Everyone is familiar with the widely varying sizes, as well as lifespans, of different mammals. A mouse, weighing in at under an ounce, lives a mere 12 to 18 months. Male elephants can weigh up to 13,000 pounds and have an average lifespan of 60 to 70 years. The blue whale dwarfs the elephant and can weigh over a staggering 400,000 pounds and can live 80 to 90 years.
All animals, large and small, as well as humans, regularly acquire what are known as somatic mutations that occur throughout the lifetime of the organism. These somatic mutations are genetic changes in cells other than the animal’s reproductive cells, with humans accumulating around 20 to 50 of these mutations a year.
While the majority of these mutations are harmless, some of them can affect the normal functioning of a cell or even trigger the cell to become cancerous. For decades, researchers have believed that these mutations must somehow also play a role in aging, but did not have the technological means to study them. The technology is now in place that enables scientists to observe these somatic mutations in normal cells.
Peto’s Paradox
But besides somatic mutations' possible role in aging, researchers also had another unanswered question about the development of cancer, known as Peto’s paradox.
The paradox goes like this: cancer develops from single cells. So larger animals, such as elephants that have many more cells than smaller animals, like a mouse, should in theory have a higher cancer risk.
Only they don’t. The incidence of cancer in different animals is totally independent of their body size. Scientists speculate that, somehow, larger animals have evolved some sort of mechanism so that they don’t develop cancer at the rate that would be expected from their size alone. One of the theories that might explain this is that larger animals have a reduced rate of the accumulation of somatic mutations in their cells, but until now, this was not able to be tested.
In a new study published on April 13, 2022 in the prestigious journal Nature, scientists examined the cells of sixteen different species: black-and-white colobus monkey, cat, cow, dog, ferret, giraffe, harbour porpoise, horse, human, lion, mouse, naked mole-rat, rabbit, rat, ring-tailed lemur and tiger. The researchers found that in spite of the tremendous variation in body size as well as lifespan, when different animal species reach the end of their natural lives, they all have similar numbers of somatic mutations.
The researchers also discovered something else related to lifespan, which confirmed their earlier suspicions. The longer the animal’s lifespan, the slower the rate at which these somatic mutations occur. This suggests that the scientists’ decades long speculations about somatic mutations playing a part in the aging process is correct.
But after the scientists accounted for lifespan, there was no association between the size of the animal and the rate of somatic mutations, leading the researchers to theorize there are other factors at play in larger animals' reduction in cancer risk relative to their body size.
Aging and Genetic Changes
Aging is a complex and multifactorial biological process, and the accumulation of genetic changes in the form of somatic mutations is not all that is occurring. Cells and body tissues can be damaged in many other ways, including the accumulations of mis-folded proteins both within and outside the cells, as well as epigenetic changes, which occur as the result of environmental influences.
Epigenetic changes don’t actually result in a change in the cell’s DNA, but can affect the way the genes work by altering how the body "reads" a particular DNA sequence. Other epigenetic changes can prevent the genes from being expressed and, as a result, the proteins encoded by those genes never get made.
Cancer and Genetic Changes
An earlier study, published in October 2018 by this same group of researchers, from the Wellcome Sanger Institute and MRC Cancer Unit, University of Cambridge, looked at esophageal cells in healthy people with no signs or symptoms of disease. The scientists became interested in esophageal cells because they already knew that healthy cells accumulate somatic mutations.
Previous research revealed that about a quarter of the cells in a person’s normal skin have cancer driven mutations. But because human skin is exposed to the sun and the ultraviolet light it contains is known to increase the development of cancer, the researchers took samples from the inside of the esophagus, where no sunlight would ever penetrate.
The research revealed that for people in their twenties, healthy cells from the esophagus already have at least several hundred mutations in each cell. This number increases dramatically to over 2,000 mutations per cell for those who are older.
But the fascinating and rather unexpected finding of the study was this: when examined under the microscope, the esophageal cells from the study participants, who were all healthy and had no symptoms of disease, looked completely normal. But when the scientists examined the genetic make-up of those same cells they discovered the esophageal tissues were completely interpenetrated with mutations, so much so that in middle age study subjects, the mutant cells actually outnumbered the normal ones!
These particular mutations have been associated with esophageal cancer and it appears that in the study subjects, these mutations gave the cells a competitive advantage and allowed them to “take over” the surrounding tissue to form a dense patchwork of mutated cells.
These studies mark just the beginning of understanding how genetic changes such as somatic mutations drive the development of cancer and what role these mutations play in the aging process. Cancer of the esophagus is notoriously hard to treat, with only 20 percent of patients surviving longer than five years after their diagnosis.
Understanding how these somatic mutations develop and also allow for a competitive advantage for cells in the esophagus that carry them could lead to diagnostic tests that could enable the disease to be discovered much, much earlier, leading to a greatly improved survival rate.
Alzheimer’s and Genetic Changes
Cells don’t always succumb to DNA damage, as they have repair pathways to deal with the effects, but in diseases such as Alzheimer’s, the neurons (brain cells) cannot keep up with the amount of damage that is being done. In fact, in people with Alzheimer’s, the neurons accumulate mutations much more quickly than in people without the disease.
These mutations result in the build-up of proteins known as amyloid-β and tau that induce the production of reactive oxygen species, contributing to the death of brain cells. In a study published in April 2022, researchers found that people with Alzheimer’s had large numbers of newly acquired mutations in their brain cells, an amount large enough to actually disable genes important to brain function.
What This Research Means for Your Health
The science of longevity and aging, as well as insights into the development of cancer, depends on these early foundational genetic studies, which sets the stage for further research and development of diagnostic and therapeutic modalities. In the meantime, you must, as an individual, optimize your health through a combination of nutrition, targeted supplementation, exercise, quality sleep and stress control to keep the effects of these inevitable mutations in check.
References:
1. Cagan, A., Baez-Ortega, A., Brzozowska, N. et al. Somatic mutation rates scale with lifespan across mammals. Nature 604, 517–524 (2022). https://doi.org/10.1038/s41586-022-04618-z
2. Martincorena I, Fowler JC, Wabik A, Lawson ARJ, Abascal F, Hall MWJ, Cagan A, Murai K, Mahbubani K, Stratton MR, Fitzgerald RC, Handford PA, Campbell PJ, Saeb-Parsy K, Jones PH. Somatic mutant clones colonize the human esophagus with age. Science. 2018 Nov 23;362(6417):911-917. doi: 10.1126/science.aau3879. Epub 2018 Oct 18. PMID: 30337457; PMCID: PMC6298579.
3. Miller, M.B., Huang, A.Y., Kim, J. et al. Somatic genomic changes in single Alzheimer’s disease neurons. Nature (2022). https://doi.org/10.1038/s41586-022-04640-1
