Inspired by long-lived animals — and human centenarians — researchers are hunting for ways to enhance DNA repair and extend healthspan.
Your DNA is under constant assault. Ultraviolet light, environmental toxins, reactive molecules made during run-of-the-mill metabolism and many other disruptors muck with the instructions that keep life humming along. Thankfully, repair crews are at the ready.
A typical cell can acquire up to a whopping 100,000 lesions each day. “The vast, vast majority are repaired,” says Morten Scheibye-Knudsen, a translational geroscientist at the University of Copenhagen. “We have very, very efficient repair.”
That’s a good thing for a couple of reasons. First, unrepaired or poorly repaired damage can introduce mutations, which can contribute to cancer. And second, DNA damage seems to be one of the main drivers of ageing.
Researchers are amassing evidence that this type of damage underlies many of the hallmarks of ageing, including chronic inflammation, metabolic malfunctions and protein-folding problems1. Such damage triggers cellular alarm bells that can promote inflammation, force cells into an ‘undead’ state known as senescence and even kill them. These responses help the body to grow and thrive, but they become more problematic as we age. The accumulation of beleaguered cells over time is associated with many age-related conditions, including cardiovascular disease, osteoporosis and Alzheimer’s.
That raises a question: if DNA damage is at the root of ageing, can boosting DNA repair slow the process, keeping people healthy for longer? For the first time, this is starting to look like a promising approach, say researchers who study DNA repair2.
Their new optimism comes from studying relatively long-lived species, such as bowhead whales (Balaena mysticetus)3 and naked mole rats (Heterocephalus glaber)4, and looking at the genetics of human centenarians. These studies are pointing to the existence of a great variety of molecular maintenance workers that make for a long and healthy life. A ‘master regulator’ of repair, discovered in 2023, also suggests that these fix-it systems could be enhanced in unison5.
Such findings come alongside a booming interest in longevity more generally, propelled by biotechnology companies, health influencers and governments overseeing ageing populations.
“If you can reduce DNA damage, you would probably have a dramatic effect on the ageing process,” says Paul Robbins, who directs the Nathan Shock Center on Genome Integrity and Aging, which opened last year at the University of Minnesota in Minneapolis. “There are tricks that we can do. But it’s not simple.”
That finding chimes with a study from 2019, in which Gorbunova and her colleagues looked at 18 rodent species with varying lifespans. They found a strong link between the maximum lifespan and the accuracy and efficiency of double-strand break repair in skin and lung cells6. That superior repair was explained in large part by one member of a family of enzymes called sirtuins, which are known to have roles in ageing, metabolism and the stability of the genome. The overexpression of the sirtuin SIRT6 had already been linked to extended lifespan in mice. In the 2019 study, the team identified five amino acids that differ between the beaver and mouse versions of SIRT6 and seem to make the beaver version more effective. Beavers live for 10–12 years in the wild, whereas mice typically live for a few years at most.
Genetic studies suggest that some human centenarians7 might also carry a superior variant of the gene SIRT6, says geneticist Jan Vijg at the Albert Einstein College of Medicine in New York City. Vijg co-leads a multiteam effort to identify important genes and pathways in centenarians, validate them and develop drugs that target them.
The team has identified a group of compounds called fucoidans, which occur naturally in brown seaweed and activate the SIRT6 protein, as potential therapeutics. Studies by Robbins, Gorbunova and others8,9 show that supplementing mouse diets with fucoidans improves the animals’ DNA repair, reduces senescence and extends their healthspan and lifespan.
Clinician-geroscientist Andrea Maier, director of the National University of Singapore’s Academy for Healthy Longevity, is now leading a study that gives fucoidans to men aged 50 to 80. The study is looking at cellular markers of ageing and clinical outcomes, measuring as directly as possible how fucoidans affect biology.
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