A Mutational Limit for Lifespan?

It has long been known that mammalian lifespan roughly correlates with animal size, i.e. larger animals live longer than smaller ones. Mice generally live less than 2 years, your average dog lives 10-13 years, and humans have a typical lifespan of 73 years. What is less clear is the mechanistic basis for this observation. Differences in various biological parameters such as metabolic rates, immune system activity, and mitochondrial function have been examined without a uniform relationship to lifespan. One parameter that is generally known to impact aging is DNA damage. Every time cells in the body divide their entire DNA genome needs to be replicated. This copying process is never perfect and mistakes are made in the new copy (like an uncorrected typo when retyping some written material). Each mistake is a mutation that is now permanently present in that cell and all its descendants. Additionally, there are both spontaneous biochemical reactions that alter DNA as well as environmental insults that damage DNA nucleotides. If not corrected by cellular DNA repair systems, these effects also result in permanent mutations. Just like the accumulation of typos in a document can garble its meaning, the build-up of mutations in the cells can distort biological activities leading to dysfunctional cells and/or cancer. This gradual accretion of damaged DNA likely contributes significantly to the slow decline in all bodily functions as cells and organs lose their youthful abilities.

Human mutations have been widely studied and there are four specific types of nucleotide changes that are most common; these types are referred to as mutational signatures. Surprisingly, similar investigations in diverse mammalian species have not been done. A new study in the journal Nature compared mutational types and rates in 16 different types of mammals ranging in size from a mouse to a giraffe. Intestinal tissues were harvested from each animal and the DNA was sequenced to identify mutations. All the mammals tested showed mutational signatures similar to humans suggesting that the underlying mutational mechanisms are similar across species. In contrast, the mutational rates varied dramatically, decreasing as animals got larger. For example, mice accumulated around 800 mutations per year, dogs 250 per year, and humans only 47 per year. Intriguingly, when the total mutations per animal lifespan (number of mutations per year times the number of years of life) were calculated, all the species, including humans, each peaked at about 3,200 mutations. The significance of that number is not known, but it could suggest that there is a mutational threshold beyond which there is too much genetic damage to sustain functional cells and thus the life of the animal. The results also imply that larger animals must have developed better systems to protect their DNA integrity and reduce the yearly mutational burden. It would be interesting to examine a broad range of humans to see if centenarians and other long-lived individuals have fewer mutations than average people. Perhaps finding ways for humans to make our mutational rates even lower could help delay aging and/or improve the quality of life in our elder years.

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