Drugs such as metformin may add 1–3 years of life at best, treatments targeting an aging organ may add 5–10 years, and no intervention can yet add more than 10 years: Gladyshev’s assessment

Drugs such as metformin may add 1–3 years of life at best, treatments targeting an aging organ may add 5–10 years, and no intervention can yet add more than 10 years: Gladyshev’s assessment

On October 27, cardiologist Eric Topol published a conversation with Harvard professor Vadim Gladyshev in his Ground Truths newsletter. Gladyshev considers aging irreversible and biological age partly reversible.

Gladyshev and his colleagues surveyed participants at the 2022 Gordon Conference: among the 103 respondents, no question about the fundamentals of aging produced a majority view, even on whether a shared definition was needed. He defines aging as the accumulation of the negative consequences of life: every biological function is imperfect, and an enzyme produces byproducts along with its intended product. Each function produces its own byproducts, so the consequences follow consistent patterns and differ across tissues and species. Aging has no underlying program, Gladyshev says, but these patterns create “the appearance of a program, a quasi-program.”

“Aging itself is irreversible because so many specific changes occur. We cannot go back. But we can still alter the biological state of an organism to make it younger.”

Biological age is estimated using “aging clocks,” which return an age in years based on DNA marks, blood proteins, or gene activity. A Cell Metabolism paper coauthored by Gladyshev defines age reversal as a reduction in this estimate below its baseline value that persists after the intervention ends.

A 2023 experiment achieved partial whole-body rejuvenation in mice: old mice shared a blood supply with young mice for three months (parabiosis), remained younger than controls two months after separation, and lived 6–9% longer on average. Gladyshev considers parabiosis the gold standard for rejuvenation, but its effects are difficult to reproduce. Transplanting young bone marrow into an old mouse did not rejuvenate it (the experiment is unpublished), suggesting that blood cells alone are insufficient to produce the effects of parabiosis. The old mouse in a joined pair also gains access to its partner’s young organs; the laboratory is using organ transplants to try to explain the effects of parabiosis.

According to Gladyshev, an old organ becomes only partly younger in a young body because some age-related changes are irreversible. In his laboratory, fat tissue from an old mouse became younger in a young mouse’s body according to aging clocks, but its mitochondria retained their aged shape; in a September preprint, a transplanted heart moved closer to the recipient’s age without changing the age of the recipient’s body.

Partial reprogramming briefly activates the Yamanaka genes, which convert an adult cell into a stem cell when active for a prolonged period. Gladyshev considers this approach promising but sees little major progress in the ten years since the key study. He is concerned that attention has focused on rejuvenating individual organs: “Suppose it is younger. What happens next?” Transplanting a young organ reproduces this situation: rejuvenating the body through such a transplant remains very difficult. Rejuvenating an aged organ may help people whose organ has aged, but whether it extends the lifespan of the whole organism remains unclear.

Because the kidneys age earlier in some people and the heart in others, Gladyshev does not expect universal interventions: treatments will need to target the aging organ. Drugs that modestly alter metabolism (metformin, rapamycin, GLP-1 drugs) could add “at best one to three years, perhaps.” He estimates that interventions targeting an aging organ could add “perhaps five to ten years” in suitable individuals.

“But what we really need is a radical change in lifespan. By radical, I mean more than ten years. And we do not yet have interventions that can achieve that.”