Turning back the epigenetic clock: Can we reverse ageing?

17 November 2025 • By Diana Turner • #Exclusive Content

In this article, based on a session at Life Sciences Baltics 2025, Diana Turner reviews the latest research into epigenetics and rejuvenation.

An epigenetic clock is a biomarker of ageing that can be used to estimate ‘biological age’. The method relies on the modifications to DNA that change over time and regulate how genes are expressed. Many epigenetic clocks are based on the analysis of DNA methylation, measuring the accumulation of methyl groups to DNA molecules. More recently, new epigenetic clocks have been developed based on the histone code, chromatin accessibility and nucleosome positioning.

There are four generations of epigenetic clocks¹. The earliest, such as Horvath and Hannum’s clocks, were trained on chronological age. The second generation, such as Levine’s PhenoAge and Lu & Horvath’s GrimAge and GrimAge2, were trained on multiple biomarkers and smoking. In the third generation, Belsky measures the pace of epigenetic ageing rather than a static age in DunedinPACE, while in the fourth generation, causal clocks use Mendelian randomisation to select sites that are putatively causal in general ageing, adaptation to ageing and age-related damage.

With an ageing global population and ever-increasing rates of age-related diseases, the role of epigenetic clocks is becoming more important. Their use is accelerating rejuvenation and regenerative drug discovery, allowing researchers to screen compounds and identify drugs that slow or reverse the ageing process, and potentially speeding up the development of treatments for age-related diseases.

The studies discussed below were shared in the ‘MultiOmics – key to personalised health and research’ session at Life Sciences Baltics 2025.

Molecular biomarkers of ageing

One of the pioneers of epigenetics, Steve Horvath PhD, is the first to speak in the session. He is now Principal Investigator at Altos Labs, which aims to restore cell health and resilience through cell rejuvenation to reverse disease, injury and the disabilities that can occur throughout life.

In discussing whether ageing can be reversed, Horvath refers to research by Jesse Poganik and colleagues which finds that biological age is fluid and exhibits rapid changes in both directions². At epigenetic, transcriptomic, and metabolomic levels, their study showed that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. They also identify transient changes in biological age during major surgery, pregnancy, and severe Covid-19 in humans and/or mice. Together, the authors argue that these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress.

So, is there a way to reverse ageing through drugs or other therapeutic interventions? Horvath first looks at plasmapheresis, a medical procedure that separates plasma from blood cells, potentially removing pro-ageing factors from circulation, and which has been associated with rejuvenating effects by altering biomarkers of ageing. However, the evidence is not available in humans. A study by Pavel Borsky and colleagues aimed to assess whether plasmapheresis without volume replacement with young plasma or albumin affects epigenetic age and other biomarkers in healthy adults³. However, no significant epigenetic rejuvenation was observed based on epigenetic clock measurements. In fact, plasmapheresis was associated with increases in DNAmGrimAge, the Hannum clock, and the Dunedin Pace of Aging, indicating that it may accelerate epigenetic ageing.

Horvath moves on to a study which aimed to evaluate semaglutide’s impact across multiple generations of DNA-methylation clocks in a Phase IIb trial in adults with HIV-associated lipohypertrophy⁴. The researchers found that 11 organ-system clocks showed concordant decreases with semaglutide, most prominently inflammation, brain and heart, providing the first clinical-trial evidence that semaglutide modulates validated epigenetic biomarkers of ageing.

Horvath suggests the mechanism of action could be semaglutide’s ability to reduce visceral fat which may mitigate adipose-driven pro-ageing signals and reverse obesogenic epigenetic memory. However, he cautions that the study has not yet been peer reviewed and that additional validation is needed.

Horvath also highlights evidence that vigorous physical activity can reverse ageing, at least temporarily. A paper by Brooke et al discusses whether epigenetic clocks can offer new pathways for developing useful biomarkers that enhance training management in professional soccer⁵. The researchers revealed that vigorous physical activity was found to rejuvenate epigenetic clocks, with significant decreases in DNAmGrimAge2 and DNAmFitAge observed immediately after games. The study also suggests a potential link between DNA methylation patterns and injury occurrence. Overall, the study suggests that DNA methylation-based biomarkers may have applications in monitoring athlete performance and managing physical stress.

Treatments for immune system regeneration and human longevity

Next on the programme is Robert Brooke, CEO at Clock Foundation, a non-profit aiming to make epigenetic ageing clocks more accessible for use with preclinical and clinical studies.

Brooke focuses on the role of the thymus in the immune system and the impact of thymus removal on disease risk and mortality. In a New England Journal of Medicine study, the researchers evaluated the risk of death, cancer, and autoimmune disease among adult patients who had undergone thymectomy⁶. They found that all-cause mortality and the risk of cancer were higher among patients who had undergone thymectomy than among controls. A total of 1420 patients who had undergone thymectomy and 6021 controls were included in the study. At five years after surgery, all-cause mortality was higher in the thymectomy group than in the control group (8.1% vs. 2.8%), as was the risk of cancer (7.4% vs. 3.7%). Thymectomy also appeared be associated with an increased risk of autoimmune disease when patients with preoperative infection, cancer, or autoimmune disease were excluded from the analysis.

Brooke goes on to ask if thymic rejuvenation can result in the opposite, a reversal of epigenetic ageing. With findings published in 2019, the TRIIM (Thymus Regeneration, Immunorestoration, and Insulin Mitigation) trial at Stanford University showed evidence of improved thymic structure and function. The trial, sponsored by Intervene Immune, investigated the possibility of using recombinant human growth hormone (rhGH) to prevent or reverse signs of immunosenescence in a population of 51–65‐year‐old putatively healthy men⁷. The researchers observed protective immunological changes, improved risk indices for many age‐related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after one year of treatment (−2.5‐year change compared to no treatment at the end of the study). The GrimAge predictor of human morbidity and mortality showed a two‐year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment.

A new trial TRIIM-X is currently ongoing, with a predicted completion date of December 2025, and has so far shown a 20% increase in physical fitness measures and reduction in body fat.

The authors conclude their paper: “Although epigenetic age does not measure all features of ageing and is not synonymous with ageing itself, it is the most accurate measure of biological age and age‐related disease risk available today. This justifies the use of epigenetic clocks to estimate the effectiveness of putative ageing interventions on a practical timescale. The present study strongly supports this approach, having demonstrated regression of epigenetic age with high statistical significance even in a one‐year pilot trial involving only nine volunteers.”

References

About the author:

Diana Turner is Deputy Editor of DDW. She has 20 years’ experience in both print and digital editorial roles for B2B publications dedicated to the life sciences sector, including medical and pharmaceutical industry journals/magazines.