||A giant leap forward to a pill for anti-aging
Researchers make a discovery that could lead to a revolutionary drug that actually reverses ageing, improves DNA repair and even help NASA get its astronauts to Mars.
In a paper just published in Science, a research team has identified a critical step in the process of cell repair to DNA.
Their mice experiments suggest a possible way to correct damage from radiation and ageing.
Their work has attracted the attention of NASA, which believes it can help their plans for a Mars mission.
While we know cells have an innate capacity to repair DNA damage — this happens every time we go out into the sun — we also know that cellular repair ability declines with age.
Scientists had already identified that NAD+ (Nicotinamide adenine dinucleotide) is an oxidizing agent which ferries electrons from one reaction to another. NAD+ accepts electrons from molecules and becomes NADH, which then donates those electrons to other molecules. Through this cellular exchange, chemical groups move between proteins. NAD+ is present in every cell in our body, and is key in regulating repair of DNA.
Treating mice with NAD+, written with a superscript plus sign because of the charge of a nitrogen atom, along with a "booster" molecule called NMN (nicotinamide mononucleotide) improves a cells' repair ability, because NMN is a molecule that binds chemically with other molecules to form DNA and RNA. NAD+ is also consumed into ADP-ribose transfer reactions which regulates several events in the cell nucleus, for DNA and telomere repair.
Human trials of NMN therapy will begin within six months.
"The cells of old mice were indistinguishable from young mice, after one week of treatment. This is the closest we are to a safe and effective anti-ageing drug, perhaps only three to five years away from being on the market — if trials go well."
David Sinclair PhD, Professor, Department of Genetics, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, Massachusetts, USA; and, Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia.
What this means for childhood cancer survivors, and all of us,
is also exciting to NASA as it faces the challenge of keeping astronauts healthy during a four-year mission to Mars.
Even on short missions, astronauts experience accelerated ageing from cosmic radiation, suffering through muscle weakness, memory loss, and more, on return. A trip to Mars will be far worse as it is anticipated that five per cent of an astronauts' cells will die in flight with chances of cancer approaching 100 per cent.
Human trials will begin this year at Brigham and Women's Hospital, in Boston.
Findings on NAD+ and NMN are adding momentum to work done by the UNSW Laboratory for Ageing Research over the past four years. Looking at the interplay of a number of proteins and molecules and their roles in the ageing process, two have already established NAD+ could be useful for treating various consequences of ageing, and perhaps female infertility, as well as in treating side effects of chemotherapy.
The work by professor Sinclair and his UNSW colleague Dr Lindsay Wu, won a NASA's iTech competition in December 2016. Dr Wu explains. "Cosmic radiation is not only an issue for astronauts. We all are exposed to it aboard aircraft, a London-Singapore-Melbourne flight is roughly equivalent in radiation to that of a chest x-ray." So, in theory, "anti-aging" pills might mitigate effects of DNA damage for frequent flyers.
One group that could well benefit are survivors of childhood cancers.
According the National Cancer Institute, 60 to more than 90 percent of childhood cancer survivors contract one or more chronic health conditions. This includes cardiovascular disease, Type 2 diabetes, Alzheimer's, and cancers unrelated to their original cancer. Dr. Wu: "All of this adds up to the fact they have accelerated ageing, which is devastating. It would be great to do something about that, and we believe we can with this molecule."
In 2003, David Sinclair made a link between the anti-ageing enzyme SIRT1 and resveratrol, a naturally occurring molecule found in tiny quantities in red wine."While resveratrol activates SIRT1 alone, NAD+ boosters activate all seven sirtuins — SIRT1-7 — and should have a greater impact on health and longevity," adds Sinclair.
NAD+ binding modulates protein interactions
An unexpected function of the oxidized form of nicotinamide adenine dinucleotide (NAD+) could underlie some effects of aging and propensity to age-related diseases. Li et al. found that the protein DBC1 (deleted in breast cancer 1) contains a domain that specifically binds NAD+. Binding of NAD+ inhibited the interaction of DBC1 with PARP1 [poly(adenosine diphosphate–ribose) polymerase 1], an enzyme important in DNA repair. Activity of PARP1 is inhibited by interaction with DBC1. Thus, the reduced abundance of NAD+ associated with aging may decrease PARP1 activity by promoting the interaction of PARP1 with DBC1. This mechanism could help explain the reported rejuvenating actions of NAD+ supplementation in older animals. Science, this issue p. 1312
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.
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