Why don't we live more than 120 years?

The first example of human literature is the epic of Gilgamesh. This 4,500-year-old poem tells the adventures of the Sumerian hero Gilgamesh in his search for the plant of eternal youth that will ensure him immortality, the great concern of humans. Although medical advances in recent decades have allowed us to double life expectancy, we have not yet extended the maximum longevity of the species. We do not know anyone who has lived longer than Jeanne Calment, a French woman who died at 122 years old at the end of the 20th century. However, the search continues. What do genetic and evolutionary studies tell us?

Each species has vital limits closely related to its metabolic rate and the maintenance of the integrity of its genetic material, DNA. The longevity of an organism depends on its cells being functional, which is the result of a balance, on the one hand, between the continuous damage they receive and the capacity for activation of cellular repair mechanisms; and, on the other hand, between the elimination of senescent cells and the capacity for regeneration. What we do know is that most of the genes involved in these processes are implicated in cancer and aging, two sides of the same coin, heads and tails.

Let's take it step by step. Human cells have an “internal clock” that counts how many times their DNA has been copied. We must consider that our body has been generated from a single initial cell that kept copying its DNA and dividing, generating new daughter cells. This replication capacity is maintained in adults in the stem cells of organs that regenerate, such as the skin; or in the stem cells of the bone marrow.

This clock depends on the length of telomeres (chromosome ends), which require an enzyme called telomerase to maintain them. However, all long-lived animals, including humans and elephants, inactivate telomerase in body cells, because, without an internal clock, even though replicative cells would become potentially immortal, more damage and mutations would also accumulate in the DNA. And this, the accumulation of mutations, causes the cell to become dysfunctional and triggers programmed cell death pathways – senescence – to make way for younger cells.

If we reactivated telomerase, mutated cells could continue to live, accumulating more mutations, and would be potentially immortal. But mutations and immortality are two characteristics of malignant cancer cells. In fact, studies in animal models show that lifespan can be extended in mice by activating telomerase, but that this intervention also increases cancer incidence. Perhaps it could be compensated by also activating cellular surveillance mechanisms responsible for eliminating cells with damaged DNA, but at the cost of eliminating too many cells. Ultimately, the balance is very difficult.

On the other hand, our neurons do not replicate once differentiated, and in this case, the internal telomere clock is not relevant. Instead, however, they accumulate waste over time, misfolded and dysfunctional proteins. And although we have more mechanisms for eliminating dysfunctional proteins and organelles, they also have limitations. Many neurodegenerative diseases, such as Parkinson's, Alzheimer's, and senile dementia, are precisely due to the excessive accumulation of proteins that we cannot recycle and that end up being toxic to neurons. Activating autophagy and dead cell clearance mechanisms would seem like a good solution, but a balance must also be found, because if we prune a tree too much, we can leave it without shoots.

Longevity also depends on genes

Recent studies show that longevity in humans has a heritability of 50%, which means that there are genetic variants that predispose to being longer-lived, and others that predispose to a shorter life, in addition to environmental factors. The analysis of the genome of very long-lived individuals indicates a set of genetic variants that are positive that would favor longevity by reducing processes such as inflammation or oxidative stress, and at the same time would increase DNA repair responses. Likewise, now that we have genetic biobanks, a retrospective genetic analysis can also be done on what the genetic determinants of death before life expectancy would be, and what has been found is that mutations that predispose to cancer would be the main cause of a shorter life.

In summary, the key to a long life is to have cells with intact DNA and without many mutations.

Finally, a very recent study in mice would show that there is an evolutionary trade-off, so that genetic variants that increase survival in young individuals simultaneously decrease maximum longevity. Biologically, the most important thing is to reproduce and give survival options to your descendants, therefore, these variants have been selected and those for living longer have not been prioritized. One of the most interesting results is that genetic variants are different in males and females and often in the opposite direction. Evolutionary trade-offs leave us perplexed, because genetic variants that would predispose a female to live a longer life could predispose her male offspring to live less time. Again, balance is needed.

But what about the future? We increasingly have more precise genetic modification tools, and more knowledge about our genome, in addition to the impact of epigenetics or the microbiome on longevity. Therefore, now the question of the 21st century is whether we will be able to tune ourselves to live more years.