Audio long read: Could mending damaged DNA prolong life?

**Benjamin Thompson** (0:02)
This 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.
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 Skybeak-Nussan, a translational geroscientist 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 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 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 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 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 Robbins, who directs the Nathan Shock 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 breaks, 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 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. 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 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 Annielle Svair, 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 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 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 1,000 times as many cells growing and dividing as humans do, cancer really 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 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 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 one member of a family of enzymes called sirtuins, which are known to have roles in aging, metabolism and the stability of 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. Genetic studies suggest that some human centenarians might also carry a superior variant of the gene Sirt6, says geneticist Jan Weg at the Albert Einstein College of Medicine in New York City. Weg 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 phucoidans, which occur naturally in brown seaweed and activate the Sirt6 protein as potential therapeutics. Studies by Robbins, Gourbanova, and others show that supplementing mouse diets with phucoidans improves the animal's DNA repair, reduces senescence, and extends their healthspan and lifespan.