All the unknowns in epigenetic rejuvenation are part of what makes the reprogramming phenomenon so attractive. Richard Klausner, the organiser and chief scientist of Altos Labs, a new research company, admits that the details of why reprogramming works remain a “complete mystery,” but that too helps explain the sudden rush to invest in the idea.

If there is a fountain of youth in the genome, the first to locate it could reinvent medicine and revolutionise how we treat the myriad of diseases that plague our old age. 

Epigenetic rejuvenation is the process of age reprogramming by which an aged epigenotype is reprogrammed to a young epigenotype that is capable of building stronger body defences against infections.

To get a reality check on Klausner’s lecture, we asked an embryologist and stem-cell specialist, Alfonso Martinez Arias, to watch a recording. Martinez, whose lab is at the Pompeu Fabra University, in Barcelona, wrote back that he had to hold his stomach while he watched, so grandiose were the claims.

“He was evangelical about something which, at the moment, is interesting but very preliminary and [on] shaky ground,” says Martinez. Klausner was speaking “as if he had drunk some Kool-Aid.”

Martinez says that to him, Altos is an alchemy project, the kind that medieval rulers once financed in the search for the philosopher’s stone – a substance they believed could turn lead into gold, not to mention cure all disease.

Martinez wasn’t entirely negative, though. “There are people at Altos who know how to do science,” he says. And, he notes, even alchemists ended up making valuable discoveries.

The basic technique Altos is exploring is the procedure discovered in 2006 by the Japanese scientist Shinya Yamanaka, who is now a scientific advisor to the company. The four proteins (now called “Yamanaka factors”) that he and his students identified could cause ordinary cells to turn into potent stem cells, just like those found in embryos. This discovery earned him a Nobel Prize in medicine in 2012. 

Initially, Yamanaka’s discovery was employed to reprogramme cells from patients to make stem cells, which could then be used to try to manufacture transplantable tissues, retina cells or neurons.

Other scientists wondered what would happen if they introduced Yamanaka’s factors into living animals. In 2013, a Spanish team did exactly that, with gruesome results. The mice sprouted tumours called teratomas, blobs of renegade embryonic tissue.

The problem for these reprogrammed mice was that the process doesn’t just make cells young; it also erases their identity and turns them into embryonic stem cells, which don’t belong in an adult. Joe Betts-Lacroix, the CEO and founder of Retro, says researchers were soon asking a new question: “Is there some way that those two phenomena can be uncoupled so that you can have some of the age wiped away, but not have all your identity wiped away so that you become a pile of stem-cell protoplasm and die?”

In 2016, researchers at the Salk Institute in California, headed by Juan Carlos Izpisua Belmonte, reported that the answer might be yes. They genetically engineered mice afflicted with progeria, a condition that causes extremely rapid aging, so that all their cells would make the Yamanaka factors, but only when they were fed a special supplement in their food. That allowed the scientists to turn on the factors for a limited period – just a few hours at a time.

Leave the genes on for too long, and the mice got cancer. But with shorter pulses – a tactic now known as partial reprogramming – they didn’t. What’s more, the mice seemed to become healthier and live a bit longer.

“You rejuvenate cells, but you didn’t lose the identity,” says Klausner, who calls it an “Aha!” moment. “That could be safe. And this has [now] been done with many animals. They don’t get cancer as long as you don’t go past this point.”

Exactly how this partial-reprogramming phenomenon works is now a major focus of Altos and other research organisations. During a meeting held in June at a Maine ski resort, reprogramming scientists described studying individual cells by the tens of thousands – tracking in detail what changes they undergo after they’re exposed to more limited pulses of the Yamanaka factors, or to subsets of them.

Researchers from the United Kingdom with connections to Altos reported that they’d made skin cells from a 53-year-old person as youthful as those of someone just out of college. They claimed the “rejuvenation point” was reached after 13 days of exposure to Yamanaka’s factors, but no more.

One way the British team concluded that the cells had become younger was by using an “aging clock.” These are measurements that detect epigenetic modifications to DNA, the chemical marks that determine whether a given gene is on or shut off.

Epigenetic controls are part of what gives every cell its specialized identity; an olfactory neuron in your nose doesn’t need the same genes activated as a liver cell that oozes bile.

Because these markers undergo tell-tale changes over a lifetime, it’s possible to estimate a person’s age, or that of any animal, within a couple of years by checking just two or three hundred of them.

In its latest catalogue of health conditions, the World Health Organization almost equated old age with disease. Then it backed off.

In part because the clocks are eerily accurate, some researchers now believe aging may be caused primarily by the gradual degradation of the epigenetic code, a little like a compact disc that’s been scratched and skips tracks.

It’s an attractive theory, and not least because one thing that reprogramming does reliably is reset these marks. After a little treatment with Yamanaka factors, a cell from a 90-year-old will have the epigenetic profile of one from a teenager.

To Klausner, the fact that cells can regain a youthful epigenetic state is remarkable and likely a gateway to important new biology. “Understanding how cells remember how to be an unscratched CD” could lead to the discovery of “missing codes” regulating the whole process of aging, he thinks.

Other scientists say it’s an open question whether aging clocks measure true rejuvenation, a term they say is already being used too loosely. To Charles Brenner, a senior researcher at the City of Hope National Medical Center, people may even be falling victim to circular reasoning when they celebrate those epigenetic changes.

“There isn’t a difference between saying they applied the Yamanaka factors and that they have changed the epigenetic profile, since that is what the factors do,” he says. “They then score their study as a rejuvenation success, but there is no scientific basis for doing that. They still don’t know what the intervention does. People should not be assuming more youthful scores on an epigenetic clock equate to better health or longer life expectancy.”