Gray hair. New wrinkles. Creaky knees.

And then there’s the whole, increasing risk of nearly all diseases and the looming specter of death, thing that comes along with getting older.

Many of us, perhaps upon finding our first white eyebrow hair (hypothetical example), have wondered if aging might be a cosmic joke rather than just the inevitable breakdown of our bodies. Scientists who study aging grapple with a similar conundrum: Is aging an unavoidable consequence of time spent in a physical body, or is it baked into our DNA?

“There is a longstanding debate in the aging field on whether aging is deterministic — whether there’s some sort of program — or is it just all entropy?” said Allen Distinguished Investigator Steve Horvath, Ph.D. “One way to address that question is to show that you have aspects of aging that are highly conserved in many different species.”

According to a pair of new studies led by Horvath, it’s the former — aging is evolutionary. These studies, published today in the journals Nature Aging and Science, suggest that we evolved to age.

In one of those studies, Horvath and his 200 collaborators debut what they call a “universal pan-mammalian epigenetic clock,” which is an assay that uses chemical changes in an animal’s DNA to predict that animal’s age.

The fact that this single clock works in mammals ranging from humans to mice to bowhead whales tells us something about why we age, said Horvath, a former professor at the University of California, Los Angeles, who is now a Principal Investigator at Altos Labs, a biotechnology company focused on aging and rejuvenation.

“These mammalian species that we studied were separated by over 200 million years of evolution, and we have found one measurement that predicts their age,” he said. “This is really the ultimate smoking gun that shows there’s some kind of pseudo-program to aging.”

The clock could also be used to predict whether potential rejuvenation treatments first tested in lab animals would work in humans, he said. Many clinical treatments are first developed through lab animal testing — typically starting with mice — but even if effective in lab animals often fail to translate to human benefit. A treatment that reverses molecular or epigenetic aging in mice, as tested by the new clock, would likely do the same in humans.

A molecular timekeeper

In evolutionary terms, traits that are conserved are those that persist despite other changes evolution enacts over time. Things like hair or fur, warm-bloodedness, having four limbs — these are all conserved in mammals. And so, it turns out, is aging.

The molecular clock works by tracking age-related changes to our DNA known as methylation. This modification is a tiny chemical addition to one of the letters of DNA’s backbone. DNA methylation serves a variety of biological purposes, but for the case of the molecular clock, what’s important is that it changes with age. Some regions of our genome increase their methylation as we get older, others decrease.

Horvath and his colleagues found that the special DNA regions — and their methylation patterns — that predict age are conserved, or close to the same, in all mammalian species the researchers studied. That includes short-lived animals like mice, which live less than 5 years, to exceptionally long-lived mammals like naked mole rats, certain bats and humans. That finding means that there must be some evolutionary pressure that drives how we age.

‘The craziest, wildest idea’

In 2011, Horvath and his collaborators, then headquartered at UCLA, discovered that age-related changes in DNA methylation are consistent enough to accurately predict humans’ age based on a saliva sample. Two years later, Horvath demonstrated the same thing in all human tissue types, including blood and organ biopsies. Then Horvath was approached by The Paul G. Allen Frontiers Group, a division of the Allen Institute, to “come up with an impossible project that could never possibly get funded, because it’s so far-fetched. And so I thought, what is the craziest, wildest idea I can come up with? Develop a clock that applies to all mammalian species,” he said.

The funding from his Allen Distinguished Investigator award allowed him to set up far-ranging collaborations with scientists and animal caretakers who had tissue samples from all manner of mammals. To name a few, over the past seven years Horvath has studied molecular aging in humans, capybaras, ring-tailed lemurs, horses and sea lions. He has collaborators from six continents.

“From everyone I asked, I heard the word yes,” Horvath said. “People had freezers full of DNA. They’d been collecting tissues for decades. And they were all looking for exciting ways to use them.”

Ultimately, he ended up collecting samples from 348 different species of mammals. The pan-mammalian clock constructed by Altos Labs Senior Scientist Ake Lu, Ph.D., Horvath, and their collaborators uses samples from 185 of those species. In another study, published in the journal Science, Altos Labs Senior Scientist Amin Haghani, Ph.D., Horvath and colleagues showed that they can use DNA methylation patterns as a proxy for evolution. Modern evolutionary biologists create evolutionary trees of different species by comparing their DNA sequences. It turns out that DNA methylation patterns work just as well — the family trees Horvath’s team constructed matched those traditionally made using DNA alone.

The scientists also found that methylation patterns most closely linked to maximum lifespan of a given species tended to cluster around certain genes important for early embryonic development, supporting the idea that maximum lifespan is determined at conception. Together, these studies support the longstanding theory that while aging may be evolutionary, it doesn’t necessarily serve a biological purpose. Rather, it’s a byproduct of how we develop and grow. A biological clock that starts ticking in the womb has no reason to stop ticking after animals reproduce, and ultimately leads to the negative side effects that we call old age.

“Since development is highly conserved across mammals, it makes sense that some important aging processes are conserved as well,” Horvath said.

The Allen Distinguished Investigator awards are funded by the Paul G. Allen Family Foundation. The Paul G. Allen Frontiers Group, a division of the Allen Institute, recommends funding and supports the administration of the awards.