clock involves telomeres, the protective caps at the ends of chromosomes. Telomere shortening is widely regarded as a hallmark of cellular aging.
Early theoretical work by Epel et al. (2009) [4] proposed that meditation could influence telomere maintenance indirectly through stress reduction and hormonal regulation, particularly by lowering cortisol and sympathetic nervous system activity.
 
Empirical studies have provided partial support for this model. For example, Mendioroz et al. (2020) [5] in Scientific Reports found that experienced meditators exhibited longer telomeres and epigenetic differences in telomere-related regions. Other studies have reported increased telomerase activity—the enzyme responsible for maintaining telomere length—in individuals undergoing meditation or mindfulness-based interventions.
However, the literature is not entirely consistent. Some longitudinal studies, including more recent controlled trials, have failed to detect significant changes in telomere length over shorter intervention periods. This inconsistency highlights the complexity of using telomeres as a reliable outcome measure in behavioral research.

Beyond Clocks: Multi-Omic and Rapid Biological Effects
 
In addition to long-term aging markers, meditation has been shown to induce short-term molecular changes that may influence aging indirectly. Studies such as Diez et al. (2023) [6] demonstrate that meditation can alter:

• DNA methylation patterns
• Cortisol rhythms
• Gene expression related to inflammation

These findings suggest that meditation may act upstream of biological clocks, modulating the physiological systems that ultimately determine aging trajectories.


Why Is It So Difficult to Prove?
 
Despite promising findings, establishing a definitive causal link between meditation and longevity remains a major challenge. Several key issues complicate clinical research in this area:
 
1. Duration Mismatch
Biological aging unfolds over decades, yet most clinical trials last weeks to months. Detecting meaningful changes in epigenetic age or telomere length within such short timeframes is inherently difficult.
 
2. Heterogeneity of Meditation Practices
“Zen mindfulness” encompasses a range of practices varying in intensity, frequency, and philosophical orientation. This lack of standardization makes it difficult to compare studies or replicate findings.
 
3. Selection Bias
Long-term meditators often differ from the general population in important ways:

• Health behaviors (diet, exercise)
• Socioeconomic status
• Stress exposure

These confounders can independently influence biological aging.
 
4. Small Sample Sizes
Many studies involve relatively small cohorts, limiting statistical power and increasing the risk of false positives or inconsistent results.
 
5. Measurement Variability
Different studies use different aging clocks (Horvath, Hannum, PhenoAge, GrimAge), which may not yield equivalent results. Similarly, telomere measurements can vary depending on methodology (qPCR vs. Southern blot).
 
6. Psychological and Placebo Effects
Meditation interventions are difficult to blind, raising the possibility that expectation effects or general relaxation—not meditation per se—may drive observed benefits.


Zen Mindfulness: A Unique Case?
 
Zen meditation, with its emphasis on non-dual awareness, breath regulation, and sustained attentional control, may offer distinct biological advantages:

• Reduced chronic stress signaling
• Enhanced parasympathetic tone
• Improved emotional regulation

 
These factors are closely tied to pathways known to influence aging, including inflammation, oxidative stress, and metabolic health. However, few studies isolate Zen specifically, and most group it under broader “mindfulness” or “meditation” categories.


Conclusion
 
The scientific evidence to date suggests that meditation—particularly long-term mindfulness practices such as Zen—may slow aspects of biological aging, as reflected in epigenetic clocks and telomere biology. The most consistent finding is not that meditation reverses aging, but that it may attenuate the rate at which aging progresses, especially in individuals with sustained practice.
 
However, the field remains in an early stage. The complexity of human aging, combined with methodological limitations in clinical trial design, makes it difficult to draw definitive conclusions. Larger, longer-term, and better-controlled studies will be necessary to determine whether meditation can meaningfully extend human lifespan—or whether its benefits are primarily confined to improving healthspan and resilience.
 
In the meantime, meditation stands as a low-risk intervention with well-documented psychological and physiological benefits. Whether or not it ultimately proves to be a tool for extending life, it may already be one of the most accessible ways to improve the quality of the years we have.

References
 

1. Chaix, R., Alvarez-López, M. J., Fagny, M., Lemee, L., Regnault, B., Davidson, R. J., ... & Kaliman, P. (2017). Epigenetic clock analysis in long-term meditators. Psychoneuroendocrinology, 85, 210-214. https://doi.org/10.1016/j.psyneuen.2017.08.016
2. Pavanello, S., Campisi, M., Tona, F., Dal Lin, C., & Iliceto, S. (2019). Exploring epigenetic age in response to intensive relaxing training: a pilot study to slow down biological age. International journal of environmental research and public health, 16(17), 3074. https://doi.org/10.3390/ijerph16173074
3. Dasanayaka, N. N., Sirisena, N. D., & Samaranayake, N. (2023). Associations of meditation with telomere dynamics: a case–control study in healthy adults. Frontiers in Psychology, 14, 1222863. https://doi.org/10.3389/fpsyg.2023.1222863
4. Epel, E., Daubenmier, J., Moskowitz, J. T., Folkman, S., & Blackburn, E. (2009). Can meditation slow rate of cellular aging? Cognitive stress, mindfulness, and telomeres. Annals of the new York Academy of Sciences, 1172(1), 34-53. https://doi.org/10.1111/j.1749-6632.2009.04414.x
5. Mendioroz, M., Puebla-Guedea, M., Montero-Marín, J., Urdánoz-Casado, A., Blanco-Luquin, I., Roldán, M., ... & García-Campayo, J. (2020). Telomere length correlates with subtelomeric DNA methylation in long-term mindfulness practitioners. Scientific Reports, 10(1), 4564. https://doi.org/10.1038/s41598-020-61241-6
6. Diez, G. G., Martin-Subero, I., Zangri, R. M., Kulis, M., Andreu, C., Blanco, I., ... & Vázquez, C. (2023). Epigenetic, psychological, and EEG changes after a 1-week retreat based on mindfulness and compassion for stress reduction in healthy adults: Study protocol of a cross-over randomized controlled trial. PLoS One, 18(11), e0283169. https://doi.org/10.1371/journal.pone.0283169

For health-conscious adults seeking wellness management, the hardest part often isn’t effort, it’s turning complex signals into steady, livable choices. Between wearables, assessments, and multiple personalized health strategies, the body can start to feel like a dashboard that never stops flashing, while stress quietly becomes the baseline. Mindfulness integration brings attention back to the mind-body connection, creating a clearer read on what helps, what harms, and what actually fits real life. Done consistently, it supports holistic well-being benefits that can be felt in everyday calm.
​
Quick Summary: Daily Mindfulness Practices

• Practice gratitude journaling daily to strengthen positive focus and support personalized wellness.
• Use breath focus techniques to calm the nervous system and reset during stressful moments.
• Practice mindful eating habits to improve awareness of hunger, fullness, and satisfaction.
• Schedule device-free time routines to reduce distractions and create space for lasting calm.

​Understanding Mindfulness and Attention Training
A useful way to define mindfulness is purposeful attention, placed on what is happening right now, without judging it. When you practice attention regulation, you notice distractions sooner and choose what you focus on. This shifts how your day feels, even when your schedule stays the same.
This matters for personalized wellness because your focus shapes your choices in sleep, food, movement, and positive mindset habits. Two mindset moves strengthen the effect: gratitude, which nudges your body toward steadier stress responses, and self-talk awareness, which reduces the quiet mental friction that drains energy.
Picture doing a weekly health checklist after a tough day. Mindfulness helps you spot the spiral of thoughts, name it, and return to one next step. You add one gratitude note, then rephrase harsh self-talk into a helpful instruction.
With this foundation, daily habits become easier to choose and repeat.

Mindfulness Habits You Can Repeat and Track
These habits turn mindfulness into a simple routine you can log alongside sleep, meals, movement, and stress notes. Over time, they help you spot patterns, choose one next action, and keep your wellness checklist realistic even during busy weeks.
Two-Minute Breath Anchor

• What it is: Do a two-minute breath count, restarting gently when your mind wanders.
• How often: Daily, before your first task.
• Why it helps: It steadies attention so your next choice feels clearer.

Five-Sense Arrival

• What it is: Name 5 things you see, 4 feel, 3 hear, 2 smell, 1 taste.
• How often: Daily, at lunch or commute transitions.
• Why it helps: It reduces rumination and brings you back to the present.

Body Scan Check-In

• What it is: Slowly scan from forehead to toes, noting tension without fixing it.
• How often: 3 times weekly, before bed.
• Why it helps: It improves body awareness, supporting more precise self-care decisions.

Structured Meditation Block

• What it is: Use a 10-minute structured practice with a timer and one focus point.
• How often: Weekly, then add one extra day per month.
• Why it helps: Consistency builds follow-through for longer wellness plans.

Mindful Listening Minute

• What it is: In one conversation, reflect back what you heard before responding.
• How often: Daily, in a key interaction.
• Why it helps: It lowers reactivity and prevents stress from snowballing.

Pick one habit, start small, and adjust it to fit your family rhythm.

Daily Mindfulness Integration Checklist
This checklist turns mindfulness into trackable steps you can fold into your health log for clearer, personalized decisions. It also helps you stay realistic since only 14% of respondents practice meditation daily.
✔ Set one fixed cue for practice
✔ Track minutes practiced next to sleep and mood
✔ Record one gratitude note after dinner
✔ Eat one snack without screens, chewing slowly
✔ Schedule a 20-minute evening electronic detox
✔ Review your stress triggers weekly and choose one adjustment
✔ Confirm your plan fits your busiest day
Check off one item today, then repeat it until it feels automatic.

Commit to One Daily Mindfulness Habit for Measurable Calm
Most wellness plans fail because life gets busy and tracking turns into pressure instead of support. A mindful approach keeps the focus on awareness over perfection, using integrated daily habits to steady attention and make choices easier to sustain. Over time, the mindfulness benefits summary is simple: less reactivity, clearer focus, better sleep, and behavioral health changes that show up in your mood, cravings, and recovery from stress, key signals for personalized wellness improvement. Mindfulness works when it becomes a small daily practice, not a someday goal. For the next seven days, you can choose one habit from the checklist and commit to doing it once daily, then note what changes. That commitment to mindful living builds the stability and resilience that make health progress last.

​Hung V. Le
Biologics & Drug Targets, ProSci LLC, Rockaway, The United States
ORCID
https://orcid.org/0000-0002-6913-2373 (Hung Van Le)
 
02/10/2026

Abstract
 
15-Hydroxyprostaglandin dehydrogenase (15-PGDH), encoded by HPGD, is the principal enzyme responsible for the metabolic inactivation of prostaglandin E₂ (PGE₂), a lipid mediator with central roles in inflammation, tissue repair, stem cell function, and cancer biology. By constraining PGE₂ signaling, 15-PGDH functions as a dominant endogenous brake on regeneration. Across multiple tissues, aging and injury are associated with increased 15-PGDH activity, leading to impaired repair capacity. Recent preclinical studies demonstrate that pharmacologic inhibition of 15-PGDH restores physiologic PGE₂ signaling and robustly enhances regeneration in skeletal muscle, neuromuscular junctions, cartilage, hematopoietic stem cell niches, and the neurovascular unit. In contrast, extensive cancer biology literature establishes 15-PGDH as a bona fide tumor suppressor that is frequently silenced in malignancy, where loss of enzymatic activity promotes tumor growth, angiogenesis, immune evasion, and metastasis. This duality presents both opportunity and challenge for drug development. This review synthesizes emerging biological and translational evidence supporting both inhibition and restoration of 15-PGDH, evaluates the current clinical and preclinical landscape, and examines safety considerations centered on oncogenic risk. We argue that successful therapeutic targeting of 15-PGDH will depend on context-specific strategies that optimize therapeutic index through temporal limitation, spatial restriction, biomarker-guided dosing, and careful patient selection.

1. Introduction
 
15-Hydroxyprostaglandin dehydrogenase (15-PGDH, encoded by HPGD) is the principal enzyme responsible for the metabolic inactivation of prostaglandin E₂ (PGE₂) and related lipid mediators. By catalyzing the NAD⁺-dependent oxidation of PGE₂ to inactive 15-keto-PGE₂, 15-PGDH functions as a critical “brake” on prostaglandin signaling. PGE₂, acting through EP receptors (EP1–EP4), exerts pleiotropic effects on inflammation, stem and progenitor cell function, tissue repair, vascular integrity, and cell survival.
 
Across multiple tissues, aging and injury are associated with pathological upregulation of 15-PGDH, resulting in diminished local PGE₂ signaling and impaired regenerative responses. Pharmacologic or genetic inhibition of 15-PGDH therefore represents a strategy to restore endogenous repair programs (1-7), rather than introducing exogenous growth factors or cell therapies. This concept underlies the recent surge of interest in 15-PGDH inhibitors such as SW033291, SW209415, and MF-300 (8-10).
 
However, PGE₂ is also a well-established pro-tumorigenic mediator, promoting proliferation, angiogenesis, immune evasion, and metastasis (11). In many cancers, HPGD expression is epigenetically silenced, and restoration of 15-PGDH suppresses tumor growth. Thus, 15-PGDH occupies a biologically paradoxical position: a regeneration brake in aging and injury, but a tumor suppressor in cancer. Any therapeutic strategy targeting this enzyme for inhibition must therefore hinge on achieving a favorable therapeutic index that maximizes benefit in degenerative or acute injury settings while minimizing long-term oncogenic risk. Conversely, strategy that aims to restore 15-PGDH expression and activity to achieve an anti-tumor effect must consider its degenerative side effects in normal tissues.

​Figure 1. Context-dependent roles of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in regeneration and tumor suppression. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH), encoded by HPGD, catalyzes the irreversible inactivation of prostaglandin E₂ (PGE₂) and functions as a metabolic gatekeeper of EP receptor signaling. Center, 15-PGDH determines local PGE₂ availability and signaling amplitude. Top, in aging and tissue injury, elevated 15-PGDH activity reduces PGE₂ below a functional threshold, impairing regeneration in skeletal muscle, neuromuscular junctions, cartilage, hematopoietic stem cell niches, and the neurovascular unit. Transient or spatially restricted inhibition of 15-PGDH restores physiologic PGE₂ signaling and re-engages endogenous repair programs. Bottom, in cancer, 15-PGDH acts as a tumor suppressor and is frequently silenced through epigenetic, oncogenic, and microRNA-mediated mechanisms, resulting in PGE₂ accumulation that promotes proliferation, angiogenesis, immune evasion, and metastasis. Restoration of 15-PGDH activity suppresses these tumor-promoting processes.

2. 15-PGDH across disease indications
2.1 Muscle and Neuromuscular Regeneration
 
A convergent body of work identifies prostaglandin E₂ (PGE₂) as a central, physiologic regulator of skeletal muscle and neuromuscular regeneration, with the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) acting as a key negative checkpoint. In young, injured muscle, transient PGE₂ signaling is required for efficient repair, whereas in aging and denervation, aberrant accumulation of 15-PGDH lowers PGE₂ below a functional threshold, impairing regenerative capacity. Pharmacologic or genetic inhibition of 15-PGDH restores PGE₂ to youthful levels, re-engaging endogenous repair programs.
 
At the level of skeletal muscle, PGE₂ directly targets muscle stem cells (MuSCs) through EP4 receptor signaling to drive rapid cell-cycle entry and clonal expansion during the early inflammatory phase of regeneration. Acute enhancement of PGE₂ signaling is sufficient to markedly augment muscle repair and recovery of strength, whereas suppression of prostaglandin synthesis (for example, by NSAIDs) compromises these processes (1). In aging, skeletal muscle exhibits a pronounced increase in 15-PGDH expression and activity, derived from both myofibers and tissue-resident macrophages, resulting in reduced PGE₂ availability. Short-term inhibition of 15-PGDH in aged mice reverses key features of sarcopenia, including reduced myofiber cross-sectional area, loss of muscle mass, and diminished contractile force. These effects are causally linked to PGE₂ restoration, as ectopic overexpression of 15-PGDH in young muscle is sufficient to induce rapid atrophy and weakness.
 
Mechanistically, restoration of PGE₂ signaling through 15-PGDH inhibition orchestrates coordinated remodeling of aged muscle tissue. This includes suppression of transforming growth factor-β and ubiquitin–proteasome–mediated atrophy pathways, alongside enhanced autophagy flux and mitochondrial biogenesis with normalization of mitochondrial ultrastructure. The convergence of these pathways explains how modest, physiologic increases in PGE₂ can yield disproportionately large functional gains, distinguishing 15-PGDH inhibition from purely anabolic or anti-catabolic strategies (2).
 
More recent work extends the relevance of 15-PGDH beyond muscle-intrinsic regeneration to neuromuscular connectivity. Denervation, whether acute after nerve injury or chronic during aging, induces robust expression of 15-PGDH in myofibers, particularly in fast-twitch fibers that are preferentially lost in sarcopenia and neuromuscular disease. Inhibition of 15-PGDH accelerates motor axon regeneration, restores neuromuscular junction (NMJ) structure, and improves force recovery after peripheral nerve injury. In aged animals with chronic denervation, 15-PGDH inhibition increases motor neuron viability and re-establishes functional NMJs. Importantly, restored PGE₂ signaling activates cAMP–CREB pathways not only in muscle but also in motor neurons, indicating coordinated pre- and postsynaptic regeneration (3).
 
Taken together, these findings position 15-PGDH as a central, druggable regulator of muscle mass, strength, and neuromuscular integrity. Inhibition of this enzyme offers a unified therapeutic strategy for sarcopenia of aging, traumatic muscle and nerve injuries, and neuromuscular or muscular dystrophies characterized by denervation and impaired regeneration. By restoring endogenous PGE₂ signaling to physiologic levels, 15-PGDH inhibitors engage intrinsic repair mechanisms across the muscle–nerve unit, supporting their broader consideration as regenerative therapeutics across multiple indications.
 
2.2 Osteoarthritis and cartilage regeneration
 
Singla et al. (4) demonstrate that 15-PGDH expression is increased in articular cartilage of aged and injured joints, particularly within hypertrophic-like chondrocyte populations. Both systemic and intra-articular inhibition of 15-PGDH with SW033291 led to robust regeneration of hyaline cartilage, reduced osteoarthritic pathology, and decreased pain behaviors in murine models.
 
Single-cell RNA-seq and multiplexed imaging revealed a key mechanistic insight: cartilage regeneration did not arise from stem or progenitor cell expansion, but rather from phenotypic reprogramming of existing chondrocytes. SW033291 reduced hypertrophic, degenerative chondrocyte subsets and expanded extracellular-matrix-producing articular chondrocytes. This distinguishes 15-PGDH inhibition from many regenerative approaches that rely on proliferation, suggesting a potentially lower oncogenic burden within cartilage itself.
 
Importantly, both local and short-term systemic inhibition were sufficient to achieve benefit, highlighting the feasibility of spatially restricted or temporally limited dosing, a key consideration for safety.
 
2.3 Hematopoietic aging and stem cell regeneration
 
Chaudhary et al. (5) extend earlier work showing that 15-PGDH constrains hematopoietic stem cell (HSC) function by degrading PGE₂. In aged mice, 15-PGDH expression and enzymatic activity remain conserved in bone marrow and spleen, making it a viable target even late in life. Prolonged pharmacologic inhibition increased the number and functional capacity of HSCs and progenitors, improved engraftment after transplantation, accelerated multilineage reconstitution, and mitigated age-associated myeloid bias.
 
A crucial observation is that 15-PGDH inhibition by SW033291 did not perturb steady-state hematopoiesis, but selectively enhanced regeneration under stress (e.g., transplantation). This context dependence suggests that 15-PGDH inhibition amplifies endogenous repair signals rather than inducing uncontrolled proliferation. Nonetheless, because hematopoietic tissues are intrinsically susceptible to malignant transformation, this indication sits close to the boundary where regenerative benefit and cancer risk intersect. Short peri-transplant courses (IV or parenteral) that boost HSC engraftment are an appealing clinical use because they are time-limited and target a high-value, high-risk clinical need (older transplant recipients).
 
2.4 Alzheimer’s disease and traumatic brain injury: Blood-Brain Barrier-centric neuroprotection
 
Koh et al. (6) identify a novel role for 15-PGDH in the brain, localized predominantly to microglia and perivascular macrophages associated with the blood-brain barrier (BBB). In human and murine Alzheimer’s disease (AD), traumatic brain injury (TBI), and aging, 15-PGDH expression and activity are markedly elevated. This elevation correlates with oxidative stress, BBB breakdown, neuroinflammation, and cognitive decline.
 
Pharmacologic inhibition or genetic reduction of 15-PGDH preserved BBB integrity, suppressed reactive oxygen species, reduced neurodegeneration, and most strikingly fully preserved cognitive function in mouse models of AD and TBI. Notably, these effects occurred without altering amyloid pathology, positioning 15-PGDH inhibition as a non-amyloid, vascular/immune mechanism of neuroprotection.
The localization of 15-PGDH to BBB-associated myeloid cells suggests that targeted modulation of inflammatory lipid metabolism underlies the benefit. This cellular specificity again raises the possibility of achieving efficacy with limited systemic exposure. However, brain indications often require chronic or repeated dosing, which reopens the long-term cancer question unless dosing can be restricted or targeted (e.g., CNS-penetrant agents given episodically).
 
2.5 Ischemic stroke and ferroptosis suppression
 
Xu et al. (7) provide a mechanistically detailed account of 15-PGDH in acute ischemic stroke. Overexpression of 15-PGDH exacerbated infarct size, edema, neurological deficits, and neuronal death, whereas inhibition with SW033291 was strongly neuroprotective in both in vivo rat middle cerebral artery occlusion (MCAO) models and in vitro oxygen glucose deprivation/reperfusion (OGD/R) neuronal cultures.
 
The key mechanistic advance is the linkage of 15-PGDH to ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated cell death. 15-PGDH inhibition activated the PGE₂/EP4 axis, leading to c-AMP responsive element-binding protein (CREB)- and NF-κB-dependent transcriptional upregulation of glutathione peroxidase 4 (GPX4), the central suppressor of ferroptosis. Genetic ablation of GPX4 abolished the protective effect of PGDH inhibition, establishing a causal pathway.
 
This work positions 15-PGDH inhibition as an acute neuroprotective strategy with a defined molecular endpoint (GPX4 restoration), well suited to short-duration intervention, arguably the safest therapeutic context for a target with oncogenic liabilities.
 
2.6 Cancer and tumor microenvironment: the countervailing evidence
 
The comprehensive review by Tulimilli et al. (11) synthesizes decades of evidence identifying 15-PGDH as a bona fide tumor suppressor across colorectal, breast, gastric, lung, pancreatic, hepatic, and other cancers . In most malignancies, 15-PGDH expression is reduced via methylation of CpG islands in the promoter region, histone deacetylation in association with transcription repressors, microRNA regulation (e.g. miR-620 in breast and prostate cancer, miR-155 in esophageal cancer), inflammatory cytokines (e.g., IL-1β, TNF-α), and oncogenic signaling pathways (EGFR, β-catenin, Snail/Slug).
 
Loss of 15-PGDH leads to PGE₂ accumulation, which drives proliferation, angiogenesis, immune evasion, and resistance to apoptosis. Conversely, restoring 15-PGDH expression suppresses tumor growth, induces apoptosis and cell-cycle arrest, and reduces metastasis in multiple in vitro and in vivo models. These data establish cancer predisposition as a credible, mechanism-based risk of chronic or systemic 15-PGDH inhibition.

3. Clinical-translation landscape: MF-300, SW033291, (+)-SW209415
 
MF-300 (Epirium Bio): an oral 15-PGDH inhibitor (Phase-1 completed)
 
MF-300 has completed first-in-human single and multiple ascending dose clinical trial. Publicly available report of this Phase-1 study indicate tolerability, dose-dependent pharmacokinetic (PK), and pharmacodynamic (PD) evidence of target engagement (changes in PGE₂ metabolites and other mechanistic biomarkers). Epirium is advancing MF-300 into Phase-2 development for sarcopenia (10).
 
This is the first publicly reported human evidence that systemic 15-PGDH inhibition can deliver pharmacological effects in humans with acceptable acute tolerability, an important “feasibility” milestone. For chronic indications (sarcopenia), MF-300 shows promise mechanistically but demands a long-term safety and cancer-surveillance strategy in later trials.
 
SW033291 (Case Western / academic program): a 15-PGDH inhibitor for pre-clinical studies
 
SW033291 is the prototypical small-molecule 15-PGDH inhibitor used across multiple published preclinical studies: hematopoietic regeneration, colon/colitis models, bone/muscle repair, and more recently in AD/TBI/stroke neuroscience studies (8). Most studies rely heavily on SW033291 for in vivo pharmacology.
 
SW033291 has a deep preclinical track record and has been used in investigator-led translational work (Case Western). If moved into humans, its profile supports both acute (IV/peri-transplant) and subchronic (oral/other) use cases, but clinical trial registration details have not been reported.
 
(+)-SW209415: a water-soluble, IV-capable second-generation analogue
 
Medicinal-chemistry work produced (+)-SW209415 (a racemate) with orders-of-magnitude improved aqueous solubility while retaining potency. This enables IV dosing for peri-operative or transplant use where short IV infusions could be given in a tightly controlled temporal window. Preclinical bone marrow transplantatio (BMT) models and other regeneration models show strong efficacy (9).
 
SW209415 (IV) directly addresses the therapeutic-index problem for hematopoietic/transplant use by enabling short, high-impact dosing windows rather than chronic systemic exposure.
 
4. Safety, cancer risk, and the therapeutic-index problem
 
In most cancers and preclinical tumor models, low 15-PGDH and high PGE₂ are associated with tumor initiation, progression, angiogenesis, and immune suppression. Restoring 15-PGDH is tumor-suppressive; conversely, sustained inhibition would raise PGE₂ and could accelerate latent premalignant clones or worsen tumor microenvironments. Successful development of a clinical candidate based on 15-PGDH inhibition depends on optimizing factors that could improve the therapeutic index for the indication of interest (Figure. 2).
 
These factors could include limiting the duration of intervention. For example, short pulses as in peri-transplant or acute stroke/TBI, minimize cumulative PGE₂ exposure and therefore cancer-promotion risk. The SW209415 IV program is prototypical of this approach. Localized administration, as in intra-articular or topical administration for osteoarthritis, concentrates drug in the joint and lowers systemic exposure (1). Rigorous patient selection and monitoring could minimize baseline risk. Excluding or closely monitoring patients with high cancer risk or known premalignant lesions will reduce the near-term oncologic hazard. Dosing  guided by biomarkers (urinary/tissue PGE₂ metabolite) could help determine minimal effective dose (7).
 
MF-300 Phase-1 shows acute tolerability and favorable pharmacodynamic, lowering a key pharmacologic uncertainty in humans. However, it does not prove long-term safety (oncologic risk requires longer observation). Similarly, preclinical SW033291 / SW209415 data support efficacy and suggest short schedules are effective and therefore safer from an oncogenic perspective.

Figure 2. Optimizing therapeutic index. The opposing biological consequences of 15-PGDH modulation define a therapeutic-index problem. Successful clinical targeting of 15-PGDH—either by inhibition for regenerative indications or by restoration for cancer therapy—will require context-specific strategies that optimize benefit while minimizing risk through temporal limitation, spatial restriction, biomarker-guided dosing, and careful patient selection.

5. 15-PGDH reactivation as a cancer treatment modality?
 
Tulimilli, S.V. et al. (11) present a comprehensive picture of 15-hydroxyprostaglandin dehydrogenase (15-PGDH, encoded by HPGD) as a central node where inflammation, prostaglandin metabolism, and tumor biology intersect. In normal physiology, 15-PGDH serves as the principal catabolic enzyme for prostaglandin E₂ (PGE₂), converting it to inactive metabolites and thereby restraining the spectrum of PGE₂-driven signaling: proliferation, angiogenesis, immune modulation, and matrix remodeling. In many tumor types, however, this restraint is lost. The review synthesizes evidence from multiple cancers showing that HPGD expression is frequently suppressed and that this suppression is functionally important for tumor progression because it permits persistent, high local PGE₂ levels that favor malignant phenotypes.
 
A key strength of the review is its emphasis on the multi-layered mechanisms by which cancers reduce 15-PGDH. Rather than a single on/off switch, repression occurs through convergent transcriptional, epigenetic, post-transcriptional and microenvironmental routes. Promoter CpG hypermethylation and recruitment of chromatin-repressive complexes (including HDACs) are repeatedly documented across tumor types and provide a durable block to transcription. On top of that, several oncogenic signaling programs, Wnt/β-catenin, EGFR/MAPK, and epithelial-to-mesenchymal transcription factors such as Snail and Slug, actively repress HPGD transcription. The tumor microenvironment amplifies repression: proinflammatory cytokines (IL-1β, TNF-α) and oxidative stress further suppress expression or activity. At the post-transcriptional level, a cohort of oncogenic microRNAs (e.g., miR-21, miR-155 and others cataloged in the review) target HPGD mRNA, reducing stability or translation and yielding multilayered, robust downregulation. The net effect is a tumor milieu that both makes and preserves high PGE₂.
 
This mechanistic heterogeneity matters for pharmacology: it suggests multiple, rational levers to restore 15-PGDH activity, and the possibility for several translational approaches. Classic epigenetic drugs, DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors, can relieve promoter methylation and chromatin compaction and thereby re-enable transcription; these agents have the advantage of clinical availability but suffer from broad, nonselective genomic effects that can activate undesired genes and cause systemic toxicity. Targeting upstream signaling is another option: inhibitors of EGFR/MEK or modulators of Wnt signaling may indirectly derepress HPGD in tumors where those pathways dominate. MicroRNA antagonists (antagomirs) offer sequence specificity and could selectively restore HPGD post-transcriptionally, particularly if delivered locally or within tumor-targeted nanoparticles. Tulimilli, S.V. et al. (11) highlights gene-delivery approaches, viral or nanoparticle vectors expressing HPGD, which bypass endogenous repression and have shown tumor-suppressive effects in preclinical models. Finally, combination strategies that pair HPGD reactivation with other modalities, including blocking PGE₂ synthesis (COX-2/mPGES-1 inhibitors) and receptor binding (12), or anti-angiogenic agents are conceptually attractive because they both reduce PGE₂ production and accelerate its catabolism.
 
The review makes several persuasive points for pursuing 15-PGDH as a cancer drug target. Restoring 15-PGDH consistently reduces tumor cell proliferation, invasiveness, and colony formation across multiple models; it curtails angiogenesis and can reprogram the tumor microenvironment away from an immunosuppressive, repair-favoring state. These effects are mechanistically coherent because PGE₂ acts on EP receptors to promote proliferation, survival and immune evasion; removing PGE₂ by enhanced catabolism should therefore reverse those signals. Moreover, HPGD status offers a potential biomarker: tumors with epigenetic silencing of HPGD and high COX-2/PGE₂ signatures may be most dependent on PGE₂ and thus most likely to respond to reactivation strategies. The availability of multiple modality options, epigenetic drugs, pathway inhibitors, miRNA tools, and gene therapy—makes HPGD a practical target for translational programs.
 
Those upsides are tempered, properly, by the risks and caveats that Tulimilli, S.V. et al. (11) emphasizes. Because 15-PGDH is the main catabolic brake on PGE₂, systemic or chronic up-regulation of the enzyme will lower PGE₂ systemically and can blunt physiological PGE₂ roles in tissue repair and homeostasis. PGE₂ has established, context-dependent pro-regenerative effects in bone, muscle, hematopoietic stem cell niches, and in ischemic tissues; lowering PGE₂ in these contexts could delay wound healing, impair fracture repair, suppress stem/progenitor cell function, and reduce protective inflammatory resolution. The review therefore argues for therapeutic strategies that preserve the antitumor benefit while limiting deleterious systemic reductions in pro-regenerative prostaglandin signaling.
 
From a translational standpoint synthesis of the available data points to several practical principles. First, localization matters: intratumoral or organ-targeted delivery of HPGD reactivation (gene delivery, local antagomirs, tumor-targeted nanoparticles) reduces systemic exposure and thus spares regenerative physiology elsewhere. Second, temporal control, short pulses timed around cytotoxic therapy or perioperative windows, may permit tumoral suppression without long-term impairment of repair. Third, combination approaches that both limit PGE₂ synthesis (COX-2/mPGES blockade) and restore catabolism may permit lower doses and mitigate compensatory feedback. Fourth, patient selection using HPGD/COX-2/PGE₂ signatures and exclusion of patients with high risk of wound-healing complications or ischemic vulnerability could focus benefit where the therapeutic index is favorable.
 
Finally, the available information on 15-PGDH as tumor suppressor underscores the need for an evidence-driven research agenda. Preclinical models must include rigorous assessments of regeneration and repair endpoints (wound healing, bone/cartilage repair, hematopoietic recovery, and neurovascular resilience) alongside antitumor efficacy. Biomarkers that report both tumor PGE₂ activity and systemic prostaglandin levels will be essential to establish safe dosing regimens. And mechanistic work to identify tumor contexts where HPGD reactivation is most likely to yield durable responses (for example, tumors with epigenetic HPGD silencing and high PGE₂ dependence) will increase the chance of a favorable clinical outcome. In sum, Tulimilli, S.V. et al. (11) present 15-PGDH not as a simple oncoprotein or tumor suppressor but as a druggable metabolic node whose therapeutic value will depend on careful engineering of modality, timing, and patient selection to exploit tumor vulnerability while avoiding impairment of normal tissue regeneration.

6. Current translational landscape for 15-PGDH restoration in cancer
 
As discussed previously, multiple direct approaches ranging from gene therapy, targeting epigenetic silencing and microRNAs , and small molecules activators, could be undertaken to restore 15-PGDH activity in cancer cells. Unfortunately, most translational studies to date remain at the experimental pre-clinical level (13-16). Only indirect studies of 15-PGDH upregulation by Vitamin D have reached clinical trials stage for chemoprevention of cancer.
 
Vitamin D upregulates 15-PGDH primarily through a genomic mechanism involving the Vitamin D Receptor (VDR). By acting as a ligand-activated transcription factor, the active form of Vitamin D (calcitriol) directly increases the production of the 15-PGDH enzyme at the mRNA level. Vitamin D supplemented with calcium is known to exert a "metabolic sandwich" effect to aggressively lower PGE2 levels. It not only upregulates 15-PGDH but also downregulates COX2 and EP2 receptor (17-21).
 
To date the clinical studies showed no effect on cancer incidence in the general population although lower incidence could be demonstrated in some subgroups including individuals with normal body mass index (BMI), and potentially African Americans. These studies also showed a small reduction in cancer mortality in the treated group (22,23 ), providing the impetus for employing a more selective 15-PGDH reactivator to avoid the potential confounding effect of Vitamin D, which is highly pleiotropic affecting multiple metabolic pathways (24).

​7. Conclusion
 
15-hydroxyprostaglandin dehydrogenase (15-PGDH) occupies a uniquely complex position at the intersection of regeneration, inflammation, aging, and cancer biology. Across diverse tissues, accumulated preclinical and emerging clinical evidence establishes 15-PGDH as a dominant endogenous brake on prostaglandin E₂ (PGE₂)–dependent repair programs. Inhibition of this enzyme restores physiologic PGE₂ signaling and reproducibly enhances regeneration in skeletal muscle, neuromuscular junctions, cartilage, hematopoietic stem cell niches, and neurovascular units. These effects are achieved not by supraphysiologic stimulation, but by reactivating latent, evolutionarily conserved repair pathways that decline with age or injury.

At the same time, decades of cancer biology research demonstrate that loss of 15-PGDH is a hallmark of tumor progression in multiple malignancies, positioning the enzyme as a bona fide tumor suppressor. This duality defines both the promise and the challenge of therapeutically targeting 15-PGDH. Sustained or systemic inhibition carries a credible, mechanism-based oncogenic risk, while restoration or activation of 15-PGDH represents a rational anticancer strategy with its own potential liabilities related to impaired tissue repair.

The translational path forward therefore hinges on therapeutic-index engineering rather than binary target validation. For 15-PGDH inhibition, the strongest near-term opportunities lie in indications that permit temporal or spatial restriction of drug exposure, including acute injury (stroke, TBI), peri-transplant hematopoietic regeneration, localized osteoarthritis, and possibly episodic treatment paradigms for sarcopenia. The development of agents such as MF-300, and IV-capable analogues like SW209415, demonstrates that pharmacologic modulation of 15-PGDH is feasible in humans and that short-duration or localized dosing strategies are realistic.

Conversely, efforts to restore or augment 15-PGDH activity in cancer highlight a complementary therapeutic direction. Epigenetic reactivation, microRNA targeting, gene-delivery strategies, and combination approaches that simultaneously suppress PGE₂ synthesis and enhance catabolism all represent viable avenues for clinical exploration. In this context, careful patient selection based on tumor PGE₂ dependence and HPGD silencing status will be critical.

Ultimately, 15-PGDH should be viewed not as a unidirectional drug target, but as a context-dependent metabolic node whose manipulation must be tailored to disease biology, treatment duration, and delivery strategy. Future clinical success will depend on rigorous biomarker-guided dosing, long-term safety surveillance, and parallel evaluation of regenerative and oncologic outcomes. If these challenges are met, targeting 15-PGDH—either by inhibition or restoration—has the potential to inaugurate a new class of therapeutics that modulate endogenous prostaglandin metabolism to restore tissue homeostasis across aging, injury, and cancer.

References
 

1. Ho, A. T., Palla, A. R., Blake, M. R., Yucel, N. D., Wang, Y. X., Magnusson, K. E., ... & Blau, H. M. (2017). Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength. Proceedings of the National Academy of Sciences, 114(26), 6675-6684.
2. Palla, A. R., Ravichandran, M., Wang, Y. X., Alexandrova, L., Yang, A. V., Kraft, P., ... & Blau, H. M. (2021). Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength. Science, 371(6528), eabc8059.
3. Bakooshli, M. A., Wang, Y. X., Monti, E., Su, S., Kraft, P., Nalbandian, M., ... & Blau, H. M. (2023). Regeneration of neuromuscular synapses after acute and chronic denervation by inhibiting the gerozyme 15-prostaglandin dehydrogenase. Sci. Transl. Med. 15, eadg1485.
4. Singla, M., Wang, Y. X., Monti, E., Bedi, Y., Agarwal, P., Su, S., ... & Bhutani, N. (2025). Inhibition of 15-hydroxy prostaglandin dehydrogenase promotes cartilage regeneration. Science, eadx6649.
5. Chaudhary, R., Cordova, B. A., Hong, M., Klein, B. R., Contreras, L. A., Rashmil, R., ... & Desai, A. B. (2025). 15-PGDH inhibition enhances hematopoietic regeneration during aging. Stem Cells, sxaf047.
6. Koh, Y., Vázquez-Rosa, E., Gao, F., Li, H., Chakraborty, S., Tripathi, S. J., ... & Pieper, A. A. (2025). Inhibiting 15-PGDH blocks blood–brain barrier deterioration and protects mice from Alzheimer’s disease and traumatic brain injury. Proceedings of the National Academy of Sciences, 122(21), e2417224122.
7. Xu, Y., Li, K., Zhao, Y., Zhou, L., He, N., Qiao, H., ... & Zhao, J. (2024). Inhibition of 15‐hydroxyprostaglandin dehydrogenase protects neurons from ferroptosis in ischemic stroke. MedComm, 5(1), e452.
8. Antczak, M. I., Zhang, Y., Wang, C., Doran, J., Naidoo, J., Voruganti, S., ... & Ready, J. M. (2017). Inhibitors of 15-prostaglandin dehydrogenase to potentiate tissue repair. Journal of medicinal chemistry, 60(9), 3979-4001.
9. Desai, A., Zhang, Y., Park, Y., Dawson, D. M., Larusch, G. A., Kasturi, L., ... & Markowitz, S. D. (2018). A second-generation 15-PGDH inhibitor promotes bone marrow transplant recovery independently of age, transplant dose and granulocyte colony-stimulating factor support. Haematologica, 103(6), 1054.
10. MacConell, L., Shah, A., Mould, D., Lavu, S., & Webster, M. (2025). Phase 1 Evaluation of MF-300: An Investigational First-in-Class Oral Candidate for Sarcopenia. Innovation in Aging, 9(Supplement_2), igaf122-3994.
11. Tulimilli, S. V., Karnik, M., Bettadapura, A. D. S., Sukocheva, O. A., Tse, E., Kuppusamy, G., ... & Madhunapantula, S. V. (2025). The tumor suppressor role and epigenetic regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in cancer and tumor microenvironment (TME). Pharmacology & Therapeutics, 108826.
12. Francica, B. J., Holtz, A., Lopez, J., Freund, D., Chen, A., Wang, D., ... & Dubensky, T. W. (2023). Dual blockade of EP2 and EP4 signaling is required for optimal immune activation and antitumor activity against prostaglandin-expressing tumors. Cancer Research Communications, 3(8), 1486-1500.
13. Kaliberova, L. N., Kusmartsev, S. A., Krendelchtchikova, V., Stockard, C. R., Grizzle, W. E., Buchsbaum, D. J., & Kaliberov, S. A. (2009). Experimental cancer therapy using restoration of NAD+-linked 15-hydroxyprostaglandin dehydrogenase expression. Molecular cancer therapeutics, 8(11), 3130-3139.
14. Backlund, M. G., Mann, J. R., Holla, V. R., Shi, Q., Daikoku, T., Dey, S. K., & DuBois, R. N. (2008). Repression of 15-hydroxyprostaglandin dehydrogenase involves histone deacetylase 2 and snail in colorectal cancer. Cancer research, 68(22), 9331-9337.
15. Monteleone, N. J., Moore, A. E., Iacona, J. R., Lutz, C. S., & Dixon, D. A. (2019). miR-21-mediated regulation of 15-hydroxyprostaglandin dehydrogenase in colon cancer. Scientific reports, 9(1), 5405.
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17. Kanwal, B., Shah, S. S., Shaheen, F., Shiferaw, M. S., Maurya, D., Li, Y., ... & Kovacevic, Z. (2025). The Effects of Vitamin D on the Breast Cancer Tumor Microenvironment. Cancers, 17(23), 3751.
18. Qin, W., Holick, M. F., Sorensen, W., Walker, C. R., & Sauter, E. R. (2016). Vitamin D3 treatment influences PGE2 and TGFβ in normal and increased breast cancer risk women. Anticancer Research, 36(10), 5347-5353.
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20. Moreno, J., Krishnan, A. V., Peehl, D. M., & Feldman, D. (2006). Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway. Anticancer Research, 26(4A), 2525-2530.
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23. Keum, N., Lee, D. H., Greenwood, D. C., Manson, J. E., & Giovannucci, E. (2019). Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials. Annals of Oncology, 30(5), 733-743.
24. Bikle, D. (2009). Nonclassic actions of vitamin D. The Journal of Clinical Endocrinology & Metabolism, 94(1), 26-34.

Introduction
 
In the previous two blogs, we discussed pulsed electromagnetic field therapy (December 17, 2025) and acupuncture (November 15, 2025) as potential treatments for osteoarthritis (OA), and we cited two comparative studies reporting that extracorporeal shock wave therapy (ESWT) was more effective than both modalities (1,2). However, the small sample sizes of these trials, together with conclusions based solely on meta-analyses, make such claims potentially tenuous. Nevertheless, it remains valuable to examine ESWT in greater detail—specifically, to review the clinical evidence supporting its effectiveness and to discuss its proposed mechanisms of action. We also review the range of ESWT devices currently available on the market for both medical professionals and consumers.
 

Two types of shock waves
 
In ESWT, a focused shock wave is a high-pressure, nonlinear acoustic pulse characterized by an extremely rapid rise time (<10 ns), a high positive peak pressure (10–100 MPa), short pulse duration (~1–10 µs), a subsequent tensile (negative-pressure) phase, and a broad frequency spectrum ranging from kilohertz to megahertz. In most focused ESWT devices used in medical practice, shock waves are generated using one of three physical principles: electrohydraulic (spark-gap), electromagnetic, or piezoelectric mechanisms (3).
 
By contrast, some devices produce so-called radial shock waves, which are generated by the impact of a ballistic projectile and result in radially dispersing pressure waves with maximal pressure at the applicator surface rather than at depth. From a physical standpoint, these waves are closer to pressure pulses than to true shock waves, and radial devices are therefore not generally considered genuine shock wave generators. The practical implications of this distinction will be discussed further below when device characteristics are examined.

ESWT device characteristics
 
Five parameters are commonly used to characterize an ESWT device:

1. Energy Flux Density (EFD) is the most important parameter. It represents the amount of energy delivered per unit area per pulse, measured in mJ/mm2. Devices are typically classified as low-, medium-, or high-energy, as shown below.
 
                                               EFD (mJ/mm²)        Classification
                                                   < 0.08                            Low energy
                                                    0.08–0.28                     Medium energy
                                                    > 0.28                             High energy

2. Peak pressure includes both the positive (P⁺) and negative (P⁻) pressure components. P⁺ reflects   the compressive force and is important for mechanotransduction, whereas P⁻ produces cavitation and plays a key role in biological signaling as well as in assessing potential tissue risk. Typical P⁺ values for focused ESWT devices range from 20 to 100 MPa, whereas radial devices operate at much lower pressures, typically 1–10 MPa. That said, peak pressure alone can be misleading because it does not account for pulse duration or focal size.
 
3. Pulse rise time and duration also influence biological effects. In most ESWT systems, rise times are less than 10 ns and pulse durations range from 1 to 10 μs. Shorter pulses tend to deliver high instantaneous mechanical stress, minimize thermal effects, and preferentially activate mechanical signaling pathways.
 
4. Pulse repetition frequency for most devices ranges from 1 to 8 Hz. In clinical practice, the total number of pulses per session vary from 500 to 3000, depending on the indication. While pulse repetition frequency does not alter the EFD, it directly affect overall treatment duration.
 
5. Focal volume and penetration depth represent a major distinction between focused and radial ESWT. In focused ESWT, energy is concentrated within an ellipsoid focal zone located at depths of approximately 10-60 mm. In contrast, radial ESWT delivers its highest energy at the skin surface, with rapid attenuation such that penetration rarely exceeds 1–2 cm. Focused ESWT is therefore often preferred for osteoarthritis—particularly knee osteoarthritis—where therapeutic targets may include deeper periarticular tissues, entheses, and subchondral bone.

Comparing ESWT devices
 
When comparing ESWT devices, the most important features to consider are the type of shock wave (focused vs. radial), the EFD at the focal point (mJ/mm²), and the focal depth and volume. Equally important are pulse reproducibility and whether device parameters are measured and reported in accordance with IEC standards.
 
Clinical studies using ESWT, should at a minimum, specify the EFD and the total pulse count delivered during treatment.
 
Numerous educational videos are available online explaining the differences and clinical roles of focused and radial ESWT. Two accessible examples that provide a useful overview of both techniques—and how they may complement one another—include:

​Clinical Proofs that ESWT is effective in the treatment of knee osteoarthritis

​Multiple randomized controlled trials and meta-analyses (4–8) consistently show that ESWT reduces pain and improves function in patients with knee osteoarthritis when compared with sham treatment or other conservative interventions. In many studies, these benefits persist for weeks to several months. Several trials also demonstrate a dose–response relationship, with medium-energy protocols producing superior clinical outcomes compared with low-energy treatments (9–11). In addition, focused ESWT—which is capable of reaching deeper structures such as subchondral bone—may provide better joint-related outcomes than radial devices (12).
 
A simplified summary of reported EFD ranges and associated biological effects is shown below:

Importantly, the beneficial effects of ESWT may extend even to patients with advanced disease. A recent study by CP, K. et al. (13) reported clinical improvements in patients with Kellgren–Lawrence (K–L) grade 4 osteoarthritis. Similarly, a randomized clinical trial by Choi, I.J. et al. (14) demonstrated reductions in suprapatellar effusion and improvements in inflammatory symptoms following ESWT, providing in vivo support for its anti-inflammatory effects.
 
Evidence for true disease-modifying effects—such as structural preservation of articular cartilage—remains mixed and incomplete. Preclinical studies and mechanistic human data suggest that ESWT can stimulate subchondral bone remodeling and activate anabolic signaling pathways in chondrocytes, which are biologically plausible disease-modifying mechanisms. However, robust long-term randomized controlled trials incorporating quantitative MRI endpoints or histological evidence of slowed cartilage loss are still scarce. Notably, at least one randomized controlled trial (15) reported potential adverse effects on cartilage under a specific low-dose protocol, highlighting that not all ESWT treatment regimens are necessarily structurally protective.
 
In summary, the evidence supporting symptomatic relief from ESWT in knee osteoarthritis is strong, whereas convincing proof of durable cartilage preservation in humans will require more standardized, long-term imaging-based clinical trials.


Comparing ESWT with other therapies for osteoarthritis
 
A systematic review and meta-analysis by Chen, L. et al. (16) compared ESWT with a wide range of treatment modalities across different forms of osteoarthritis. The analysis focused specifically on pain reduction and functional improvement. The overall findings are summarized in the table below.

“+” indicates results favoring ESWT over the comparator; “–” indicates comparable or superior results for the comparator; “?” indicates insufficient or inconsistent evidence. HA: hyaluronic acid; PRP: Platelet Rich Plasma
 
These findings can be contrasted with the results reported by Cao, S. et al. (2), who restricted their analysis to non-pharmacological interventions for knee osteoarthritis—a study discussed previously in the November 15, 2025 blog on acupuncture for knee OA. Selected results from that analysis are reproduced below for comparison.

Efficacy rankings based on the Visual Analog Scale (VAS) pain scores:

shock wave therapy > needle-knife (acupotomy) > laser therapy > acupuncture > ultrasound > exercise > transcutaneous electrical nerve stimulation
 
Efficacy rankings based on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales:

• Pain: shock wave therapy > needle-knife (acupotomy) > laser therapy > acupuncture > exercise > transcutaneous electrical nerve stimulation > ultrasound

 

• Stiffness: laser therapy > exercise > shock wave therapy > acupuncture > needle-knife > ultrasound > transcutaneous electrical nerve stimulation

 

• Physical function: shock wave therapy > laser therapy > needle-knife > acupuncture > ultrasound > transcutaneous electrical nerve stimulation > exercise

 
The two datasets overlap in their comparison of ESWT with ultrasound and acupotomy (needle-knife). For ultrasound, the findings are consistent: ESWT outperformed ultrasound in both analyses. In contrast, the results for acupotomy diverge. Cao, S. et al. reported that ESWT was superior for both pain reduction and functional improvement, whereas Chen, L. et al. found acupotomy to perform as well as—or better than—ESWT in these same outcomes.
 
These discrepancies highlight the need for well-designed, head-to-head randomized controlled trials directly comparing treatment modalities. Meta-analyses based on small, heterogeneous trials with variable protocols and controls have inherent limitations and should be interpreted with appropriate caution.


ESWT Mechanism of Action
 
Clinical studies indicate that ESWT typically employs low- to medium-energy flux densities to elicit beneficial biological responses in osteoarthritis without causing tissue damage. How this mechanical energy interacts with cells and biomolecules—and which molecular pathways translate these interactions into therapeutic effects—is therefore of considerable interest. A clearer understanding of these mechanisms can inform more rational ESWT protocol design tailored to specific patient populations.
 
ESWT delivers very high peak stresses with an extremely rapid rise time to cellular structures, particularly cell membranes. The resulting steep spatial pressure gradients, together with cavitation effects, activate mechanotransduction pathways, many of which have been identified over the past two decades. Most mechanistic studies to date have been conducted in animal models or in isolated cells and tissues derived from cartilage and subchondral bone.

Dose effect, angiogenesis, cartilage/subchondral bone remodeling
 
A clear dose-dependent effect of ESWT was demonstrated by Wang, C.-J. et al. (17) using a surgically induced knee osteoarthritis (KOA) rat model. In this study, an optimal dose of 800 pulses delivered at an energy flux density of 0.22 mJ/mm², administered once or twice weekly, was sufficient to inhibit deterioration of both articular cartilage and subchondral bone in periarticular regions. These effects were assessed using X-ray imaging, histomorphological analysis, and immunohistochemistry.
Articular cartilage integrity was evaluated by immunostaining for collagen type II and matrix metalloproteinase-13 (MMP-13), whereas subchondral bone remodeling and angiogenesis were assessed through immunostaining of von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), bone morphogenetic protein-2 (BMP-2), and osteocalcin.
 
The main biological effects observed in response to ESWT can be summarized as follows:

• Cartilage effects:
  ESWT → ↑ collagen type II, ↓ MMP-13 → improved cartilage integrity
• Subchondral bone and angiogenesis:
  ESWT → ↑ vWF, ↑ VEGF, ↑ BMP-2, ↑ osteocalcin → enhanced angiogenesis and subchondral bone remodeling

 
Effect on bone homeostasis
 
Direct effects of ESWT on bone homeostasis—specifically on osteoblast and osteoclast differentiation—have been reported by Li, B. et al. (18) and Chen, B. et al. (19). Using cultured rabbit bone marrow–derived stem cells, these authors demonstrated that ESWT promotes differentiation toward osteoblasts, as shown by classical histochemical staining and mRNA profiling of osteogenesis-related markers, including alkaline phosphatase (ALP), osteocalcin (OCN), osteoprotegerin (OPG), and runt-related transcription factor 2 (Runx2).
 
In vivo, using a rabbit model of osteoporosis, ESWT increased trabecular bone volume, number, and thickness, while reducing trabecular separation in the femur when compared with untreated controls.
 
To examine effects on osteoclastogenesis, immortalized mouse macrophage RAW264.7 cells induced with receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) were used as a model system. In this context, ESWT inhibited differentiation into osteoclasts, as determined by histochemical staining and reduced mRNA expression of two key osteoclast markers, cathepsin K and dendritic cell–specific transmembrane protein (DC-STAMP). ESWT also suppressed cell proliferation and reduced expression of NFATc1 as well as p65, a subunit of the NF-κB transcriptional complex, indicating that inhibition of NF-κB signaling underlies the anti-osteoclastogenic effect. Consistent with these findings, ESWT increased trabecular bone volume, number, and thickness and decreased trabecular separation in mouse femora.
 
The principal cellular effects of ESWT on bone homeostasis can be summarized as follows:

• Osteoblastogenesis:
  ESWT → ↑ ALP, ↑ OCN, ↑ OPG, ↑ Runx2 → increased osteoblast differentiation
• Osteoclastogenesis:
  ESWT → ↓ cathepsin K, ↓ DC-STAMP → reduced osteoclast differentiation
• Cell proliferation signaling:
  ESWT → ↓ NFATc1, ↓ p65 → ↓ NF-κB signaling → reduced cell proliferation

 
Zhao, Z. et al. (20) identified an additional molecular pathway mediating the effects of ESWT in subchondral bone–derived stem cells. Using primary human stem cells isolated from patients with knee osteoarthritis, the authors showed that ESWT increased colony-forming capacity in a dose-dependent manner. This effect was driven by enhanced proliferation without measurable changes in apoptosis. Although no significant effect on osteogenic differentiation was observed, ESWT strongly suppressed adipogenic differentiation and modestly enhanced chondrogenic differentiation. Expression of cartilage-related markers, including collagen type II and proteoglycans, was consistently higher than in untreated controls.
 
Notably, these phenotypic changes were associated with increased expression of the mechanosensitive co-transcriptional regulators YAP and TAZ and their translocation into the nucleus. YAP/TAZ signaling is well recognized for its role in mechanotransduction, organ size regulation, tissue regeneration, wound healing, and stem cell maintenance.
 
These effects may be summarized schematically as:

• Stem cell fate modulation:
  ESWT → actin stress fiber remodeling → YAP/TAZ nuclear localization → ↑ stem cell proliferation → ↓ adipogenesis, ↑ chondrogenesis → ↑ collagen II, ↑ proteoglycans

 
Finally, it is worth noting the apparent discrepancy between the findings of Li, B. et al. (18), who observed ESWT-induced osteogenic differentiation in healthy rabbit bone marrow stem cells, and those of Zhao, Z. et al. (20), who did not detect osteogenic differentiation in subchondral bone stem cells derived from patients with knee osteoarthritis. Differences in species, tissue origin, and disease state may plausibly account for this divergence and underscore the complexity of translating mechanistic findings across experimental models.

Apoptosis and autophagy
 
The effects of ESWT on apoptosis and autophagy have been demonstrated in a cellular model of osteoarthritis using primary rat chondrocytes stimulated with interleukin-1β (IL-1β) (21). This model was validated by showing that IL-1β downregulated collagen type II expression, a hallmark of cartilage degeneration, and that ESWT was able to reverse this effect.
 
The authors further demonstrated that ESWT inhibited IL-1β–induced apoptosis, as assessed by Annexin V–FITC/propidium iodide flow cytometry. In contrast, autophagy was enhanced, as evidenced by changes in both mRNA and protein expression of key autophagy markers, including Beclin-1, Atg5, LC3B, and p62. This dual effect—suppression of apoptosis alongside activation of autophagy—is consistent with the overall protective role of ESWT in cartilage degeneration.
 
The anti-apoptotic effect of ESWT also aligns with earlier findings reported by Zhao, Z. et al. (22), who observed reduced nitric oxide (NO) levels in the knee joint and synovial fluid following ESWT in a rabbit model of knee osteoarthritis. Given the established pro-apoptotic role of NO in chondrocytes, this observation provides additional mechanistic support.
 
The key molecular effects can be summarized as follows:

• Apoptosis:
  ESWT → ↓ NO → reduced apoptosis
• Autophagy:
  ESWT → ↑ Beclin-1, ↑ Atg5, ↑ LC3B, ↓ p62 → enhanced autophagy

 
Reactive oxygen species (ROS) signaling
 
Building on earlier reports of increased intracellular reactive oxygen species (ROS) following ESWT, Shen, P.-C. et al. (23) used primary porcine chondrocytes to characterize this response in greater detail. They demonstrated a dose-dependent but transient increase in ROS levels, peaking at approximately 10 minutes after treatment and returning to baseline within one hour. The authors identified xanthine oxidase as the primary source of ROS generation.
 
Importantly, this transient ROS burst was followed by increased extracellular matrix (ECM) synthesis, without adverse effects on cell viability or proliferation. Enhanced ECM production was accompanied by increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and ERK1/2, as well as nuclear translocation of nuclear factor erythroid 2–related factor 2 (Nrf2), a key transcription factor regulating cellular antioxidant and detoxification pathways.
These findings suggest that a brief, well-controlled ROS signal acts as a beneficial second messenger rather than a source of oxidative damage in the context of ESWT.
 
The principal signaling events can be summarized as follows:

• ECM synthesis:
  ESWT → transient ROS ↑ → increased ECM production
• MAPK signaling:
  ESWT → transient ROS ↑ → ↑ p-ERK1/2, ↑ p-p38 MAPK
• Antioxidant response:
  ESWT → transient ROS ↑ → Nrf2 nuclear translocation → increased antioxidant production

 
1a,25-Dihydroxy vitamin D3 rapid signaling pathway
 
Using a surgically induced rat model of knee osteoarthritis combined with a proteomic approach, Hsu, S.-L. et al. (24) showed that ESWT treatment (800 impulses delivered at 0.18 mJ/mm² and 4 Hz) optimally induced expression of protein disulfide isomerase–associated 3 (Pdia-3) within two weeks of treatment. Pdia-3 has been implicated as a membrane-associated co-receptor for 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃, calcitriol), which, together with the classical nuclear vitamin D receptor, mediates rapid, non-genomic signaling.
 
This rapid signaling pathway is known to activate voltage-gated Ca²⁺ channels, increase intracellular Ca²⁺ flux, and trigger several downstream kinase cascades (25). Activation of the 1α,25-dihydroxyvitamin D₃ rapid signaling pathway in ESWT-treated articular cartilage and subchondral bone was supported by increased expression of four downstream effectors—ERK1, osteoprotegerin (OPG), alkaline phosphatase (ALP), and matrix metalloproteinase-13 (MMP-13)—all of which are associated with bone remodeling and formation.
 
The proposed signaling cascade can be summarized as follows:

• Vitamin D–related rapid signaling:
  ESWT → ↑ Pdia-3 → activation of 1α,25-dihydroxyvitamin D₃ rapid signaling → ↑ ERK1, ↑ OPG, ↑ ALP, ↑ MMP-13 → enhanced bone formation

 
Vitamin D–related signaling is increasingly recognized as relevant in osteoarthritis because of its central role in regulating calcium homeostasis, bone turnover, and chondrocyte function. Articular cartilage and subchondral bone both express components of the vitamin D signaling machinery, and disturbances in this pathway have been associated with altered bone remodeling, cartilage degradation, and OA progression. Beyond its classical genomic actions, rapid, non-genomic vitamin D signaling influences mechanosensitive pathways, intracellular calcium flux, and kinase activation—processes that are highly responsive to mechanical stimuli. The ability of ESWT to engage this rapid signaling axis therefore provides a plausible mechanistic link between mechanical energy delivery and coordinated biological responses in cartilage and subchondral bone, particularly in the mechanically driven environment of osteoarthritis.

Wnt5a/Ca2+ signaling pathway
 
Evidence for activation of the Wnt5a/Ca²⁺ signaling pathway by ESWT was reported by Yu, L. et al. (26) using both an in vivo chemically induced rat model of knee osteoarthritis and in vitro experiments with bone marrow–derived mesenchymal stem cells (BMMSCs) isolated from rat femur and tibia.
 
Immunostaining of subchondral bone plates from KOA rats treated with radial ESWT (1 bar, 6 Hz, 800 pulses) revealed higher Wnt5a expression compared with both sham-treated KOA rats and normal controls. This increased expression correlated with improved histological morphology, reflected by lower Mankin scores, relative to sham-treated animals.
 
In vitro, BMMSCs exposed to ESWT exhibited a time-dependent increase in Wnt5a expression. Levels peaked approximately 30 minutes after treatment and gradually declined with longer exposure times of up to 3 hours. Quantitative RT-PCR indicated that optimal Wnt5a induction occurred at 0.6 bar with a 30-minute exposure. ESWT also induced expression of several downstream components of the Wnt5a/Ca²⁺ pathway, including calcium/calmodulin-dependent protein kinase II (CaMKII), phospholipase C (PLC), and protein kinase C (PKC), with variable temporal patterns over a 3-hour time course.
 
The proposed signaling sequence may be summarized as:

• Non-canonical Wnt signaling:
  ESWT → Ca²⁺ influx → Wnt5a activation → PLC / PKC / CaMKII signaling → effects on bone and cartilage remodeling (?)

 
The authors attributed the observed improvements in cartilage and subchondral bone morphology following ESWT to activation of the Wnt5a/Ca²⁺ signaling pathway. However, such a conclusion should be interpreted with caution. Wnt5a is a pleiotropic signaling molecule involved in a wide range of biological processes, including embryonic development, inflammation, and cancer. Notably, Wnt5a has also been implicated in osteoarthritis pathogenesis, where it may promote cartilage degradation and inflammation by activating catabolic pathways, increasing matrix-degrading enzymes such as MMPs, and disrupting joint homeostasis (27,28).
 
Taken together, these findings suggest that while ESWT can modulate Wnt5a/Ca²⁺ signaling, the net biological outcome is likely to be highly context-dependent, influenced by dose, timing, tissue state, and disease severity.

 
Mechanistic Summary
 
Taken together, the available mechanistic evidence suggests that ESWT acts as a pleiotropic biomechanical stimulus that engages multiple, interconnected signaling pathways in cartilage and subchondral bone (Figure 1).

At low to medium energy flux densities, ESWT delivers rapid, high-peak mechanical stress that activates mechanotransduction at the cell membrane, leading to downstream modulation of inflammation, apoptosis, autophagy, and tissue remodeling. ESWT promotes angiogenesis and subchondral bone remodeling, enhances osteoblast differentiation while suppressing osteoclastogenesis, and shifts stem cell fate away from adipogenesis toward chondrogenesis. Transient increases in reactive oxygen species function as second messengers that activate MAPK and Nrf2-dependent antioxidant pathways, supporting extracellular matrix synthesis without compromising cell viability. ESWT also engages rapid, non-genomic vitamin D signaling through Pdia-3, linking mechanical stimulation to calcium flux and bone-forming cascades.

Finally, modulation of non-canonical Wnt5a/Ca²⁺ signaling highlights the context-dependent nature of ESWT responses, emphasizing the importance of dose, timing, and disease state. Collectively, these mechanisms provide a biologically plausible framework for the clinical benefits of ESWT in knee osteoarthritis while underscoring the need for carefully optimized treatment protocols.

Common commercially available ESWT devices
 
Commercially available ESWT systems can be broadly divided into two categories: clinical-grade devices intended for use by medical professionals and devices marketed directly to consumers for general wellness applications.
 
Clinical ESWT Devices (Professional Use)
 
Clinical ESWT devices are designed to deliver precisely controlled energy flux densities (EFDs) and pulse frequencies. These systems are capable of generating substantial mechanical forces that can modulate tissue physiology, including effects on subchondral bone remodeling, angiogenesis, and chondrocyte mechanotransduction. As such, their safe and effective use requires appropriate training in dosimetry, anatomical targeting, and patient selection.
 
Improper self-application—particularly without imaging guidance or professional assessment—may result in subtherapeutic treatment or, in some cases, tissue injury. For this reason, focused ESWT devices operating at medium to high EFDs are typically restricted to clinical settings.
 
It is also important to note that there are currently no FDA-approved focused ESWT devices intended for direct consumer or self-use, especially at the energy levels required to reach deep joint tissues such as the knee. Focused shockwave systems are generally regulated as prescription-only medical devices due to safety considerations and the need for clinical oversight. Many are used off-label for osteoarthritis based on clinician judgment and emerging evidence rather than explicit FDA indications.
 
Examples of focused and radial ESWT devices commonly found in outpatient physical therapy, sports medicine, and rehabilitation clinics are listed below. Device parameters—such as pressure or EFD, pulse frequency, and applicator size—are adjustable and tailored to the clinical indication and patient tolerance.

Focused type:
OrthoGold 100 (MTS)
Endopuls FSWT (Enraf-Nonius) 
PiezoWave2® (Richard Wolf)
DolorClast® Focused Shock Waves (EMS Electro Medical System SA)
Emfocus (GZ MTS Electronics Co., Ltd.): Electromagnetic focused ESWT
 
Radial type:
Endopuls 811 (Enraf-Nonius) 
DolorClast® Radial Shock Waves (EMS Electro Medical System SA)
Softshock 2.0 (Medray Laser & Technology): Radial ESWT device.
Z Wave® Q (Zimmer MedizinSystems): Radial ESWT device.
Klinogicare Shockwave Storm Radial (Klinogicare)
PHS Radial Shockwave, PHS6B (PHSDME)
AWT Radial Shockwave Therapy (Hedone/clinics)
INWAVE Radial Shockwave (INWAVE Medical)
MTS SWT9 Radial ESWT System (GZ MTS Electronics Co., Ltd.)
Modus ESWT® Radial Shockwave (Refizo)
 
An example of a modular mixed-use type
Duolith® SD1 Ultra (Storz Medical): A modular system for both focused and radial ESWT with optional Ultrasound diagnostics.

Consumer-Targeted “Shockwave” Devices
 
A separate category includes devices marketed directly to consumers for general wellness, pain relief, or soft-tissue massage. While some of these products advertise “shockwave” technology and adjustable energy output, they are not FDA-cleared for specific medical indications such as osteoarthritis or tendinopathy.
 
Reported energy outputs are typically not standardized to clinical EFD measurements, are rarely independently verified, and lack validation in peer-reviewed clinical trials. These devices generally deliver lower, more variable energy levels rather than those of true therapeutic shock waves. Consequently, they should not be considered equivalent to clinical ESWT systems and should be used with caution.
 
Examples of consumer-market devices include:
 
Shape Tactics Radial Shockwave Therapy Device (Cavitation Machines)
PSP20 Extracorporeal Shock Wave Therapy Machine (Pervita Medical)
Q60A Extracorporeal Shock Wave Therapy (Sheyera)
MODOY ESWT02 (MODOY)
 
Finding a provider of shock wave therapy
 
Primary care doctors, orthopedic surgeons, and physical therapists can offer reliable information or references. Additional resources and platforms include:
 
Shockwave Provider Directories
 
Several private or industry-associated directories list clinics or providers offering shockwave treatments:

• Shockwave Center of America— lists various clinics, including PT practices, chiropractors, and other providers that offer shockwave therapy in different U.S. regions. You can search by location to find providers
• Shockwave Near Me — a web directory where you can search for local shockwave therapy providers and view profiles and reviews.
• Medical Shockwave Institute — searchable list of certified radial and focal shockwave providers.

 
These directories are not exclusively physical therapists, but they include PTs alongside other clinicians.
 
Vendor-Specific “Find a Provider” Tools
 
Some shockwave device manufacturers maintain provider locators through their own channels. For example, SoftWave Clinics site lets patients locate clinics (including physical therapy clinics) that use its technology. These are useful if you know the brand of devices being used in your area.
 
Local Clinic Search and Therapy Networks
 
You can also use generalized health provider search services (not specialty directories) to find ESWT-offering PT practices. For example, JustHealthy.com and similar “find a provider near me” services list nearby clinics offering shockwave therapy based on city or zip code.

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