Multi-Species Study Confirms Somatic Mutations’ Role in Aging

Researchers in the United Kingdom have conducted the first study comparing somatic mutations across multiple animal species in order to better understand the role these genetic changes play in aging and cancer development.

By analyzing the genomes of 16 species of mammals, including mice, humans, and giraffes, the Wellcome Sanger Institute team found that the quantity of mutations was similar over lifetimes, despite vast differences in lifespan and body mass.  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.

The findings, published recently in Nature, confirm that the longer the lifespan of a species, the slower the rate at which mutations occur, lending support to the long-standing theory that somatic mutations play a role in ageing.

“Somatic mutations have been speculated to contribute to aging since the 1950s, but studying them had remained difficult,” says coauthor Dr. Inigo Martincorena. “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.”

The study used new methods for measuring somatic mutations in 16 mammalian species, including human, mouse, lion, giraffe, tiger, and the long-lived, highly cancer-resistant naked mole-rat. Whole-genome sequences were generated from 208 intestinal crypts taken from 48 individuals. The researchers found that somatic mutations accumulated linearly over time and that they were caused by similar mechanisms across all species, including humans, despite their very different diets and life histories.

“To find a similar pattern of genetic changes in animals as different from one another as a mouse and a tiger was surprising,” says Dr. Alex Cagan, of the Wellcome Sanger Institute. “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.”

Another long-standing question the study hoped to shed light on is Peto’s paradox: because 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. Animal species with large bodies are believed to have evolved superior mechanisms to prevent cancer. Whether one such mechanism is a reduction in the accumulation of genetic changes in their tissues has remained untested.

The work did not provide any insights into Peto’s paradox, however. 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.

 “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,” says Dr. Adrian Baez-Ortega. “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.”