Governing aging rate indicators from clinical trials to clinical use

Dr Michael S. Ringel, Life Biosciences, USA; Dr Carolyn B. Ringel, Harvard Medical School, USA — Biomarkers of aging can inform drug trials and clinical decisions as supportive evidence while formal validation continues.

DOI: https://doi.org/10.25453/plabs.33854755

Published on September 17th, 2026

 Introduction 

Recent advances in molecular and physiological biomarkers have created the prospect that an individual’s rate of biological aging could be measured over short timescales (1, 2). If realized, such measures could facilitate development of gerotherapeutics (i.e., agents designed to address multiple age-related diseases or aging itself) and support more personalized treatment decisions. They may be particularly valuable for preventative therapies used before symptoms manifest, when few other sources of information are available. In their recent Frontiers in Science article, Austad et al. argue that aging rate indicators (ARIs) could accelerate gerotherapeutic research and clinical trials (2). Although the lead article focuses on ARIs, many of the same policy principles apply to aging biomarkers more broadly. Accordingly, we therefore consider this broader set of biomarkers as a whole, focusing on how uncertainties surrounding their use and the gerotherapeutics they may enable raise special considerations for clinical trials and clinical care. Given the rapidly increasing interest in gerotherapeutics (3), assessing these policy implications is timely. 

Clinical trials 

Drug approval is typically based either on direct demonstration of clinical benefit or validated surrogate endpoints that reliably predict clinical outcomes. The evidentiary standards for surrogate endpoint qualification are intentionally high, reflecting numerous examples in which biologically plausible biomarkers failed to translate into clinical benefit, such as the failure of high-density lipoprotein (HDL)-raising therapies. United States Food and Drug Administration (FDA) guidance emphasizes mechanistic understanding, epidemiological evidence, and evidence from multiple clinical trials showing that intervention-induced changes in the surrogate predict clinical outcomes (4). Similarly, a European Medicines Agency (EMA) workshop presentation on surrogate endpoint validation emphasizes biological plausibility, epidemiological evidence, interventional evidence across studies, and quantitative predictiveness (5). 

Some commentators have argued that surrogate endpoint qualification requirements should be relaxed, with broader reliance on conditional approvals and post-marketing evidence generation, particularly in the aging field where long follow-up may be required. Such proposals reflect a legitimate tension between respecting patient autonomy and providing timely access to potentially beneficial therapies, on the one hand, and requiring evidence of safety and efficacy, on the other. 

The history of obesity interventions illustrates the value of rigorous standards. For decades, weight-management products with limited supporting evidence were widely marketed, and many proved ineffective or unsafe (6). By contrast, therapies such as glucagon-like peptide 1 (GLP-1) receptor agonists demonstrated substantial benefits in rigorous clinical testing. 

Similar challenges could emerge if biomarkers of aging were treated as surrogate endpoints before adequate validation. The concern is not merely theoretical: there is already a large market for longevity supplements despite limited clinical evidence for many products (7). Although some have argued that deficiencies in pre-approval evidence could be mitigated through post-marketing data collection, the experience with marketed agents proposed as gerotherapeutics, such as rapamycin, metformin, spermidine, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, suggests that definitive evidence regarding effects on multimorbidity or longevity may remain limited despite years of monitoring. 

At the same time, biomarkers of aging face unique challenges because multimorbidity outcomes are complex to measure and preventative therapies may take years to yield clinical outcomes. Some biomarkers nevertheless have evidence supporting their biological relevance. For example, DunedinPACE, a DNA methylation measure of the pace of aging, is associated with mortality, morbidity, and functional decline (8), responds appropriately to interventions (9), captures biological processes involved in aging (10, 11), and shows promise in clinical settings (12). For these reasons, an appropriate intermediate position may be for clinical trial sponsors to use biomarkers of aging as secondary or exploratory endpoints and for regulators to consider them, where appropriate, as supportive evidence in approval decisions (13). 

Clinical care 

The potential use of biomarkers of aging in clinical care settings raises several issues: the degree of certainty required if biomarkers are used to inform decisions; communication with patients about uncertainty; protection of patient privacy; and, if biomarkers are used to inform decisions about gerotherapeutics, the ethical and policy implications of the therapies themselves. 

Given the evidentiary requirements for validation of surrogate endpoints, it may be years or decades before many biomarkers of aging are validated. Deferring all use in clinical care until validation is complete could mean overlooking potentially useful information in the interim. At the same time, premature implementation without a better understanding of biomarker performance—including measurement variability, longitudinal stability, and the degree to which biomarkers predict individual outcomes—could mislead physicians and patients. This suggests a near-term intermediate position in which physicians use better-supported biomarkers as adjunctive information while additional evidence accumulates. This could be left to the discretion of individual providers, but another potential model would require or recommend that providers be accredited and participate in a process for collecting and sharing patient data before using such biomarkers in clinical decision-making. This is similar in principle to how South Korea manages access to certain advanced therapies under the Advanced Regenerative Bio Act (14). 

Related questions arise regarding how physicians should communicate the uncertainty associated with these measures, including their incomplete clinical validation and limitations in predicting outcomes for individual patients. Consistent with established principles of biomedical ethics, respect for patient autonomy calls for transparent communication of potential benefits, risks, uncertainties, and alternatives to enable informed decision-making (15). 

A further concern is how information derived from biomarkers of aging may be used in employment, insurance underwriting, and other non-medical contexts. In the United States, the Affordable Care Act (ACA) prohibits health insurers from denying coverage or charging higher premiums because of pre-existing conditions, although how these protections would apply to aging biomarker results is less clear. The Health Insurance Portability and Accountability Act (HIPAA) protects medical information held by covered entities, but information generated through at-home or other private testing may fall outside its scope. Moreover, protections in other contexts come mainly from a patchwork of laws that do not always extend to life, long-term care, or disability insurance or to employment decisions (16). In the European Union, the General Data Protection Regulation (GDPR) provides protections for health-related personal data, although national laws and insurance systems vary (17). Given this legal uncertainty, patients should be informed of the potential financial and privacy risks of collecting aging biomarker data. 

Lastly, a major potential use of biomarkers of aging is to enable the development and deployment of gerotherapeutics. Assessments of the policy implications of biomarkers of aging should therefore also consider the downstream impacts of resulting therapies. A full discussion is beyond the scope of this article but available elsewhere (18, 19). Relevant concerns include issues of justice (e.g., equity, resource allocation, and financial and environmental sustainability), societal effects (e.g., impact on institutions, and potential stagnation), and existential questions (e.g., the perceived unnaturalness of intervention and the meaning of life). Many, although not all, of these concerns can be addressed by governance mechanisms developed for other novel therapeutics. 

Recommendations 

Based on these considerations, some preliminary recommendations are: 

• Regulators should establish guidance defining how biomarkers of aging may be incorporated into clinical development programs as supportive evidence and what evidence would be required for their qualification as validated surrogate endpoints. 

• Pharmaceutical companies and health systems should expand prospective data collection on long-term clinical outcomes associated with candidate gerotherapeutics and on the predictive accuracy of biomarkers of aging. Such data can help clarify treatment effects, support biomarker validation, and inform the design of conditional approval pathways, where warranted. 

• Medical associations should develop clinical guidelines covering the interpretation of biomarker results, transparent communication of uncertainty, and, where appropriate, standards for provider accreditation and secure collection and sharing of patient data. Patients should be informed about potential benefits, risks, and alternatives. 

• Lawmakers should address the existing heterogeneity and uncertainty regarding the use of biomarker information to avoid unintended consequences in employment, insurance, and other contexts. In the United States, one potential approach would be to extend protections similar to those provided by the Genetic Information Nondiscrimination Act (GINA) to non-genetic biomarkers and address remaining gaps in life, long-term care, and disability insurance. 

• Policymakers should engage patients and the public in considering the broader justice, social, and existential concerns raised by gerotherapeutics, including how to ensure equitable access to future therapies and associated biomarker testing.  

Research into gerotherapeutics is expanding rapidly, and ARIs and other biomarkers of aging may help guide this work. Translating research into patient benefit will require balancing timely access against the risks arising from uncertain validity. Privacy protections and informed consent will also require attention as biomarkers move beyond research settings. Many of these issues have precedents in other emerging technologies. Principles of transparency, informed consent, risk–benefit balance, and a clear focus on patient value can policy development as the field evolves. 

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Acknowledgements  

We gratefully acknowledge input from Steve Austad on the manuscript. 

Disclaimer 

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations. 

Conflicts of interest 

Michael Ringel is affiliated with Life Biosciences, Hevolution Foundation US, American Federation for Aging Research, Sheba Longevity Clinic, and Applied Longevity Intelligence Service. Carolyn and Michael Ringel are married. 

Copyright statement 

Copyright: © 2026 Michael S. Ringel and Carolyn B. Ringel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in Frontiers Policy Labs is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.     

Generative AI statement 

The authors declared that generative AI was not used in the creation of this manuscript. 

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