The Long Ride with Greg Pallone
In 2013, a UCLA geneticist named Steve Horvath published something unusual in science: a scientific paper authored by a single author.
In a field where research papers typically list entire teams, Horvath worked alone. What he had found was unexpected enough that he needed to be certain it was his own conclusion before sharing it with the world.
The paper, published in Genome Biology, described a method for estimating the biological age of any human tissue — not the age on your birth certificate, but the age your cells appear to be, as measured by chemical patterns in your DNA.
The discovery was called, appropriately, the Horvath Clock. It launched a field that has since produced more than a dozen competing and complementary biological age measures, generated hundreds of clinical studies, and fundamentally changed how researchers think about the relationship between how long you have lived and how old your body is.
For readers of The Long Ride, this matters in very practical terms. Your chronological age is fixed, but your biological age is not. The gap between them may be the most important health number you have never measured.
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To understand what Horvath discovered, it helps to understand what DNA methylation is — and why it changes.
Your DNA is not simply an instruction set that remains constant from birth. It is a dynamic document, continuously modified by chemical tags called methyl groups that attach to specific sites along the molecule. These tags act like volume controls on gene expression — turning certain genes up and others down — and they accumulate in predictable patterns as you age. Methylation patterns in a 60-year-old consistently differ from those in a 30-year-old, in ways that transcend ethnicity, sex, and lifestyle.
What Horvath found was even more surprising. He analyzed 8,000 samples across 51 tissue and cell types and discovered that 353 specific sites in the human genome — known as CpG sites — changed with age in a pattern consistent enough across all tissue types to serve as a universal biological age estimate. Your blood, your brain, your liver, your colon — all tell roughly the same methylation story. He called the resulting measure DNAmAge, or DNA methylation age. The shorthand became known as the Horvath Clock.
The clock’s most striking property was that it deviated from chronological age in biologically meaningful ways. People whose DNAmAge was older than their chronological age — whose clocks ran fast — faced a meaningfully higher mortality risk. People whose clocks ran slow lived longer and in better health.
Horvath found that five percent of the population ages at a measurably accelerated biological rate, resulting in a 50 percent higher risk of death at any given age. These individuals can follow every healthy lifestyle guideline and still carry elevated biological risk that appears only in the methylation data.
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Horvath’s 2013 clock was the first. It is not the last, and in some respects, it is not the most useful for the questions that matter most to older adults. Understanding what the different generations of clocks measure — and what it means when they disagree — is where the field becomes genuinely interesting.
The first-generation clocks, including Horvath’s original and the contemporaneous Hannum clock, were calibrated to chronological age. They answer one question: how old does your DNA look?
The second generation — including PhenoAge, developed by Morgan Levine, and GrimAge, developed by Horvath and his collaborator Ake Lu — were calibrated to health outcomes and mortality. They answer a different question: based on your methylation pattern, how much biological life do you have left?
GrimAge, in particular, has emerged as one of the strongest predictors of all-cause mortality.
The most recent development is DunedinPACE, developed at Duke University, which functions not as a biological age estimate but as a speedometer. It does not tell you how old you are. It tells you how fast you are aging right now — this month, this year. A DunedinPACE score below 1.0 means you are aging slower than the population average. Above 1.0 means you are aging faster. It is arguably the most actionable of the existing measures for someone trying to change their trajectory.
When these clocks disagree — when GrimAge says one thing and DunedinPACE says another — the disagreement is information, not an error.
Research by Jesse Poganik and colleagues has established that biological age is fluid, not fixed. It shifts in both directions in response to physiological stress and recovery. Major surgery temporarily accelerates biological age. Pregnancy accelerates it, then reverses the effect. A sustained period of poor sleep, chronic stress, or overtraining measurably increases the pace of aging. The clocks are not a verdict. They are a readout of where you currently are — and whether the direction is right.
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Here is where the popular health conversation diverges from the research.
Walking 10,000 steps a day is good for you. The cardiovascular, metabolic, and psychological benefits of consistent daily movement are well documented. However, 10,000 steps — or any similar measure of general physical activity — does not appear to move the epigenetic clock as structured exercise does.
A 2025 research perspective published in the journal Aging, led by Takuji Kawamura at Tohoku University, reviewed the evidence and drew a clear distinction.
General physical activity — walking, household tasks, light movement — provides health benefits but has weaker effects on epigenetic aging than structured exercise routines that are planned, repetitive, and goal-directed. Physical fitness, particularly high cardiorespiratory capacity, is closely associated with slower epigenetic aging, unlike step counts.
The specific finding worth understanding: sedentary middle-aged women who completed eight weeks of combined aerobic and resistance training reduced their epigenetic age by two years. Not their risk of disease. Their measured biological age. Eight weeks. The intervention was structured, intentional, and intensity-driven — not a daily step target.
This is the distinction the wellness press tends to flatten.
Movement is not exercise.
Volume is not intensity.
The epigenetic clock responds to the stimulus that challenges the body’s systems, not merely to the activity that keeps them ticking over.
For readers in their sixties and seventies who already walk regularly, this is not a reason to stop. It is a reason to add the structured component that walking alone cannot provide.
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Of all the findings in the biological aging literature, the one that surprised me most — and that I find most relevant to The Long Ride’s readership — is the direct epigenetic evidence of the health impact of social connection.
Two studies published in 2024 examined the link between loneliness and epigenetic aging. The larger study used data from the Health and Retirement Study, following 4,018 US adults who had provided blood samples for DNA methylation analysis.
Five epigenetic clocks were used to assess methylation profiles. The finding was unambiguous: higher levels of loneliness were significantly associated with accelerated epigenetic aging across multiple clock measures.
The lonely participants were not merely unhappy. Their biological clocks were running faster.
This finding matters because it is not indirect. It is not loneliness predicting poor sleep, which predicts worse health, which predicts shorter life. It is loneliness directly imprinted in the DNA methylation pattern.
The molecular evidence for social connection as a health variable is now as strong as that for many pharmaceutical interventions.
I wrote about loneliness earlier in this series — the Surgeon General’s advisory, the cardiovascular data, and the vulnerability of recently retired men whose social architecture was built around work.
The epigenetic research adds another layer to that picture, one I think is worth highlighting: isolation is not just emotionally costly. It is biologically accelerating your aging. The clock is keeping an honest account.
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The relationship between weight loss and biological age is more nuanced than most health articles suggest — and more relevant to the specific demographic of my subscribers.
A 2025 study published in Nutrients examined biological age in three groups: adults of normal weight, adults with obesity, and adults with obesity following a very low-calorie ketogenic diet.
Three epigenetic clocks — Horvath, Hannum, and Levine — were used to assess biological age across all groups. The findings were consistent across all three measures: obesity was associated with accelerated biological aging, and dietary weight loss slowed that acceleration.
The mechanism matters here, and it is not simply mechanical. The primary pathway by which excess body weight accelerates the biological clock is chronic inflammation. Adipose tissue — fat, particularly visceral fat — is not inert. It is metabolically active and produces inflammatory signals that circulate throughout the body, creating a sustained, low-grade inflammatory environment that drives epigenetic aging.
Losing weight reduces the inflammatory load, which slows the clock.
This has implications beyond the obvious. For adults in their sixties who have gained weight since retirement — I noticed it in myself in the first two years after I sold the business, the particular combination of less structure, more sedentary time, and the comfort of a good dinner becoming a nightly habit — the epigenetic data makes the case for weight management in terms that go beyond aesthetics or even cardiovascular risk. Excess weight accelerates aging beyond what your chronological age would predict. Addressing it moves the clock in the other direction.
The GLP-1 research intersects here in a way worth noting. The weight-loss and anti-inflammatory effects of semaglutide and tirzepatide are now being studied for their potential epigenetic impact. Early findings suggest that meaningful weight loss and reduced systemic inflammation may produce measurable biological age reversal on the clocks. This is an area to watch closely.
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The interventions the research points to are the same ones this series has been building toward. What the biological clock adds is the molecular explanation for why they work — not just at the organ level, but at the cellular level.
Structured exercise combining aerobic and resistance training is the strongest single modifiable factor identified in the current literature. The eight-week RCT reporting two years of biological age reversal is the headline finding, but it sits within a consistent body of evidence showing that cardiorespiratory fitness and muscle mass are independently associated with slower epigenetic aging.
The multi-domain lifestyle approach comes second. A randomised controlled trial of 43 healthy men aged 50 to 72 found that an eight-week programme combining diet, sleep, exercise, and relaxation was associated with a 3.23-year reduction in measured biological age compared with controls. No single element drove the effect; the combination was the intervention. This finding is significant because it aligns directly with what the rest of this series has described — not one lever, but several, pulled consistently.
Social connection now has direct epigenetic evidence, not just downstream health data. And sleep, which The Long Ride will address in a dedicated piece, has been shown to accelerate DunedinPACE when disrupted and slow it when optimised.
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Steve Horvath is now the principal investigator at Altos Labs, a company focused on cellular rejuvenation — specifically, on whether biological aging can not only be slowed but also reversed. In 2025, he co-authored a review with Cynthia Kusters in the Annual Review of Public Health arguing that epigenetic clocks hold genuine promise for preventive medicine, early detection of chronic conditions, and monitoring the effectiveness of interventions aimed at improving population health.
That last phrase is the one I keep returning to. Monitoring the effectiveness of interventions. The clock is not just a verdict. It is a feedback mechanism. A way of knowing whether what you are doing is working — not in ten years, when the outcome becomes visible, but now, in the methylation pattern your cells write every day.
The number on your birth certificate is not negotiable. The number your biology is writing is.
I find that distinction more motivating than almost anything else in this series. The research is not telling you how old you are. It is telling you what you can still do about it.
Biological age testing is becoming commercially available through companies including TruDiagnostic, Elysium Health, and others. Results should be interpreted with a physician familiar with the field. The clocks are powerful predictors but not diagnostic tools, and no single measurement should be acted on in isolation.
Research & sources referenced in this piece
Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome Biology, 14, R115. DOI: 10.1186/gb-2013-14-10-r115
Kusters, C.D.J. & Horvath, S. (2025). Quantification of Epigenetic Aging in Public Health. Annual Review of Public Health, 46, 91–110. DOI: 10.1146/annurev-publhealth-060222-015657
Fitzgerald, K.N. et al. (2021). Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial. Aging, 13(7), 9419–9432. PMC8064200.
Kawamura, T. et al. (2025). Exercise as a geroprotector: focusing on epigenetic aging. Aging. DOI: 10.18632/aging.206278
Beam, C.R. et al. (2024). Loneliness and epigenetic age acceleration. Journal of Gerontology B: Psychological and Social Sciences, 79(12), gbae169.
Freilich, S. et al. (2024). Associations between loneliness, epigenetic aging, and multimorbidity through older adulthood. Journal of Gerontology B: Psychological and Social Sciences, 79(12).
Izquierdo, A.G. et al. (2025). Epigenetic aging acceleration in obesity is slowed down by nutritional ketosis following very low-calorie ketogenic diet (VLCKD). Nutrients, 17(6), 1060. PMC11945372.
Ammous, F. et al. (2025). Physical activity is associated with decreased epigenetic aging: findings from the Health and Retirement Study. Journal of Cachexia, Sarcopenia and Muscle, 16(3), e13873. PMC12163535.
eBioMedicine longitudinal multi-cohort study (December 2025). Smoking, BMI, glucose, blood pressure, and physical activity as drivers of epigenetic aging pace.
Poganik, J.R. et al. Biological age is increased by stress and restored by apheresis. Nature Aging. Referenced in Life Sciences Baltics 2025 session by Steve Horvath.
Note: verify all citations before publication. The epigenetic clock field is moving rapidly — check for updated GrimAge2 and DunedinPACE findings between drafting and publishing.
The encouraging message for everyone, including retirees, is that small changes in our daily lives can make a surprisingly positive difference.
This is really interesting! I’m 59 and suddenly thinking about mortality and what kind of future I want, and this intersected with a number of things on my mind. Thanks!