A new tool from Belsky and his colleagues, introduced in 2020 and updated earlier this year, acts as an aging speedometer. In creating their pace of aging biomarker, they quantified the rate of change of 19 markers of organ function at four ages, assembled them into a single index, and modeled it with methylation. “We’re actually quantifying the ongoing process of age-related degradation and system integrity,” Belsky said. Those who age faster by this measure die younger, he said, adding that it predicts mortality about as well as GrimAge and might be even better at predicting stroke and dementia.
In 2017, representatives of the Paul G. Allen Family Foundation approached Horvath after one of his lectures. They liked his work and suggested that he dream big because the foundation supports risky ventures. Find a project that no one else would fund, they said.
It wasn’t long before Horvath proposed an aging clock that would apply to all vertebrates. The proposal was accepted – it was odd enough – but once Horvath realized the magnitude of what it would entail, the plan morphed into a relatively low-key clock for all mammals.
As of January 2021, Horvath had methylation data from 128 mammalian species and published his clock on the preprint server biorxiv.org. “The same mathematical formula, the same cytosines for a mouse or a rat or a dog or a pig. We can measure aging in all of these species,” Horvath said. Still, he searched the globe for more.
In late summer of last year, Horvath was in contact with Darren Pietersen, a pangolin expert at the Tikki Hywood Foundation in Harare, Zimbabwe, and offered him material for data collection on pangolins and several other species. No one knew for sure how long pangolins live. Some official reports said 15 to 20 years, but Pietersen thought at least some species lived longer. “The only animal we aged recently was about 34 years old (although with a fairly large margin of error),” he wrote.
From the tissue data provided, Horvath built a Pangolin clock, another lifespan timer to add to his collection. “You want a pig watch, I have a pig watch. I have a watch for kangaroos and for elephants,” said Horvath. Each species-specific clock has been a boon to scientists in the field. For example, elephant researchers wanted the elephant clock so they could determine the age structure of wild populations to aid in conservation efforts.
But a clock that brings everyone together can help answer a more fundamental question: what is aging? One view is that like your shoes, your body ages, gradually fading and falling apart with wear and tear. But the successful predictions of the pan-mammal clock imply that something is also causing cells to fail on a specific schedule, perhaps because developmental genes don’t turn off when their work is done. “This suggests a deterministic element to aging,” said Raj, one of the watch’s more than 100 builders.
Methylation clock data suggests that aging begins very early, long before the body breaks down. In a 2021 paper, Gladyshev and colleagues describe a methylation clock that dates stages of mammalian development. They found that during early embryogenesis in mice, a type of rejuvenation resets the embryo’s age to zero. Biological aging then proceeds rapidly, although human children may be growing stronger, not weaker, during this time, and human mortality declines until around age 9. “This is very profound to me because it pins this issue of aging to a process that is inextricably linked to the developmental process,” Raj said.