Epigenetic “reboot” reverses aging in mice and could extend lifespan

Scientists at Harvard Medical School have investigated why we age, and identified a possible way to reverse it. In tests in mice, the team showed that epigenetic “software glitches” drive the symptoms of aging – and a system reboot can reverse them, potentially extending lifespan.

Our genome contains our complete DNA blueprint, which is found in every single cell of our bodies. But it’s not the whole picture – an extra layer of information, known as the epigenome, sits above that and controls which genes are switched on and off in different types of cells. It’s as though every cell in our body is working from the same operating manual (the genome), but the epigenome is like a table of contents that directs different cells to different chapters (genes). After all, lung cells need very different instructions to heart cells.

Environmental and lifestyle factors like diet, exercise and even childhood experiences could change epigenetic expression over our lifetimes. Epigenetic changes have been linked to the rate of biological aging, but whether they drove the symptoms of aging or were a symptom themselves remained unclear.

For the new study, researchers at Harvard conducted experiments in mice to find out. Using a system called inducible changes to the epigenome (ICE), the team sped up the natural process of DNA damage and repair in mice, to check whether this also accelerated aging symptoms.

In mammal cells, our chromosomes experience as many as a million DNA breaks per minute, and epigenetic factors very quickly coordinate repairs before returning to their original locations. The team engineered mice that experience DNA breaks at a rate of three times faster than normal.

Over time, they found that the epigenetic factors became more “distracted” and wouldn’t return home after they repaired the DNA breaks, leading to the epigenome becoming jumbled. Sure enough, by the age of six months the mice showed the physical signs of aging, appearing to be in much worse health compared to unedited mice of the same age.

With this, the scientists say they’ve confirmed the role of the epigenome in aging. The next step was to test whether we can do anything about it, so the team administered a gene therapy cocktail of three genes, known as Oct4, Sox2 and Klf4. These are active in stem cells, and in previous work the team found that they could be used to restore vision to mice with age-related glaucoma.

In this case, the ICE mice experienced a dramatic reduction in biomarkers of aging. Their epigenomes became unscrambled and returned their tissues and organs to a more youthful state.

“It’s like rebooting a malfunctioning computer,” said David Sinclair, senior author of the study. “[It] set in motion an epigenetic program that led cells to restore the epigenetic information they had when they were young. It’s a permanent reset.”

This discovery is potentially huge, the team says. By tackling aging itself, many diseases that arise out of this natural process could be treated more effectively.

“If correct, it means that cancer, diabetes and Alzheimer’s might have the same underlying cause that can be reversed to treat or cure age-related conditions with a single treatment,” Sinclair posted on Twitter.

While there’s still plenty more research to be done before such lofty goals could be realized, work is already underway. A preprint paper, yet to be peer reviewed, administered the same gene therapy cocktail systemically to elderly mice, at an age equivalent to 77 years old in humans. These mice lived 9% longer than untreated mice.

The new study was published in the journal Cell. The team describes the work in the video below.

Epigenetics and Aging: The effects of DNA breakage and repair

Source: Harvard Medical School

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