A new systematic review in Frontiers in Genetics — co-authored by David Sinclair — identified 41 human studies testing interventions against next-generation epigenetic aging clocks. The findings are unusually direct: specific lifestyle, supplement, and pharmaceutical interventions measurably reduce biological age. Here's the full ranked breakdown.
Most supplement marketing is built on animal studies. Or in vitro data. Or "promising early signals."
What Adiv Johnson and David Sinclair published in *Frontiers in Genetics* on May 29, 2026 is different: a systematic review of 41 human interventional studies that measured the effect of specific interventions on next-generation epigenetic aging clocks — the newer, more predictive models that have become central to longevity research.
The headline finding: a diverse set of interventions can measurably reduce biological age in living humans. The list includes obvious entries, some surprising ones, and one that will raise eyebrows.
The original epigenetic clocks — Horvath, Hannum — were trained to predict chronological age from DNA methylation patterns. They were good at that. But they weren't designed to track biological aging in a way that related to mortality risk or health outcomes.
Next-generation clocks changed the objective. Models like DunedinPACE, GrimAge, GrimAge2, PCGrimAge, and PCDNAmTL were trained to predict mortality, morbidity, and health decline rather than just match someone's birth year. The result: these clocks correlate more strongly with all-cause mortality and age-related disease risk than the first-generation models.
This matters for intervention research. A clock that predicts who lives longer is a more meaningful outcome measure than one designed to guess birthdays. When an intervention moves a next-generation clock, there is a real argument that it is modifying biological aging — not just a methylation artifact.
Johnson and Sinclair performed systematic database searches to identify every published human study measuring the effect of any intervention on at least one next-generation epigenetic clock. The full list came to 41 studies across four categories:
1. Pharmaceutical interventions
2. Supplement and lifestyle interventions
3. Non-pharmaceutical clinical and psychosocial interventions
4. Non-significant results — equally important
Here's what moved the needle, and why it matters.
Semaglutide reduced epigenetic age in human studies. This is consistent with what's already known about GLP-1 receptor agonists: they reduce chronic inflammation, improve insulin sensitivity, suppress visceral adiposity, and modify several aging-associated pathways simultaneously. The effect on epigenetic clocks adds a biomarker dimension to a class of drugs already ranked highly for longevity on the basis of metabolic endpoints.
The mechanism is plausibly multi-factorial: weight loss alone is associated with reduced epigenetic age, but GLP-1 receptors are expressed throughout the brain and vasculature, suggesting systemic effects beyond metabolic normalization.
This is the result that will raise eyebrows. Ketamine — used clinically as an anesthetic and increasingly at sub-anesthetic doses for treatment-resistant depression — appeared as an intervention that reduces epigenetic age in human studies.
The likely mechanism involves its acute effects on neuroinflammation, BDNF (brain-derived neurotrophic factor) upregulation, and synaptic plasticity. Chronic neuroinflammation accelerates epigenetic aging; interventions that reduce it may produce measurable clock effects. Whether these findings translate into a practical longevity use case for ketamine is an open question, but the biological signal is worth tracking.
Plasma exchange using umbilical cord plasma reduced biological age on next-generation clocks. This aligns with the parabiosis literature — work from the Conboy lab and others — suggesting that diluting age-associated circulating factors while introducing younger plasma components has measurable epigenetic effects.
The clinical accessibility remains limited and expensive, but the proof-of-concept is strengthening. This is the human data that parabiosis researchers have been building toward.
Exercise reduced biological age on next-generation clocks. The review doesn't disaggregate by exercise type, but the existing literature points toward a combination: Zone 2 cardio for mitochondrial density and insulin sensitivity, and resistance training for muscle preservation and metabolic health. Both likely contribute through different mechanisms — aerobic exercise via VO2 max and mitochondrial biogenesis, resistance training via myokine signaling and glucose handling.
The practical takeaway: 150+ minutes of Zone 2 per week alongside 2–3 resistance sessions is the exercise configuration most consistently supported by longevity biology, and this review adds epigenetic clock data to that case.
A diet high in plants — consistent with the Mediterranean-style diet — reduced epigenetic age. The mechanism includes polyphenol-mediated effects on DNA methylation enzymes, reduced dietary advanced glycation end-product (AGE) exposure, and the anti-inflammatory and microbiome-supporting effects of a high-fiber eating pattern.
Polyphenols from olive oil, berries, and dark vegetables appear to influence the same methylation patterns that next-generation clocks read. The Mediterranean diet's consistent performance across longevity biomarkers is not coincidental — it provides a dense load of these compounds alongside low levels of the processed food inputs that accelerate clock aging.
Caloric restriction reduced biological age — one of the most replicated findings in longevity biology, now confirmed in human epigenetic clock data. The CALERIE trial, which ran the most rigorous long-term caloric restriction intervention in healthy non-obese humans, showed measurable reductions in next-generation clock readings in the restriction group.
For practical implementation, time-restricted eating achieves some of the same metabolic effects — particularly around insulin sensitivity and mTOR modulation — with better long-term adherence than continuous caloric restriction.
Omega-3 supplementation reduced epigenetic age. The VITAL study and subsequent methylation analyses have established that EPA and DHA influence DNA methylation at specific sites associated with immune function and cardiovascular aging. The anti-inflammatory effect of omega-3s — via resolvin and protectin synthesis — likely reduces the chronic low-grade inflammation that drives epigenetic clock acceleration.
Dose matters: the effect signal in human studies is strongest at 2–4 g EPA+DHA daily, consistent with the VITAL trial protocol. Most over-the-counter fish oil provides less than 1 g per capsule — reaching the relevant dose requires either high-concentration products or multiple doses.
A multivitamin-multimineral supplement reduced epigenetic age in human study data. The mechanism is specific: vitamins B12, B6, and folate, along with magnesium, are direct cofactors in one-carbon metabolism — the biochemical pathway that produces the methyl groups used in DNA methylation. Deficiencies in any of these cofactors impair the cell's ability to maintain methylation patterns correctly, which is exactly what next-generation clocks detect.
This is not an argument for arbitrary multivitamin use. It is an argument that nutritional adequacy in the specific cofactors that feed one-carbon metabolism is mechanistically linked to epigenetic aging, and that supplementing them in a verified, bioavailable form may maintain clock performance in ways that dietary intake alone may not.
The review identified additional interventions outside the lifestyle/supplement/drug categories that also reduced epigenetic age. Psychosocial interventions — which address the chronic psychological stress load — showed measurable effects on next-generation clocks.
This is consistent with the mechanistic link between chronic psychological stress and accelerated epigenetic aging: glucocorticoid signaling, sustained sympathetic activation, and the inflammatory consequences of chronic stress all influence methylation patterns. Meditation and mindfulness and strong social connection rank in this platform's top-25 interventions partly for this reason — and this review's data strengthens the argument that their effects are biologically measurable, not just self-reported.
Table 4 of the review is as important as the positive findings. Several interventions tested in human studies did not produce significant changes in next-generation epigenetic clocks. The general pattern from the existing literature suggests that isolated high-dose antioxidant supplementation (Vitamins C and E alone) and certain short-duration or low-intensity interventions often fail to move these clocks meaningfully.
This matters. It means next-generation epigenetic clocks are not uniformly responsive to everything with an anti-aging label — which is exactly what you want from a biomarker that's supposed to mean something. The interventions that do move them appear to be ones that address fundamental aging pathways: inflammation, metabolic dysregulation, mitochondrial function, and nutritional adequacy in core cofactors.
Before translating this review into a personal protocol, three caveats:
Study quality varies. A systematic review collects all human studies meeting the criteria — including small pilots, short interventions, and studies without adequate control arms. Positive findings are directionally informative but require replication in larger RCTs to establish reliable effect sizes.
Clock choice matters. Not every study used the same next-generation clock. DunedinPACE measures the *pace* of aging and is particularly sensitive to lifestyle interventions. GrimAge2 is trained on mortality prediction and may respond differently to the same intervention. An intervention that moves one may not move the other equivalently.
Confounding in lifestyle studies. Exercise trials can't be blinded. Diet studies depend on dietary recall. The lifestyle and supplement findings should be read as consistent with a causal interpretation, not proof of precise effect sizes.
Taking the review's findings at face value, the evidence-backed stack is:
Exercise: Zone 2 cardio at 150+ min/week and resistance training 2–3x/week
Diet: Mediterranean-pattern eating with caloric restraint — plant-rich, high in polyphenols, low in processed inputs
Supplements: Omega-3 (EPA/DHA) at 2–4 g/day, a comprehensive multivitamin covering B12, folate, D3, and magnesium in bioavailable forms
Pharmaceutical (where clinically appropriate): GLP-1 agonists for individuals with metabolic risk factors who qualify
These are also — not coincidentally — among the highest-ranked interventions on this platform. The GlyNAC protocol (glycine + NAC) and quercetin-based senolytic protocols address related mechanisms and are worth considering alongside this core stack.
The consistent finding across longevity biology — from ITP mouse trials to human epigenetic clock studies — is that the same interventions keep appearing at the top of the evidence hierarchy. This review, co-authored by David Sinclair at Harvard, adds systematic human evidence to a picture that is becoming increasingly coherent.
Johnson AA, Sinclair DA. Turning back time: a comprehensive list of interventions that decrease next-generation epigenetic aging clocks in humans. *Frontiers in Genetics*. 2026;17. https://doi.org/10.3389/fgene.2026.1836446