Aging is a seemingly inevitable process that concerns us all, individually and through its effects on the community. Decreased physical strength, resistance to infections or the effects of extreme temperatures, loss of memory and cognition, all well-known manifestations of all. Added to this are the increased risks of cancer and degenerative diseases of the brain and vascular system.
Can we fight aging, slow it down, prolong healthy life? Or even, as some dream, extend life expectancy beyond the known limits of around a hundred years? I am not convinced that this aspiration to a biblical fantasy (sort of going back to Methuselah and his kindred) is desirable. Do we want a society with an inverted age pyramid that would result in the height of gerontocracy? Also, is it doable? What does biology tell us?
We know today that our cells accumulate mutations within their genome, that is to say modifications of the DNA sequence. These variations can be neutral, or modify a biological function by disturbing the level of expression or function of a protein, or even confer on these cells a survival or growth advantage. This is the case with cancers, but also with certain bone marrow abnormalities that promote inflammation of the vessels and increase the risk of cardiovascular accidents.
An inverse correlation between the number of acquired mutations and life expectancy
However, our cells are armed with protective systems. They repair most of the mutations that appear when the genome is copied during cell divisions or when DNA is copied into messenger RNA. We also know that the rare genetic anomalies of these systems for correcting “spelling errors” in the genome cause premature ageing.
These somatic mutations are however difficult to study because it would be necessary, except in special cases, to sequence the genome individually of many cells, in several tissues at different ages and, finally, to determine the consequences of the mutations observed. The state of science does not allow it. However, recent studies looking for mutations in a relatively easily accessible tissue, the villi of the intestine, in different species of mammals, provide information of great interest: there is an inverse correlation between the number of mutations per genome and the ‘life expectancy. In other words, a mouse whose life expectancy is around 2 to 3 years accumulates as many mutations in these cells as an 80-year-old man. The rate of mutations per year of life is about 800 in mice against 47 in humans.
The explanation lies in the much better efficiency of the genome protection systems (spelling error correctors) that we have. Nevertheless, if we admit that we can extrapolate cells from the intestine to our whole body, we accumulate mutations that can be deleterious. The neurons of patients with Alzheimer’s disease have a greater number of mutations than the neurons of people of the same age without the disease. One of the most visible abnormalities concerns, in humans, the loss of the Y chromosome observable in blood cells, which correlates with a lower life expectancy.
Avoid premature aging
What conclusions can be drawn from this work? It seems that somatic mutations, which are ten to twenty times more frequent than germline mutations carried by gametes and therefore heritable, account for most (82%) of the variability in life expectancy between species, which is considerable. This accumulation of mutations is inevitable even if the prevention of exposure to mutagenic substances (tobacco, etc.) can slightly reduce the rate.
Therefore, it is perfectly illusory to consider prolonging human life beyond known biological limits or really to consider a “rejuvenation” of our cells by transforming them into stem cells. This operation is feasible, but such cells will always carry the weight of mutations accumulated during life… It seems much more relevant to act on known factors (physical and mental activity, nutrition) to avoid premature aging and to set up support measures for the elderly with dignity and empathy.
Prof. Alain Fischer is Professor of Pediatric Immunology, Honorary Professor at the Collège de France and member of the Academies of Medicine and Sciences.