Gerontologist Richard Miller argues that researchers should study what controls the rate of aging, calling the search for a “cause of aging” and the calculation of “biological age” mistakes

Gerontologist Richard Miller argues that researchers should study what controls the rate of aging, calling the search for a “cause of aging” and the calculation of “biological age” mistakes

On October 27, The EMBO Journal published Miller’s commentary “Seven ways to avoid thinking carefully about aging”. Miller, of the University of Michigan, is one of the leaders of a program that tests whether compounds extend lifespan in mice.

In Miller’s view, aging affects the whole organism and has no single cause: declines in cognition, immunity, and muscle strength result from many changes, while inflammation, DNA damage, and senescent cells are consequences of aging.

Miller calls “biological age,” a single number standing in for a set of measurements, an error of reification: treating an abstraction as a thing. It is tempting to describe healthy 70-year-olds as “biologically younger,” but Miller argues that combining their measurements into one number is like rating a dancer, a carpenter, and a wine connoisseur on a single scale of “skill.”

“Aging clocks” use complex mathematics to calculate “biological age,” usually from chemical marks on DNA. Miller says this complexity discourages scrutiny of the result: a claim that a drug has rejuvenated a group is accepted without testing hearing, strength, or immune responses.

Miller cites a 2023 study by Vadim Gladyshev’s group at Harvard Medical School: in older patients who underwent emergency surgery for a hip fracture, the clocks showed a jump in “age” within a day, followed by a return to baseline after 4–7 days. They also showed reversible increases during pregnancy. The authors interpreted these findings as evidence that biological age is reversible; Miller interpreted them as evidence that the instrument responds to unrelated influences:

“If a Rolex starts running fast on a pregnant woman’s wrist and runs backward after she gives birth… the conclusion is clear: such a watch is useless for telling time, timing a basketball game, or choosing when to launch a rocket to Mars.”

Miller traces the idea of “cellular aging” to Leonard Hayflick’s 1961 experiment: human fetal lung cells grown in culture stopped dividing after roughly 50 doublings. Miller counters that intestinal cells divide throughout life, whereas adult neurons apparently do not, so a limit on cell division cannot explain most aging.

The idea of “cellular aging” led to senolytics, drugs that kill senescent cells. According to Miller, only one unreplicated 2016 study showed that removing these cells extended lifespan in mice. The proposed senolytic fisetin did not extend lifespan in a mouse experiment conducted by Miller’s program. However, two studies published in 2018 found that dasatinib with quercetin and fisetin extended lifespan in old mice.

Miller says the circular “hallmarks of aging” diagram, which groups processes into 12 categories, opens many presentations and grant applications and allows applicants and reviewers to sidestep the strength of the evidence. When a reviewer noted the framework’s usefulness for securing funding, Miller replied: “I think the ‘hallmarks of aging’ framework has done more harm than good.”

According to Miller, gerontologists have spent decades searching for the cause of aging in hopes of developing a drug to counter it, but blocking one of dozens of forms of damage is unlikely to substantially slow aging overall. He asks what controls the rate of aging. Miller counts about a dozen diets, mutations, and drugs that act on different targets yet slow aging across many tissues in mice. He proposes looking for a shared mechanism by comparing young mice that will age at different rates: this would keep age-related changes separate from changes caused by a drug or diet. He argues for indicators of the rate of aging (a “speedometer”) in place of biomarkers of age (an “odometer”).