Scientists searching for the Fountain of Youth find little evidence of a ‘longevity gene’

Apr 24, 2020 | 0 comments

By Amanda Elizabeth Kowalczyk

What do naked mole rats, elephants, bats and whales have in common? They are all exceptionally long-lived mammals, and recent research suggests that studying commonalities in the ways they evolved extreme life spans may provide fresh insights into the genetic basis of longevity.

Distantly related mammals evolved long life spans through a biological phenomenon known as convergent evolution, a process by which unrelated species independently develop the same trait. As species evolved similarly extended life spans via convergent evolution, genes related to long life also underwent convergent evolution in those species. By making the connection between evolutionary changes in life span and gene evolution, my colleagues and I were able to find genes associated with life span that are shared by many species.

One caveat in the study of longevity is the relationship between body size and life span across mammal species. Large mammals like whales and elephants have long life spans; small mammals like mice and rats have short life spans. Most mammals follow the general trend, but some defy it. Key examples include the naked mole rat, a hamster-sized creature that can live up to 40 years, and the little brown bat, a similar-sized flighted mammal that can live up to 34 years. We examined the genetic basis of both types of extreme life span to understand the different modes by which species evolved extreme longevity.

Our results were surprising. Rather than finding genes that evolved faster to drive increase in life span, we instead found that gene evolutionary rates primarily decreased as species evolved longer lives. In other words, rather than experiencing genetic changes associated with longer life, many genes were instead prevented from undergoing genetic changes. On an individual level, slower evolutionary rates indicate that genes are protected from developing potentially harmful mutations. The occurrence of many generations of lower mutation rates in a genetic region translates to slower evolution, or less change, than expected over millions of years. Genes that evolve slower likely have important functions, which is why they are protected from potentially harmful mutations.

For large, long-lived species, key genes played a role in cancer prevention. Slowly evolving genes were involved in DNA repair, cell cycle control, cell death, and immunity, all of which are mechanisms to prevent cancer cell formation and proliferation. Consider the molecular origins of cancer. For an organism to get cancer, first a genetic mutation must occur and fail to be corrected through DNA repair mechanisms.

As a result of the mutation, the now-cancerous cell fails to undergo programmed cell death and instead divides uncontrollably and independently of normal cell cycle control mechanisms. Carcinogenic cells evade immune response and eventually replicate and expand into cancerous tumors. Large, long-lived species show slower evolution of genes in every stage of the path toward developing cancer, which suggests that preventing cancer is a key functionality underlying the evolution of extended life span in those species.

These findings are part of a larger, much older story about the connection between cancer, life span and body size known as Peto’s paradox. According to the paradox, large animals should get cancer much more often than small mammals, but they don’t. Assuming every cell has the same probability of becoming cancerous at any given moment, large species should get cancer more often simply by virtue of their numerous cells. Large species that are also long-lived further multiply the problem by allowing more time for cancer to develop.

However, cancer incidences in different species are about the same, implying a lower rate of cancer development in large species compared to smaller species. In fact, if cancer rates in whales were the same as those in mice, all whales would die of cancer before they ever had the chance to reproduce. Our findings suggest that lower cancer rates in large mammals may be driven by slower evolution of genes related to many cancer prevention functionalities.

In species like bats and the naked mole rat that are small and long-lived, cancer control is a lesser concern. Accordingly, slowly evolving genes in those species are related primarily to DNA repair as opposed to other facets of cancer control. Prevention of DNA damage may help to prevent DNA degradation throughout a long life span that eventually leads to aging and disease.

Unlike many studies that focus on genetic changes unique to one or a few particularly long-lived species, this work identified the genetic basis of longevity throughout mammals. Accordingly, the results are generalizable to all mammal species, including humans, and can be used to guide further research focus regarding efforts to increase human life span.

The importance of cancer control and DNA repair to long life suggests that the answer to why humans age may be as simple as things wearing out over time, whether those things are cells or DNA. Over a life span, DNA accumulates damage that eventually results in cancer or broad-scale deficits to gene function that cause senescence, disease and eventual death. Our findings, coupled with existing evidence, suggest that there is no “longevity gene” that can be altered to increase life span in mammals, because aging is a complex, multifaceted process. Increasing human life span may instead depend on reducing the damage DNA incurs over time and tackling diseases related to old age.
Although there probably is no genetic fountain of youth, DNA may still be the key to a longer life.
Credit: Scientific American

Susan Burke March

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