Genes determine species longevity, though within a species, and particularly within our species, the estimated involvement of genetic variants in individual life expectancy is becoming ever smaller as ever more data accumulates. Nonetheless, researchers are very interested in the comparative biology of aging, the question of why long-lived species are long-lived in comparison to their closest relatives. Which of the many evolved differences tend to produce a longer life span?
A longer species life span necessarily requires a lower incidence of cancer. Cancer is a numbers game: a larger body size means that there are more cells that can suffer mutation and become cancerous; a longer life allows more time for those cells to suffer mutation and become cancerous. Thus in larger and longer-lived species there must be mechanisms that either (a) lower the rate at which cancerous mutations can occur, or (b) increase the efficiency of cancer suppression mechanisms. These mechanisms are layered, ranging from those inside cells that provoke self-destruction when damage is identified, to the ability of the immune system to detect and destroy cancerous cells.
Elephants are both large and long-lived, and yet have a lower risk of cancer than is the case for our species. In recent years, researchers identified that elephants have many duplicated copies of the TP53 cancer suppression gene. The protein p53 produced from this gene is involved in DNA repair, as well as induction of cellular senescence and programmed cell death in response to DNA damage. It is thus an important part of cellular responses to potentially cancerous mutations. In today's open access paper, researchers report on their discovery of similar duplications in genes related to longevity and cancer suppression in long-lived Galapagos tortoises, indicating that this sort of evolutionary change is probably commonplace in longer-lived species.
It is interesting to consider that continually upregulating TP53 expression in short-lived mammals such as mice does improve cancer suppression, but also shortens life span, via mechanisms that likely include a reduction in stem cell activity and increase in the burden of cellular senescence. Too much vigilance has its costs. Researchers have worked around this issue, in mice at least, via forms of intermittent upregulation that only operate when TP53 is called upon, or via combining p53 upregulation with telomerase upregulation.
Concurrent evolution of anti-aging gene duplications and cellular phenotypes in long-lived turtles
A recurring theme in lifespan and aging regulation is the critical role played by processes that promote cellular protection and maintenance, including the ability of cells to recycle materials, repair damage, and remove waste. Senescent cells, whose numbers greatly increase with age, exhibit declines in these processes, and are also associated with pro-inflammatory phenotypes that are linked to age-related diseases. At the same time, apoptosis, which is the programmed destruction of unfit or damaged cells, is reduced in older individuals. This decline in cell performance in combination with a decreased ability to remove poor-performing cells is central to the aging process. Similarly, cancer can arise from cumulative genotoxic and cytotoxic stress, and apoptosis also plays a primary role in cancer resistance by removing potentially cancerous cells. Thus, if cancer-suppressing mechanisms are similar across species, then larger, longer-lived organisms should be at greater risk of cancer than smaller, shorter-lived ones. While this correlation exists within species, for example, cancer incidence increases with increasing adult height for most cancer types in humans and overall body mass in dogs, there is no such correlation between species - an observation often referred to as "Peto's paradox".
The molecular and cellular mechanisms underlying the evolution of large bodies and long lifespans have been explored in mammals such as elephants, whales, bats, and naked mole rats, but are less well studied in other vertebrates. Reptiles are an excellent system in which to study the evolution of body size and longevity because diverse lineages have repeatedly evolved large body sizes and long lifespans. Turtles, in particular, have lower rates of neoplasia than snakes and lizards, are especially long-lived, and are "slower aging" than other reptiles. Most notably, Galapagos giant tortoises (C. niger) and Aldabra giant tortoises (Aldabrachelys gigantea) can live over 150 years (3-5 times longer than their closest relatives) and weigh over 200 kg (50-100 times heavier than their closest relatives). Galapagos giant tortoises also appear to have evolved a suite of cellular traits that may contribute to their longevity, such as a slower rate of telomere shortening and extended cellular lifespans compared to mammals.
Here, we explore the evolution of body size and lifespan in turtles by integrating several approaches: (1) phylogenetic comparative analysis of body size, lifespan, and intrinsic cancer risk in turtles; (2) gene duplication analysis of aging and cancer-related genes across available turtle genomes; (3) cell-based assays of apoptosis and necrosis in multiple turtle species varying in body size and lifespan. We show that species with remarkably long lifespans, such as Galapagos giant tortoises, also evolved reduced cancer risk. We also confirm that the Galapagos giant and desert tortoise genomes encode numerous duplicated genes with tumor suppressor and anti-aging functions. Our comparative genomic analysis further suggests that cells from large, long-lived species may respond differently to cytotoxic stress, including endoplasmic reticulum (ER) stress and oxidative stress. The combined genomic and cellular results suggest that at least some turtle lineages evolved large bodies and long lifespans, in part, by increasing the copy number of tumor suppressors and other anti-aging genes and undergoing changes in cellular phenotypes associated with cellular stress.