Fight Aging!

Much of the recent research into the longevity of large mammals such as elephants has focused on Peto's paradox. If the odds of cancer are based on the number of cells in the body, all of which undergo stochastic and potentially cancerous mutations at some rate, then how is it that large mammals, with many times more cells in their body, do not exhibit a correspondingly larger risk of cancer? The answer being that for larger mammals to evolve at all, their cancer risk must be managed downward by changes in cellular biochemistry that reduce mutation rate or more efficiently destroy potentially cancerous cells. In elephants this appears to be achieved, in large part at least, by the 20-fold duplication of TP53, a cancer suppression gene.

There is a lot more to think about when it comes to the longevity of elephants, however, and today's open access review paper is an interesting read on this topic. For example, the unusual biology of hormones in male elephants, combined with the mating behavior of elephants in general, leads to greater reproductive success later in life, which likely puts selection pressure on greater longevity. Something much like this, or analogous situations such as the Grandmother hypothesis in humans, in which intelligence and culture allows older individuals to materially contribute to the reproductive success of their grandchildren, must exist in order to drive the evolution of increased longevity in a species.

Aging: What We Can Learn From Elephants

Elephants are large-brained, social mammals with a long lifespan. Studies of elephants can provide insight into the aging process, which may be relevant to understanding diseases that affect elderly humans because of their shared characteristics that have arisen through independent evolution. Elephants become sexually mature at 12 to 14 years of age and are known to live into, and past, their 7th decade of life. Because of their relatively long lifespans, elephants may have evolved mechanisms to counter age-associated morbidities, such as cancer and cognitive decline. Elephants rely heavily on their memory, and engage in multiple levels of competitive and collaborative relationships because they live in a fission-fusion system in which groups change membership frequently. Female matrilineal relatives and dependent offspring form tight family units led by an older-aged matriarch, who serves as the primary repository for social and ecological knowledge in the herd. Similar to humans, elephants demonstrate a dependence on social bonds, memory, and cognition to navigate their environment, behaviors that might be associated with specializations of brain anatomy.

Males have a unique combination of behavioral and physiologic traits that reflect the intense pressure to compete for access to estrous females. In general, females are in estrous for only 3-6 days every 3-9 years. Males grow throughout much, or perhaps all, of their lifespan, in terms of stature, as well as body and tusk weight. Males experience musth, unique to elephants, which is characterized by bouts of elevated testosterone and aggression, and heightened sexual activity. Females prefer larger males and those in musth, which may explain why paternity success steadily increases in males from the mid-20s until it peaks around early 50s, after which, it is comparable to a male in his early 40s. This observation suggests male elephants may undergo sexual selection for longevity.

One mechanism allowing elephants to reach longer lifespans may be their multiple copies of the tumor suppressor gene TP53, colloquially known as the "guardian of the genome." Humans have one copy of TP53, whereas savanna, forest, and Asian elephants are estimated to have 19-23, 21-24, and 19-22 TP53 copies, respectively. This is compared to estimates of 19-28, and 22-25 TP53 copies in the extinct woolly mammoth and straight-tusked elephant, respectively. Of the multiple elephant TP53 genes, only one appears to have a comparable gene structure to other mammals, while the other copies appear to be retrogenes, as they lack true introns. Retrogenes can have functional biological roles. Indeed, genetic variation at some elephant TP53 retrogenes is conserved across all three extant elephant species, providing evidence of the functionality of at least some TP53 retrogenes. As reported recently, TP53 is activated in response to cellular stresses in addition to DNA damage. Thus, these multiple copies may have various effects in response to cell stress. Elephants appear to have an enhanced apoptotic response to DNA damage owing to their extensive number of TP53 retrogenes and, as a result, develop cancer at lower rates than expected for their body size and lifespan.