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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.”

Impressive toolkit

Despite having such a big job, DNA is remarkably fragile. Left unrepaired, its many breaks, kinks, lost bases and crosslinks can physically block the processes necessary to make proteins or to form new cells. That means that for life to get anywhere with DNA as a blueprint, maintenance is essential.

“DNA damage has been the fundamental problem at the origin of life,” says Björn Schumacher, a geroscientist at the University of Cologne in Germany.

Cells have an ancient and varied toolkit. There are six major DNA-repair systems, a few smaller ones and probably some that haven’t been discovered, Schumacher says. Different systems respond to different forms of damage. If a single DNA base, such as guanine, gets oxidized — an oxygen atom gets added to its structure — then a process known as base-excision repair can make the fix. This removes and replaces one base at a time. Nucleotide-excision repair, by comparison, removes a couple of dozen nucleotides along a single strand at once — a heftier fix often triggered by UV damage.

The repair systems tend to require several steps. They call on many proteins and overlap with one another, with one system jumping in if another is not active. Some are sloppier than others, prone to introducing errors as they make their fixes. One way to repair a break that spans both strands of the DNA double helix, for example, is homologous recombination. This uses an intact DNA strand to serve as a template and is generally accurate. Nonhomologous end joining, however, another way to fix double-strand breaks, doesn’t require a template and does a more slapdash job by fusing broken ends together. This sometimes introduces errors that can lead to cancer-driving mutations, but a repair with a small risk of mutation is better than no repair at all.

Naked mole rats live for decades — genetic tweaks reveal insights into ageing

Many genes are involved in these repair systems; some researchers suggest that 10% of the genome plays a part in genome maintenance. In searching for ways to enhance repair, “this complexity has always been a limiting factor”, says Shumacher. When researchers have tried to enhance repair directly, by switching on one repair system or overexpressing a repair enzyme, the effect has often been limited — or, worse, it has thrown the whole process out of balance.

One of the big challenges is that there are so many repair pathways, says Agnel Sfeir, a molecular geneticist at the Memorial Sloan Kettering Cancer Center in New York City who studies DNA repair in the context of cancer. “At the moment, we do not know which DNA repair can be boosted or should be boosted,” she says.

Animal inspiration

The animal kingdom might provide clues. Scientists are studying species with long, relatively cancer-free lives, including naked mole rats, Greenland sharks (Somniosus microcephalus), elephants, bats and lobsters.

For one of her latest projects, biologist Vera Gorbunova at the University of Rochester, New York, and her team chose bowhead whales. These marine mammals weigh in at more than 80,000 kilograms and glide and dive through frigid Arctic waters year-round. Although the whales can live for more than 200 years and have 1,000 times as many cells growing and dividing as humans do, cancer rarely creeps in.

In a study published last year³, Gorbunova and her colleagues went looking for reasons why bowhead whales are resistant to cancer. They thought they might find extra copies of genes that help to suppress and kill cancers. But instead they found that whale cells had very accurate double-strand break repair. “The whales don’t need to kill the cells; they just don’t let cells mutate as far,” Gorbunova says.

A protein, called CIRBP (cold-inducible RNA-binding protein), that helps cells to survive cold-related stress seems to have a role. When expressed in human cells, the whale protein increased two types of double-strand break repair.

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 others^8,9 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.

This whale lives for centuries: its secret could help extend human lifespan

The ins and outs of DNA repair don’t just differ from organism to organism; they also differ from cell to cell. Sperm and egg cells seem to accumulate much less DNA damage than other cell types do; DNA repair is energetically costly, so it makes sense that it would be prioritized in cells that must pass genetic information down the generations. “Our germ cells are in a sense immortal,” Schumacher says.

He and his colleagues have identified a possible key to this immortality. In 2023, the team reported from experiments in the roundworm Caenorhabditis elegans that a protein complex already known for its role in cell proliferation represses many DNA-repair genes in non-reproductive, or somatic, cells⁵. This ‘DREAM complex’ is found across species. When the team turned it off in a mouse model of a premature-ageing syndrome, the mice showed less DNA damage. Switching it off in human cells boosted the expression of DNA-repair genes.

In the study, Schumacher’s team suppressed the DREAM complex by inhibiting an enzyme that helps to build it. The enzyme, called DYRK1A, is already a potential drug target: it is overexpressed in people with Down’s syndrome, and is tied to cognitive impairments and neurodegeneration associated with the condition.

Schumacher sees DREAM as a game changer for the field because it seems to act as a master regulator of repair, affecting many systems. “For the first time, we could really boost the overall capacity to repair,” he says.

Robbins agrees that the finding is exciting, calling the study “beautiful work”. But he says that there’s a lot more research to do to work out whether the complex could be targeted and how best to do it.

Staying pristine

Studying other types of cell with different apparent levels of repair could inform future strategies. There is evidence, for example, that stem cells, which also need to maintain their genome across many divisions, have lower mutation rates than do other somatic cells. If stem cells are better at DNA repair, then partially reprogramming somatic cells into a stem-like state could, among other advantages, improve their repair.