David Sinclair

Scientists reverse aging in mice by repairing damaged DNA

March 30, 2017

Could lead to an anti-aging drug that counters damage from old age, cancer, and radiation.

A research team led by Harvard Medical School professor of genetics David Sinclair, PhD, has made a discovery that could lead to a revolutionary new drug that allows cells to repair DNA damaged by aging, cancer, and radiation.

In a paper published in the journal Science on Friday (March 24), the scientists identified a critical step in the molecular process related to DNA damage.

The researchers found that a compound known as NAD (nicotinamide adenine dinucleotide), which is naturally present in every cell of our body, has a key role as a regulator in protein-to-protein interactions that control DNA repair. In an experiment, they found that treating mice with a NAD+ precursor called NMN (nicotinamide mononucleotide) improved their cells’ ability to repair DNA damage.

“The cells of the old mice were indistinguishable from the young mice, after just one week of treatment,” said senior author Sinclair.

Disarming a rogue agent: When the NAD molecule (red) binds to the DBC1 protein (beige), it prevents DBC1 from attaching to and incapacitating a protein (PARP1) that is critical for DNA repair. (credit: David Sinclair)

Human trials of NMN therapy will begin within the next few months to “see if these results translate to people,” he said. A safe and effective anti-aging drug is “perhaps only three to five years away from being on the market if the trials go well.”

What it means for astronauts, childhood cancer survivors, and the rest of us

The researchers say that in addition to reversing aging, the DNA-repair research has attracted the attention of NASA. The treatment could help deal with radiation damage to astronauts in its Mars mission, which could cause muscle weakness, memory loss, and other symptoms (see “Mars-bound astronauts face brain damage from galactic cosmic ray exposure, says NASA-funded study“), and more seriously, leukemia cancer and weakened immune function (see “Travelers to Mars risk leukemia cancer, weakend immune function from radiation, NASA-funded study finds“).

The treatment could also help travelers aboard aircraft flying across the poles. A 2011 NASA study showed that passengers on polar flights receive about 12 percent of the annual radiation limit recommended by the International Committee on Radiological Protection.

The other group that could benefit from this work is survivors of childhood cancers, who are likely to suffer a chronic illness by age 45, leading to accelerated aging, including cardiovascular disease, Type 2 diabetes, Alzheimer’s disease, and cancers unrelated to the original cancer, the researchers noted.

For the past four years, Sinclair’s team has been working with spinoff MetroBiotech on developing NMN as a drug. Sinclair previously made a link between the anti-aging enzyme SIRT1 and resveratrol. “While resveratrol activates SIRT1 alone, NAD boosters [like NMN] activate all seven sirtuins, SIRT1-7, and should have an even greater impact on health and longevity,” he says.

Sinclair is also a professor at the University of New South Wales School of Medicine in Sydney, Australia.

Abstract of A conserved NAD+ binding pocket that regulates protein-protein interactions during aging

DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD+ (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD+ to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate–ribose) polymerase], a critical DNA repair protein. As mice age and NAD+ concentrations decline, DBC1 is increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD+. Thus, NAD+ directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging.

References:

http://www.kurzweilai.net/scientists-reverse-aging-in-mice-by-repairing-damaged-dna

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Scientists reverse ageing process in mice; early human trials showing ‘promising results’

November 8, 2014

Scientists from Harvard and the University of New South Wales say they have discovered how to reverse the ageing process.

The research has focused on mice, but early clinical trials have also been conducted on humans.

The scientists said they switched youthful genes on and older genes off, using naturally occurring proteins and molecules.

Professor of genetics at Harvard and UNSW, David Sinclair, led the research team.

“We’ve discovered genes that control how the body fights against ageing and these genes, if you turn them on just the right way, they can have very powerful effects, even reversing ageing – at least in mice so far,” he said.

“We fed them a molecule that’s called NMN and this reversed ageing completely within just a week of treatment in the muscle, and now we’re looking to reverse all aspects of ageing if possible.”

Professor Sinclair said the breakthroughs could be used to develop drugs to restore youthfulness in human cells.

“We’ve gone from mice into early human studies actually. There have been some clinical trials around the world, and we’re hoping in the next few years to know if this will actually work in people as well,” he said.

The clinical trials were small studies but showed promising results in humans, he said.

“They show that the molecules that extend lifespan in mice are safe in people; they seem to be anti-inflammatory, so they might be useful against disease’s inflammation, like skin redness or even inflammatory bowel disease,” he said.

“Eventually we want these molecules to be taken by many people to prevent diseases of ageing and make them live longer, healthier lives.”

Professor Sinclair was named by Time Magazine as one of most influential people in the world.

He has been taking the red wine molecule, resveratrol, for a decade.

“I’ve been taking resveratrol for the last 10 years because it seemed to be very safe,” he said.

“I think the risks are, for myself, worth it, though I don’t ever promote it.

“But the more research that I see done, and there are now thousands of papers on it, I think that there’s a good chance that it’ll have some benefit.”

Professor Sinclair said the latest discovery could, one day, be seen in the same light as antibiotics.

“Some people say it’s like playing God, but if you ask somebody 100 years ago, what about antibiotics? They probably would have said the same thing,” he said.

“Some people worry about big advances in technology and medicine, but once it’s adapted and it’s natural for people to live until they’re 90 in a healthy way … we’ll look back at today like we do at the times before antibiotics when people died from an infected splinter.”

http://www.abc.net.au/news/2014-11-04/scientists-reverse-ageing-process-in-mice/5865714