Audio long read: Could mending damaged DNA prolong life?

DNA damage and the aging process

0:00This is an audio long read from Nature. In this episode, Could mending damaged DNA prolong life? Written by Elizabeth Quill and read by me, Benjamin Thompson.

0:16Your 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 Skyby Knudsen, a translational

0:50geroscientist at the University of Copenhagen. Quote, we have very, very efficient repair. End quote. 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,

1:23metabolic malfunctions, and protein folding problems. 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.

1:58That 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 repair. Their new optimism comes from studying relatively long-lived species, such as bowhead whales and naked mole rats, and looking at the genetics of human centenarians. These studies are pointing to the existence of a great variety of molecular

2:32maintenance workers. A master regulator of repair, discovered in 2023, also suggests that these fix-it systems could be enhanced in unison. 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

3:05process, says Paul Robbins, who directs the Nathan Shock Centre on Genome Integrity and Ageing, which opened last year at the University of Minnesota in Minneapolis. Quote, there are tricks that we can do, but it's not

Cellular repair toolkits and systems

3:18simple. End quote. Despite having such a big job, DNA is remarkably fragile. Left unrepaired, its many breaks, kinks, kinks, lost bases, and cross-links 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 Bjorn Schumacher, a geroscientist at the University of Cologne in Germany. Cells have an ancient

3:54and 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 oxidised, 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

4:29single 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

5:07accurate. Non-homologous 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. Many genes are involved in these repair systems. Some researchers suggest

5:38that 10% of the genome plays a part in genome maintenance. In searching for ways to enhance repair, quote, this complexity has always been a limiting factor, says Schumacher. 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 Agniel

6:13Sverre, 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. The animal kingdom might provide clues. Scientists

Clues from long-lived animals

6:33are studying species with long, relatively cancer-free lives, including naked mole rats, Greenland sharks, elephants, bats and lobsters. For one of her latest projects, biologist Vera Gorbanova 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 a thousand times as many cells growing

7:08and dividing as humans do, cancer rarely creeps in. In a study published last year, Gorbanova 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, Gorbanova says. A protein called cold-inducible RNA binding protein that helps

7:45cells 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 Gorbanova 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 cells. That superior repair was explained in large part by

8:21one 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 seemed to make the beaver version more effective. Beavers live for 10 to 12 years in the wild, whereas mice typically live for a few years at most.

8:57Genetic studies suggest that some human centenarians might also carry a superior variant of the gene sirt6, says geneticist Jan Weig at the Albert Einstein College of Medicine in New York City. Veg co-leads a multi-team 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.

9:31Studies by Robbins, Gorbanova, and others show that supplementing mouse diets with fucoidans improves the animal's DNA repair, reduces senescence, and extends their healthspan and lifespan. Clinician geroscientist Andrea Meyer, 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

10:04as possible how fucoidans affect biology. The ins and outs of DNA repair don't just differ

Master regulators and clinical trials

10:11from 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 prioritised 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.

10:44In 2023, the team reported from experiments in the roundworm C. elegans that a protein complex already known for its role in cell proliferation represses many DNA repair genes in non-reproductive or somatic cells. 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

11:15boosted 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 DERK1A, is already a potential drug target. It is overexpressed in people with Down 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.

11:49For the first time, we could really boost the overall capacity to repair, he says. Robbins agrees that the finding is exciting, calling the study, quote, beautiful work, end quote. 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. 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

12:21maintain 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. Even among other somatic cells, there might be variations in DNA-fixing habits and strategies. Vick's team has found that cells in the liver have relatively high numbers of mutations,

12:51and one hypothesis is that because the liver acts as a detoxifier, its cells are exposed to more DNA-damaging agents than are those in other tissues. Liver cells commonly have more than two copies of chromosomes, a situation known as polyploidy. Maybe, Vick says, making these extra copies is a cheaper solution than trying to create better repair. A special case involves cancer cells, in which DNA repair is a double-edged sword.

13:23Cancer cells rely heavily on good repair to divide so rapidly, but they can also take advantage of defective repair to evolve quickly, thus evading cancer-targeting drugs. Rather than enhancing DNA repair, some existing and emerging treatments block specific DNA repair pathways to ultimately kill the cancer cells. Since cancer is a disease of ageing, researchers hoping to prolong healthy life will need not only to treat cancer, but also to prevent it from forming in the first place, Sphere says.

13:58It's tempting to think that boosting DNA repair might solve cancer and other aspects of ageing at once, but there's not yet evidence that such a double-blow is possible, says Sphere. Scheibe Knusen has been thinking about age-related diseases since he was a teenager. His grandmother had Alzheimer's disease, and his grandfather had Parkinson's. I was young, and I thought this was something that we must be able to fix, he says. In the years since, he has landed on a molecule that seems to stimulate DNA repair,

14:29extend lifespan in fruit flies, and improve memory in a mouse model of Alzheimer's disease. Although Scheibe Knusen hasn't published on it yet, he has received funding from the Lundbeck Foundation in Denmark to develop the compound into a drug. I'm very enthusiastic about this, but we'll see how it pans out, he says. Beyond Meyer's Vukoydan study, six other human studies are underway at a clinical trial centre that opened last year at the National University of Singapore's Academy for Healthy Longevity.

15:00One of those studies is investigating nicotinamide adenine dinucleotide, or NAD, a key metabolite involved in energy production and DNA repair. Supplements that aim to raise NAD levels are widely marketed as boosting energy and promoting longevity, but there's little evidence backing up the claims, says Meyer. Although NAD is clearly important for mitochondrial function, she says, quote, there is huge hype, end quote.

15:31That's why the study is asking, quote, how much do you need? How can we measure it? She says, quote, and if we're supplementing it, what kinds of effects do we have? End quote. Meyer has also founded a longevity clinic that includes personalised NAD testing and supplementation among its offerings. Because the molecules being tested probably have multiple targets, Meyer's team tries to measure many hallmarks of ageing, including senescence, epigenetic alterations, and mitochondrial dysfunction,

16:04as well as oxidative stress and other aspects of DNA quality. Lifestyle factors such as exercise, diet, and smoking also have an important role in genome stability, she says. They can lead to DNA damage, but might also influence repair capacity. One limitation is the lack of direct markers of DNA repair. Even DNA damage can't be easily measured in a meaningful way across organ systems in people, she says. Vig's team focuses on mutations because they are a major consequence of DNA damage.

16:39Except for large structural variations, mutations are pretty easy to quantify. But mutations alone don't seem to explain ageing. My great frustration is that we cannot really demonstrate that accumulating mutations in cells make them sick, says Vig. The only example is cancer, he says, in which it is a reasonable assumption, given that mutations accumulate with age and cause cancer. But what about heart disease? What about neurodegeneration? It's likely that for some conditions, the signalling that accompanies DNA damage

17:13is more important than the damage or mutations themselves, says Scheiby-Knursen. But what types of DNA damage are most responsible for the problematic signalling, why some damage seems to persist without being fixed, and how that damage accumulates with age remain big questions. Ultimately, what's most relevant for ageing might differ from tissue to tissue, making it a long shot to attempt to treat it in just one way. Robbins, who has been pursuing ways to kill or neutralise senescent cells for more than a decade,

17:47predicts that the field will progress as researchers identify small ways to enhance healthspan, and then find synergy among those smaller effects. Still, he says, quote, If enough people are testing drugs and looking at this, you'd just never know what home run you are going to get. End quote.

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