A new study carried out by the the Wellcome Trust Sanger Institute sheds new light on the role of genetic changes in ageing and cancer. By comparing the accumulation of mutations across many animal species, researchers found that despite a huge variation in lifespan and size, different animal species end their natural life with similar numbers of genetic changes.
The study (published 13 April 2022 in Nature) analysed genomes from 16 species of mammal, from mice to giraffes. The analyses confirmed that the longer the lifespan of a species, the slower the rate at which mutations occur, lending support to the theory that somatic mutations play a role in ageing.
Somatic mutations are genetic changes that occur in all cells throughout the life of an organism. In this natural process, in humans cells acquire around 20 to 50 mutations per year. Most of these are harmless, but some can start the process of developing cancer or impairing the normal functioning of a cell.
Since the 1950s there has been speculation that these mutations may play a role in ageing, but it is only now with technology able to observe genetic changes in normal tissue that research can start to answer whether this is the case.
Peto's paradox. Since cancers develop from single cells, species with larger bodies (and therefore more cells) were thought to have a higher risk of cancer. But cancer incidence across animal species is independent of body size. Large bodied animal species are thought to have evolved mechanisms to prevent cancer but until now this has not been tested.
The Wellcome Sanger Institute study used new methods to measure somatic mutation in 16 mammalian species with a wide range of lifespans and body sizes, including human, mouse, lion, giraffe, tiger and the long-lived and highly cancer resistant naked mole-rat. Mutation rates were measured in intestinal stem cells. Analysis of the patterns of mutations indicated that somatic mutations accumulated linearly over time, and were caused by similar mechanisms across all species, including humans, despite different diets and life histories. Also the rate of somatic mutation decreased as the lifespan of each species increased. Researchers now want to study further diverse species, including insects and plants.
Peto's paradox still needs an answer, since after accounting for lifespan, researchers found no significant link between somatic mutation rate and body mass, indicating that other factors must be involved as well. It does not seem that evolution has chosen a single way of controlling the incidence of cancer, but that it is possible that every time a species evolves a larger size than its ancestors, evolution might use a different solution to the problem.
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 exact causes of ageing remain unsolved, though it is likely to be caused by the accumulation of multiple types of damage to cells and tissues throughout life, including somatic mutations, protein aggregation and epigenetic changes.
Source: Mutations across animal kingdom shed new light on ageing in Science Daily, 13th April 2022.
