Audio long read: Could mending damaged DNA prolong life?

0:00This is an audio-long read from Nature. In this episode, could mending damage DNA prolonged life, written by Elizabeth Quill and read by me Benjamin Thompson. 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 Morton Skybeak-Nuson, a translational geoscientist 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

1:04can introduce mutations which can contribute to cancer. And second, DNA damage seems to be one of the main drivers of aging. Researchers are amassing evidence that this type of damage underlies many of the hallmarks of aging, including chronic inflammation, metabolic 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. That raises a question. If DNA damage is at the root of aging, can boosting DNA repair

2:05slow 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. Then new optimism comes from studying relatively long-lived species, such as boheid 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 maintenance workers that make for a long and healthy life. A master regulator of repair discovered in 2023 also suggests that these fixate 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 aging populations. If you can reduce DNA damage, you would probably have a dramatic effect on the aging process, says Paul Robins, who directs the Nathan

3:08Shock Center on Genome Integrity and Aging, which opened last year at the University of Minnesota in Minneapolis. Quote, there are tricks that we can do, but it's not simple. End quote. Despite having such a big job, DNA is remarkably fragile. Left unrepaired, its many brakes, kinks, lost bases and cross-links can physically block the process is 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 of the origin of life, says Bjorn 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,

4:11gets oxidized and 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. Nuclear tide excision repair by comparison removes a couple of dozen nuclear tides along a single strand at once, a hefty of 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. Non-homologous end joining however, another way to fix double strand breaks doesn't

5:14require a template and does a more slapped-dash 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 that 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 Anniel Svehr, a molecular geneticist at the Memorial Sloan Kettering Cancer Center in New

6:18York 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 are 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 Gordbanova at the University of Rochester, New York and her team chose bo-head 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 and dividing as humans do, cancer really creeps in. In a study published last year, Gordbanova and her colleagues went looking for reasons why

7:18bo-head 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 us use the same thing. The whale cells mutate as far, Gordbanova says. A protein called 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 Gordbanova 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 one member of a family of enzymes called

8:23searchuins, which are known to have roles in aging, metabolism and the stability of the genome. The overexpression of the searchuins, search6, 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 search6 and seem to make the beaver version more effective. Beaver's live for 10 to 12 years in the wild, whereas mice typically live for a few years at most. Genetic studies suggest that some human centenarians might also carry a superior variant of the gene search6, says geneticist Jan Veig at the Albert Einstein College of Medicine in New York City. Veig 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

9:23fucoidans, which occur naturally in brown seaweed and activate the search6 protein as potential therapeutics. Studies by Robins, Gorbanover and others show that supplementing mouse diets with fucoidans improves the animal's DNA repair, reduces senescence and extends their health span and lifespan. Clinician-geroscientist Andrea Meyer, director of the National University of Singapore's Academy for Healthy Long Gevity, is now leading a study that gives fucoidans to men age 50 to 80. The study is looking at cellular markers of aging and clinical outcomes, measuring as directly as possible how fucoidans affect biology. The ins and outs of DNA repair don't just differ from organism to organism, they also differ from cell to cell. Spurman egg cells seem to accumulate much less DNA damage than other cell types do. DNA repair is energetically costly,

10:26so 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 Sea 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 aging 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 Dirk1A, is already a

11:29potential 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. 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, 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 maintain their genome across many divisions, have lower mutation rates than do other somatic cells. If stem cells are better at DNA repair,

12:30then 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. The X team has found that cells in the liver have relatively high numbers of mutations, and 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 VIX 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. Cancer 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.

13:36Rather than enhancing DNA repair, some existing in emerging treatments block specific DNA repair pathways to ultimately kill the cancer cells. Since cancer is a disease of aging, 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. It's tempting to think that boosting DNA repair might solve cancer and other aspects of aging at once, but there's not yet evidence that such a double blow is possible, says Sphere. Shybeek Newsson 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, extend lifespan in fruit flies, and improve memory in a mouse model of Alzheimer's disease. Although Shybeek Newsson hasn't published on it yet, he has received funding from the Lundbeck

14:40Foundation 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 Myers for Coidown Study, six other human studies are underway at a clinical trial centre that opened last year with the National University of Singapore's Academy for Healthy Long Chievity. One of those studies is investigating nicotinamide adenine dinucleotide, or NAD, a chemotabolite 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. That'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.

15:43Meyer has also founded a longevity clinic that includes personalized 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 aging, including senescence, epigenetic alterations, and mitochondrial dysfunction, as well as oxidative stress and other aspects of DNA quality. Lifestyle factors such as exercise, diet and smoking also have an important role in genomes 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. VIX team focuses on mutations because they are a major consequence of DNA damage. Except for large structural variations, mutations are pretty easy to quantify.

16:45But mutations alone don't seem to explain aging. My great frustration is that we cannot really demonstrate that accumulating mutations in cells make them sick, says VIX. 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 signaling that accompanies DNA damage is more important than the damage and mutations themselves, says Shibik Nursun. But what types of DNA damage are most responsible for the problematic signaling? 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 aging might differ from tissue to tissue, making it a long shot to attempt to treat it in just one way? Robins, who has been pursuing ways to cure law and neutralise

17:45senescent cells for more than a decade, predicts that the field will progress as researchers identify small ways to enhance health span and then find synergy among those smaller effects. Still, he says, quote, if enough people are testing drugs and looking at this, you just never know what home run you are going to get. End quote. To read more of Nature's long-form journalism, head over to nature.com slash news.