Scientists have tried to reverse ageing for decades. Have they finally cracked it?

“That’s why we haven’t really seen that field advance since the mid-to-late two thousands.”

For more than a decade, Australian biologist David Sinclair, a professor of genetics and co-director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, has been a leading voice in anti-ageing research and lifespan extension.

Instead of trying to create a blank slate in the cells, Sinclair (who considers ageing a “disease”) has focused on partially resetting the epigenetic instructions.

This is because he believed the hypothesis that the more damaged the DNA, the more disrupted the epigenetic signals would become, leading to cellular dysfunction and senescence (when a cell ages and permanently stops dividing but does not die). In other words, it was epigenetics, not just DNA damage driving ageing.

He wondered whether ageing was essentially a “glitch in the software of the body” that causes it to malfunction. By rebooting the software, restoring the cell’s ability to read its original DNA so it remembers how to function, he hoped he could fix the glitch.

In a paper published in Nature in 2020, Sinclair and his team were able to restore vision to old mice by injecting their eyes with a benign virus carrying three of the four Yamanaka factors (OSK).

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In his new paper, published this week in Cell, he took this research a step further, partially turning back the biological clocks in multiple organs, including the eyes, of mice they prematurely aged.

“We think of the processes behind ageing, and diseases related to ageing, as irreversible,” Sinclair told TIME. “In the case of the eye, there is the misconception that you need to regrow new nerves. But in some cases, the existing cells are just not functioning, so if you reboot them, they are fine. It’s a new way to think about medicine.”

The 53-year-old added: “Underlying ageing is information that is lost in cells, not just the accumulation of damage. That’s a paradigm shift in how to think about ageing.”

Dr Christian Nefzger the group leader in the Cellular Reprogramming and Ageing laboratory at the University of Queensland says: “It should be considered a seminal study as it most directly links epigenetic erosion to ageing.”

But, it’s still very early days. “Conceptually, the risk is that you could induce too much reprogramming,” says Wu, who has worked with Sinclair and is involved in a company with him. “That’s why there is obviously a lot of caution being used here.”

Nefzger agrees. Although he says it is good news as epigenetic changes can potentially be reversed, unlike DNA mutations, he adds: “There are safety and efficacy concerns regarding the gene therapy approach used here, and it should not be considered a viable treatment option as of now.”

Along with the risk of teratomas, such a treatment “might induce cancer in longer-lived species like ours”. We also do not yet understand what other, potentially undesirable epigenetic changes might be introduced with this kind of tinkering.

Though it holds promise as a targeted therapy for certain age-related diseases, Nefzger anticipates it will take decades more research to get it right and ensure its safety.

The next step for Sinclair and his team is to test the approach in non-human primates. They are also continuing to experiment with switching on and off cells throughout the body to try and reverse ageing entirely.

Of this, Wu says:

“We’ve already got interventions which are much safer and much more powerful in terms of their ability to keep us young and healthy.”

Those interventions are quality diet and exercise, maintaining muscle mass via resistance training, eating less, avoiding sun damage and getting good sleep. Sinclair’s own anti-ageing regime involves regular exercise, sauna steams and ice baths, only one or two meals a day, a mostly vegetarian diet and taking the diabetes drug metformin as well as a range of supplements.

Wu says that in our lifetime we are likely to see these therapies rolled out in humans to treat specific issues, but we are unlikely to see them being used in humans to treat ageing itself.

“Testing whether an intervention makes you younger or extends the overall life span in humans is really difficult to do,” he says. “It would take a very long time.”

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