The Clock is Ticking, But is it Driving? Genetic Study Decouples Epigenetic Clocks and Telomeres from Human Lifespan

#1

A cornerstone of modern longevity science is the belief that by measuring the biological “clock”—via telomere length or DNA methylation patterns (epigenetic clocks)—we are looking directly at the speedometer of our remaining life. However, a robust Mendelian randomization (MR) study from the School of Public Health, University of Hong Kong (published in Human Genomics, United Kingdom) suggests we may be monitoring the symptoms rather than the causes of aging.

The research team analyzed genetic data from approximately 500,000 individuals in the UK Biobank to determine if genetically predicted telomere length and four major epigenetic clocks (GrimAge, PhenoAge, HannumAge, and Intrinsic Epigenetic Age Acceleration) actually dictate how long a person lives. The results were stark: despite strong observational correlations between these markers and mortality in previous studies, this genetic analysis found no evidence that telomere length or common epigenetic clocks are causal drivers of lifespan in either men or women.

While telomere length showed a link to specific age-related pathologies like cardiovascular disease, it did not translate into a statistically significant extension or reduction of total life years when isolated from confounding factors. The “Big Idea” here is a necessary correction for the longevity community: these biomarkers are excellent reporters of biological status, but they may not be the levers we need to pull to significantly extend the human lifespan. The researchers conclude that therapeutic efforts should pivot away from “fixing” the clock itself and toward the upstream metabolic and inflammatory drivers that the clock is merely recording.

Open Access Paper: Biological aging and lifespan in men and women using a Mendelian randomization study
Impact Evaluation: The impact score of this journal is 4.3, evaluated against a typical high-end range of 0–60+ for top general science, therefore this is a High impact journal within the specialized field of genetics and genomics.

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#2

If one took some of the most common supplements (high dose vitamin D, omega-3, and maybe 20 more) that people had claimed had some health-promoting and anti-aging effects for decades prior to the advent of epigenetic clocks, and then if later when those clocks became available (and were designed to predict things like all cause mortality, say, over a given span of time) they showed some of those supplements had a big effect on the numbers (epigenetic age), then I’d lean a little more towards believing they really do reduce mortality rates and improve health.

However, if someone started with some clocks, and then looked at a large number of supplements and combinations thereof that move the clock readings in retrospective studies, and then if they picked out the ones with the strongest signal and suggested they seem to have some anti-aging effect, I would be skeptical. When this is done you run into the “false discovery” problem. It’s also worth mentioning that it reminds me of “overfitting” and also “Goodhart’s Law” that when a measure becomes a target, it ceases to be a good measure.