Why epigenetic clocks may fail to measure anti-aging effects

“It is not easy to distinguish Type 1 from Type 2, but a clock based on a mixture of Type 1 and Type 2 methylation is likely to produce inconsistent and misleading results, when applied to anti-aging technologies.”

BUFFALO, NY — June 10, 2025 — A new research perspective was published in Aging (Aging-US) Volume 17, Issue 5, on May 5, 2025, titled “Methylation clocks for evaluation of anti-aging interventions.”

In this perspective article, Dr. Josh Mitteldorf explores how current epigenetic clocks—used to estimate biological age—might mislead scientists trying to evaluate anti-aging therapies. The paper challenges a widespread assumption: that all changes in DNA methylation with age are equally valid for measuring biological decline. Dr. Mitteldorf proposes that failing to distinguish between different types of epigenetic changes could lead to inaccurate conclusions, potentially even favoring treatments that reduce repair processes rather than extend healthy lifespan.

Methylation clocks have become a popular tool in aging research. These clocks use patterns of DNA methylation, a form of gene regulation that changes over time, to predict a person’s biological age. Because human aging trials are long and expensive, these clocks offer a faster way to evaluate whether a therapy slows or reverses aging. However, this article warns that not all methylation changes are equal in meaning or effect.

The perspective identifies two main categories of methylation changes that occur with age. One type, called ‘Type 1,’ seems to support the idea that aging may be programmed, with gene activity changing in ways that could cause damage, such as more inflammation or increased cell loss. The second type, “Type 2,” involves increased gene activity aimed at repairing age-related damage. If a therapy reduces the activity of Type 2 genes, it may appear to slow aging while actually interfering with the body’s repair response.

“Paradoxically, an intervention that “sets back” the body’s methylation clock to a younger state is shutting off vital repair mechanisms, so it is likely inimical to health and longevity.” 

This distinction is important because most methylation clocks, including popular models like GrimAge, do not separate these two types. As a result, they may incorrectly suggest that a treatment is reversing aging when it is only suppressing beneficial repair mechanisms. According to Dr. Mitteldorf, this could lead researchers to draw the wrong conclusions and unintentionally slow down progress in anti-aging research.

The author also addresses a growing trend in the scientific community that aims to explain age-related methylation as random drift rather than directed change. In a pilot analysis using publicly available data, Dr. Mitteldorf attempted to construct a clock based purely on stochastic, or random, changes. The results showed a weak correlation with age, suggesting that random drift is an unreliable basis for assessing biological aging.

Dr. Mitteldorf argues that most age-related methylation changes are likely intentional and regulated, rather than random. If so, epigenetic clocks must be refined to reflect the biological purpose behind methylation shifts. Without distinguishing between changes that indicate damage and those that indicate repair, current clocks may not only mismeasure age but also misguide intervention strategies.

This article highlights the urgent need to improve how methylation data are interpreted before such clocks can reliably assess anti-aging therapies. A clearer understanding of these molecular patterns could help reshape the future of aging research and therapy evaluation.

Read the full paper: DOI: https://doi.org/10.18632/aging.206245

Corresponding author: Josh Mitteldorf – aging.advice@gmail.com

Keywords: methylation, stochastic entropy, programmed aging, aging clock, epigenetic clock

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