14 April 2022

Mutations and aging

The life expectancy of mammals was associated with the frequency of mutations in their DNA

Daniil Sukhinov, Naked Science

Genetic changes, known as somatic mutations, occur in all somatic (that is, all but sexual) cells of the body throughout its life. This is a natural process in which, for example, human somatic cells acquire from 20 to 50 mutations per year. Most of these mutations are harmless because they do not affect vital parts of DNA, but some of them can disrupt the normal functioning of the cell and even contribute to its transformation into cancer.

Since the 50s of the last century, a number of scientists have suggested that these mutations can play a significant role in the aging of cells and the whole organism. However, the complexity of observing somatic mutations in individual cells made it difficult to study this possibility. Only in the last few years, technological progress in the reproduction and sequencing of single cells of the body has allowed such genetic changes to be observed, which means that the answer to this long-standing question can finally be found. 

Another question from the last century is the Peto paradox. It was formulated by the English statistician and epidemiologist Richard Peto in 1977 and is as follows: if cancer develops from individual cells, species with larger bodies (and, consequently, with more cells) theoretically should have a higher risk of developing cancer. Nevertheless, it has been repeatedly shown that the incidence of cancer in animals does not depend on their body size.

The paradox may have several permissions. For example, it is most likely that animal species with large bodies have simply developed more advanced cellular mechanisms to prevent the development of cancer. But it is still unclear whether one of these mechanisms is a decrease in the accumulation of genetic changes in their tissues. 

A group of scientists from the UK decided to test these theories by studying somatic mutations in 16 species of mammals covering a wide range of life expectancy and body weight. Among the studied species: man, monkey, mouse, cat, lion, tiger, dog, giraffe and a long-lived naked digger with a known high resistance to cancer. The results of the study are published in the journal Nature (Cagan et al., Somatic mutation rates scale with lifespan across mammals). 

The authors found that somatic mutations accumulate linearly over time, they are caused by similar mechanisms in all studied species, including humans, despite their significant differences. At the same time, the frequency of somatic mutations decreases as the life expectancy of each species increases: therefore, DNA mutations play an important role in the aging of the body.


Linear regression of the burden of somatic substitutions (the number of mutations in somatic cells) depending on individual age on the example of dogs, humans, mice and naked diggers. Shaded areas indicate 95% confidence intervals of the regression line. Figures from the article by Cagan et al.

"The identification of a similar pattern of genetic changes in animals as unlike each other as a mouse and a tiger was unexpected. But the most exciting aspect of the study was the discovery that life expectancy is inversely proportional to the frequency of somatic mutations. This suggests that somatic mutations may play some role in aging, although alternative explanations are possible. Over the next few years, it will be interesting to expand these studies to include even more diverse species, such as insects or plants," explains Dr. Alex Cagan from the Sanger Institute (UK) and the first author of the study. 

However, Peto's paradox still remained unresolved. After taking into account life expectancy, the authors did not reveal a significant relationship between the frequency of somatic mutations and body weight. This means that the ability of larger animals to reduce the risk of cancer should be influenced by other factors. 


The dependence of the frequency of mutations per year on life expectancy (c) and on the logarithm of adult body weight (e) for all mammals studied.

According to the authors, mutation correction seems to be a very elegant way to control the incidence of cancer, but evolution, apparently, did not follow this path, but came up with another solution to the problem. 

Interestingly, despite the huge differences in life expectancy and body weight between the 16 studied species, the differences in the number of somatic mutations acquired during the life of each animal were relatively small. On average, a giraffe is 40 thousand times larger 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 life between these three species is "only" three times. This means that the diseases of old age can be very similar in a wide range of mammals, regardless of whether this old age begins at seven months or at 70 years.

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