Originally published 2017-10-11.
Scientists at the Salk Institute in California showed that some signs of ageing can be partly reversed in mice and in human cells grown in the lab. They did it by briefly and repeatedly switching on four genes, known as the Yamanaka factors, that can wind adult cells back toward an embryonic-like state. In mice with a premature-ageing disease, the treatment extended lifespan by about 30 percent, and in middle-aged mice it helped damaged tissue heal better.
What it did not show is that ageing can be reversed in people. The study, published in the journal Cell in December 2016, was early laboratory research. Here is what the team did, what they found, where the risks lie, and how the field has developed since.
The idea behind the experiment
Every cell in your body carries essentially the same DNA. What makes a skin cell different from a nerve cell is which genes are switched on or off, and that is controlled by chemical tags and packaging around the DNA known as the epigenome. Over a lifetime, this pattern drifts. Many researchers think that drift is one of the drivers of ageing, as cells gradually lose their sense of what they are supposed to be doing.
In 2006 the Japanese scientist Shinya Yamanaka found that four genes, Oct4, Sox2, Klf4 and c-Myc, could turn adult mouse cells into induced pluripotent stem cells, cells that behave much like those in an early embryo. The discovery earned him a share of the 2012 Nobel Prize in Physiology or Medicine. Full reprogramming wipes a cell’s age-related marks, but it also erases its identity: a skin cell stops being a skin cell.
The Salk team, led by Juan Carlos Izpisua Belmonte with first author Alejandro Ocampo, asked a simple question. What if you switched those genes on only briefly, enough to reset some of the ageing marks but not long enough for cells to forget what they are? This approach is now called partial reprogramming.
What the Salk team found
The researchers first worked with skin cells from mice with progeria, a rare genetic condition that causes very rapid ageing, and with human skin cells grown in the lab. After short bursts of the four factors, the cells looked and behaved younger: signs of DNA damage fell and the epigenetic pattern moved toward a more youthful state. Crucially, they stayed skin cells.
Next they tested genetically engineered mice that carry a mutation causing a form of progeria and could switch on the four genes on demand. The genes were switched on for two days out of every seven. Treated mice looked healthier, kept better organ function and lived about 30 percent longer than untreated ones, roughly 24 weeks instead of 18.
Finally, they tried the method in normal middle-aged mice. After injuries to the pancreas and to muscle, the treated animals recovered better than untreated ones. Izpisua Belmonte summed up the team’s view in a widely quoted line: “aging is something plastic that we can manipulate.”
The risks the study exposed
Turning back the clock on cells is not without danger, and the study made that clear. When the four genes were left switched on continuously, mice developed serious problems, including tumours, and some died within about a week. Only the carefully timed, intermittent schedule produced benefits without that result.
This is the central challenge for the whole field. c-Myc is a known cancer-related gene, and cells that are pushed too far toward an embryonic state can grow out of control. Any future treatment would need to be extremely precise about how much reprogramming happens, in which tissues and for how long.
Other scientists also pointed to the limits. The lifespan gain was seen in mice with an accelerated-ageing disease, not in normal mice living out a natural lifespan, and progeria is not the same as ordinary ageing. Harvard geneticist David Sinclair, who was not involved but works in the same area, was enthusiastic but cautious about tumour risk, telling Scientific American: “We’ve all been playing with fire.” He estimated that learning to reprogram cells safely could take about a decade.
What it does not mean
Headlines at the time said scientists had found a way to reverse ageing in mice and humans. That overstated things. The human part of the work was done on cells in dishes, not on people, and no one received any treatment. There was also no evidence that life expectancy in humans would change as a result.
It is also important to steer clear of products sold online claiming to “reprogram” your cells or reverse your epigenetic age. No approved therapy based on this research exists. Anyone interested in healthy ageing, or in joining a clinical study, should talk to a doctor rather than rely on supplements or clinics promising rejuvenation.
The careful takeaway is still striking. Ageing in cells appears to be at least partly reversible, rather than a one-way process of wear and tear. University of Washington biologist Matt Kaeberlein, also not involved, called that prospect exciting, saying it suggested “even in elderly people it may be possible to restore youthful function”.
How the field has moved since 2016
The Salk paper helped launch a wave of research and investment. In 2020, Sinclair’s group reported in Nature that using three of the factors, leaving out the risky c-Myc, restored vision in older mice and in mice with a glaucoma-like condition. Other labs have tested partial reprogramming in muscle, liver, skin and other tissues, and have built “epigenetic clocks” that estimate a cell’s biological age from its chemical tags.
Investors noticed too. Altos Labs, a company focused on cellular rejuvenation, launched in January 2022 with around $3 billion in funding, and Izpisua Belmonte became one of its founding scientists. Several other start-ups are pursuing the same idea.
Whether any of this will lead to treatments for age-related diseases, let alone longer lives, is still unknown. But the question has moved from science fiction into mainstream biology, and the experiment described here was one of the moments that made that happen.
Sources: Scientific American: Aging is reversible, at least in human cells and live mice; Wikipedia: Induced pluripotent stem cell; Wikipedia: Altos Labs; Salk Institute: Turning back time (15 December 2016); KPBS: Salk researchers reverse signs of aging in mice; Wikipedia: David Sinclair.
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