The first study to compare the accumulation of mutations across many animal species has shed new light on decades-old questions about the role of these genetic changes in aging and cancer. Researchers from the Wellcome Sanger Institute found that despite huge variations in lifespan and size, different animal species end their natural life with similar numbers of genetic changes. The results of whole-genome sequencing across 16 different mammalian species confirmed that the longer the species lifespan, the slower the rate at which mutations occur. This lends support to the long-standing theory that somatic mutations play a role in aging.

Inigo Martincorena, PhD, senior author of the team’s report, which is published in Nature, said, “Aging is a complex process, the result of multiple forms of molecular damage in our cells and tissues. Somatic mutations have been speculated to contribute to aging since the 1950s, but studying them had remained difficult. With the recent advances in DNA sequencing technologies, we can finally investigate the roles that somatic mutations play in aging and in multiple diseases. That this diverse range of mammals end their lives with a similar number of mutations in their cells is an exciting and intriguing discovery.” In their report, titled “Somatic mutation rates scale with lifespan across mammals,” the authors concluded, “These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in aging.”

Genetic changes, known as somatic mutations, occur in all cells throughout the life of an organism. This is a natural process, with cells acquiring around 20 to 50 mutations per year in humans. Most of these mutations will be harmless, but some of them can start a cell on the path to cancer or impair the normal functioning of the cell. Since the 1950s, some scientists have speculated that these mutations may play a role in aging. “They underpin the development of cancer and, for decades, have been speculated to contribute to aging,” the team noted.

But the difficulty of observing somatic mutations has made it challenging to study this possibility. “Directly studying somatic mutations in normal tissues has been challenging owing to the difficulty of detecting mutations present in single cells or small clones in a tissue,” Martincorena and colleagues further stated.

In the last few years, technological advances have finally allowed genetic changes to be observed in normal tissues, raising hopes of answering this question. “Only recent technological developments, such as in vitro expansion of single cells into colonies, microdissection of histological units, single-cell sequencing, or single-molecule sequencing, are beginning to enable the study of somatic mutation in normal tissues,” the team further noted.

Another long-standing question is Peto’s paradox. Since cancers develop from single cells, species with larger bodies (and therefore more cells) should theoretically have a much higher risk of cancer. Yet cancer incidence across animals is independent of body size. “Some models predict that the risk of cancer should increase proportionally to the number of cells at risk of transformation. However, there appears to be no correlation between body mass and cancer risk across species,” the investigators noted. Animal species with large bodies are believed to have evolved superior mechanisms to prevent cancer. Yet, as the researchers acknowledged, “Whether evolutionary reduction of cancer risk across species is partly achieved by a reduction of somatic mutation rates remains unknown … If somatic mutations contribute to aging, theory predicts that somatic mutation rates may inversely correlate with lifespan across species. This prediction has remained largely untested owing to the difficulty of measuring somatic mutation rates across species.”

In their reported study, the Wellcome Sanger Institute team and colleagues set out to test these theories, and used whole-genome sequencing technology to measure somatic mutations in 16 mammalian species, covering a wide range of lifespans and body masses. The species included human, mouse, lion, giraffe, tiger, and the long-lived, highly cancer-resistant naked mole-rat. “To study somatic mutations across a diverse set of mammals, we isolated 208 individual intestinal crypts from 56 individuals across 16 species with a wide range of lifespans and body sizes …” they wrote. Samples for analysis were provided by a number of organizations including the Zoological Society of London.

Analysis of the patterns of mutations (or mutational signatures) provided information on the mutational processes at work. The researchers found that somatic mutations accumulated linearly over time and that they were caused by similar mechanisms across all species, including humans, despite the animals’ very different diets and life histories.

Evidence of a possible role of somatic mutations in aging was provided by the discovery that the rate of somatic mutation decreased as the lifespan of each species increased. “Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association,” the investigators reported.

Despite vast differences in lifespan and body mass between the 16 species studied, the quantity of somatic mutations acquired over each animal’s lifetime was relatively similar. On average, a giraffe is 40,000 times bigger than a mouse, and a human lives 30 times longer, but the difference in the number of somatic mutations per cell at the end of lifespan between the three species only varied by around a factor of three. “Despite widely different life histories among the species we examined—including variation of around 30-fold in lifespan and around 40,000-fold in body mass—the somatic mutation burden at the end of lifespan varied only by a factor of around 3,” the team stated in their paper.

First author Alex Cagan, PhD, from the Wellcome Sanger Institute, commented on the results. “To find a similar pattern of genetic changes in animals as different from one another as a mouse and a tiger was surprising. But the most exciting aspect of the study has to be finding that lifespan is inversely proportional to the somatic mutation rate. This suggests that somatic mutations may play a role in aging, although alternative explanations may be possible. Over the next few years, it will be fascinating to extend these studies into even more diverse species, such as insects or plants.”

The search for an answer to Peto’s paradox does go on. After accounting for lifespan, the authors found no significant association between somatic mutation rate and body mass, indicating that other factors must be involved in larger animals’ ability to reduce their cancer risk relative to their size.

Adrian Baez-Ortega, PhD, a first author of the study from the Wellcome Sanger Institute, said: “The fact that differences in somatic mutation rate seem to be explained by differences in lifespan, rather than body size, suggests that although adjusting the mutation rate sounds like an elegant way of controlling the incidence of cancer across species, evolution has not actually chosen this path. It is quite possible that every time a species evolves a larger size than its ancestors—as in giraffes, elephants, and whales—evolution might come up with a different solution to this problem. We will need to study these species in greater detail to find out.”

Simon Spiro, PhD, a Zoological Society of London wildlife veterinary pathologist, said, “Animals often live much longer in zoos than they do in the wild, so our vets’ time is often spent dealing with conditions related to old age. The genetic changes identified in this study suggest that diseases of old age will be similar across a wide range of mammals, whether old age begins at seven months or 70 years, and will help us keep these animals happy and healthy in their later years.”

Understanding the exact causes of aging remains an unsolved question and an area of active investigation. Aging is likely to be caused by the accumulation of multiple types of damage to our cells and tissues throughout life, including somatic mutations, protein aggregation, and epigenetic changes, among others. Comparing the rates of these processes across species with very different lifespans can shed light on their role in aging.

And as the authors concluded in their report, “Altogether, this study provides a detailed description of somatic mutation across mammals, identifying common and variable features and shedding light on long-standing hypotheses. Scaled across the tree of life and across tissues, in species with markedly different physiologies, life histories, genome compositions, and mutagenic exposures, similar studies promise to transform our understanding of somatic mutation and its effects on evolution, aging, and disease.”

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