Can Repairing Damaged DNA Help Extend Lifespan?

DNA is under constant attack. Ultraviolet (UV) radiation, environmental toxins, reactive molecules produced during normal metabolism and other stressors can damage the genetic instructions that keep cells functioning. Fortunately, cells have powerful DNA-repair systems that continually identify and fix this damage.

A typical cell can experience up to 100,000 DNA 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 efficiency matters for two key reasons. First, unrepaired or incorrectly repaired DNA damage can create mutations that contribute to cancer. Second, accumulating DNA damage appears to be one of the major biological drivers of ageing.

Researchers are finding increasing evidence that DNA damage contributes to several hallmarks of ageing, including chronic inflammation, metabolic dysfunction and problems with protein folding¹. DNA damage activates cellular alarm systems that can promote inflammation, push cells into a dormant but metabolically active state called senescence or trigger cell death. These responses are essential for growth, development and protection from disease, but they can become harmful over time. The build-up of damaged and senescent cells is linked to age-related conditions such as cardiovascular disease, osteoporosis and Alzheimer’s disease.

This raises an important question: if DNA damage helps drive ageing, could enhancing DNA repair slow the process and help people stay healthier for longer? For the first time, researchers who study genome maintenance say that this possibility is beginning to look promising².

The optimism comes partly from studies of unusually long-lived animals, including bowhead whales (Balaena mysticetus)³ and naked mole rats (Heterocephalus glaber)⁴, as well as genetic research involving human centenarians. Together, these studies suggest that many molecular maintenance systems may support a long and healthy life. The discovery of a potential “master regulator” of DNA repair in 2023 also raises the possibility that several repair pathways could be enhanced at the same time⁵.

These findings come as interest in longevity research continues to grow, driven by biotechnology companies, health influencers and governments preparing for ageing populations.

“If you can reduce DNA damage, you would probably have a dramatic effect on the ageing process,” says Paul Robbins, director of 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.”

DNA repair: an impressive cellular toolkit

Although DNA is the blueprint for life, it is remarkably fragile. Without repair, DNA breaks, kinks, missing bases and crosslinks could block the processes needed to produce proteins or create new cells. Maintaining the integrity of the genome is therefore essential for life.

“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 possess an ancient and diverse DNA-repair toolkit. There are six major repair systems, several smaller pathways and probably others that scientists have yet to identify, Schumacher says. Each pathway responds to particular types of damage. If a single DNA base, such as guanine, becomes oxidized — meaning that an oxygen atom is added to its structure — a process called base-excision repair can remove and replace that individual base. Nucleotide-excision repair, by contrast, removes and replaces several dozen nucleotides from one DNA strand. This larger-scale repair pathway is often activated by UV-induced damage.

DNA repair usually involves multiple steps and many proteins. The different pathways can also overlap, allowing one system to compensate when another is unavailable. Some repair mechanisms are more accurate than others and can introduce errors while fixing damage. For example, homologous recombination repairs breaks affecting both strands of the DNA double helix by using an intact DNA sequence as a template. This process is generally precise. Non-homologous end joining, another way to repair double-strand breaks, does not use a template. Instead, it joins the broken ends directly, which can introduce mutations. Even so, a repair process with a small risk of error is often safer than leaving a dangerous DNA break unrepaired.

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

Many genes contribute to DNA repair and genome maintenance. Some researchers estimate that as much as 10% of the genome may be involved in protecting and preserving genetic information. This complexity has made it difficult to develop ways to improve repair, says Schumacher. Attempts to enhance one pathway or increase production of a single repair enzyme have often produced limited benefits — or disrupted the balance between repair systems.

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

Long-lived animals offer clues about healthy ageing

Long-lived animals could provide important insights into how DNA repair supports longevity. Scientists are studying species that survive for decades or centuries while maintaining relatively low cancer rates, including naked mole rats, Greenland sharks (Somniosus microcephalus), elephants, bats and lobsters.

For one recent project, biologist Vera Gorbunova of the University of Rochester in New York and her team studied bowhead whales. These marine mammals can weigh more than 80,000 kilograms and spend their lives swimming and diving through the cold Arctic Ocean. They can live for more than 200 years and have roughly 1,000 times as many cells as humans, yet cancer is uncommon.

In a study published last year³, Gorbunova and her colleagues investigated why bowhead whales are so resistant to cancer. They initially expected to find extra copies of genes that suppress tumours or destroy cancerous cells. Instead, they discovered that whale cells repair double-strand DNA breaks with exceptional accuracy. “The whales don’t need to kill the cells; they just don’t let cells mutate as far,” Gorbunova says.

A protein called CIRBP, or cold-inducible RNA-binding protein, appears to play a role. CIRBP helps cells withstand cold-related stress. When the bowhead-whale version of the protein was expressed in human cells, it increased the activity of two double-strand break-repair pathways.

The finding builds on research published in 2019, when Gorbunova and her colleagues compared 18 rodent species with different lifespans. They found a strong relationship between maximum lifespan and the accuracy and efficiency of double-strand break repair in skin and lung cells⁶. Much of this improved repair was linked to a member of the sirtuin enzyme family. Sirtuins are involved in ageing, metabolism and genome stability.

Previous research had linked increased activity of the sirtuin SIRT6 to longer lifespans in mice. In the 2019 study, the researchers identified five amino-acid differences between the beaver and mouse versions of SIRT6 that appeared to make the beaver protein more effective. Beavers can live for 10–12 years in the wild, whereas mice generally survive for only a few years.

Genetic studies suggest that some human centenarians might also carry a more effective version of the SIRT6 gene⁷, says geneticist Jan Vijg of the Albert Einstein College of Medicine in New York City. Vijg co-leads a research programme investigating genes and biological pathways associated with exceptional human longevity, with the goal of validating them and developing drugs that target them.

The team has identified fucoidans — compounds naturally found in brown seaweed — as potential SIRT6-activating treatments. Studies by Robbins, Gorbunova and others^8,9 suggest that adding fucoidans to the diets of mice can improve DNA repair, reduce cellular senescence and extend healthspan and lifespan.

Clinician-geroscientist Andrea Maier, director of the Academy for Healthy Longevity at the National University of Singapore, is now leading a study in which men aged 50 to 80 receive fucoidans. The trial is measuring markers of cellular ageing and clinical outcomes to assess how the compounds affect human biology.

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

DNA-repair activity differs not only between species but also between cell types. Sperm and egg cells appear to accumulate less DNA damage than many other cells. Because DNA repair requires substantial energy, prioritizing it in cells that pass genetic information to future generations may be advantageous. “Our germ cells are in a sense immortal,” Schumacher says.

Schumacher and his colleagues have identified a possible explanation for this protection. In 2023, they reported experiments in the roundworm Caenorhabditis elegans showing that a protein complex involved in regulating cell proliferation suppresses many DNA-repair genes in non-reproductive, or somatic, cells⁵. Known as the DREAM complex, this regulator is found across many species.

When the researchers switched off the DREAM complex in a mouse model of premature ageing, the animals had less DNA damage. In human cells, disabling the complex increased the activity of genes involved in DNA repair.

The researchers suppressed the DREAM complex by inhibiting DYRK1A, an enzyme that helps assemble it. DYRK1A is already being investigated as a possible drug target. The enzyme is overexpressed in people with Down syndrome and has been associated with cognitive impairment and neurodegeneration linked to the condition.

Schumacher describes the DREAM complex as a potential game changer because it appears to regulate multiple DNA-repair systems at once. “For the first time, we could really boost the overall capacity to repair,” he says.

Robbins agrees that the discovery is exciting, calling the research “beautiful work”. However, he says considerably more research is needed to determine whether the complex can be safely targeted and how such an approach might be developed into a treatment.

Can better DNA repair slow ageing?

Studying cells with different levels of DNA repair could help researchers develop future anti-ageing strategies. Stem cells, for example, must preserve their genomes through many rounds of division and appear to have lower mutation rates than other somatic cells. If stem cells are particularly effective at repairing DNA, partially reprogramming ordinary cells into a stem-like state could potentially improve genome maintenance, among other benefits.