Animals with a large difference in lifespan and size end their natural lives with a similar number of genetic changes, researchers have discovered.
The findings come from a study by the Wellcome Sanger Institute which analysed genomes from 16 species of mammal to understand the role genetic changes play in ageing and the development of cancer.
The study1 lends support to the idea that genetic changes play a role in ageing by confirming that the longer the lifespan of a species, the slower the rate at which mutations occur.
Theory on ageing
Genetic changes – also known as somatic mutations – occur in all cells throughout the life of an organism. For humans, this natural process sees cells acquiring around 20 to 50 mutations every year. Most of these mutations will be harmless but some will start to develop in cancer or impair the normal functioning of the cell.
Since the 1950s, scientists have theorised that somatic mutations play a role in the ageing process. However, the theory hasn’t been able to be confirmed due to the difficulty of observing these changes. Technological advances now mean genetic changes can be observed in human tissue.
Scientists have also questioned a theory known as Peto’s paradox which states that because cancer develops from single cells, animals or species with larger bodies should have a higher risk of cancer. However, cancer incidence across animals is independent of body size. It’s thought that animal species with large bodies have evolved superior mechanisms to prevent cancer. What isn’t known though is whether this particular mechanism corresponds to a reduction in the number of genetic changes in tissue.
Researchers at the Wellcome Sanger Institute tested these theories by using new methods to measure somatic mutation in 16 mammalian species, covering a wide range of lifespans and body masses. These included species such as human, mouse, lion, giraffe, tiger, and the long-lived, highly cancer-resistant naked mole-rat, with samples provided by a number of organisations including the Zoological Society of London.
The team then generated whole-genome sequences from 208 intestinal glands, taken from 48 individuals, to measure mutation rates in single intestinal stem cells.
The researchers found that somatic mutation, or genetic changes, were caused by similar mechanisms across all species, despite their very different diets and lifestyles. The team did find evidence of a possible role of somatic changes in ageing, with the rate of genetic changes decreasing as the lifespan of each species increased.
The team however did not find an answer to Peto’s paradox. 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.
Interestingly, the number of genetic mutations acquired over the lifespan of each of the species 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.
The researchers didn’t find the exact cause of ageing but believe it to be likely 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.
Next steps could be to compare the rates of these processing across species with very different lifespans to see the correlation to ageing.
“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 ageing, 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,” said Dr Alex Cagan, Wellcome Sanger Institute.
“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, added,” Dr Adrian Baez-Ortega, Wellcome Sanger Institute.