LONGECITY

The most interesting comparative biology programs aim to use the cellular biochemistry of unusually regenerative, long-lived, and cancer resistant species as a tool to better understand our vulnerabilities to aging and injury. In principle, understanding why a species is unusually long-lived could point to a basis for therapies to slow aging in humans, while understanding why species such as naked mole-rats, elephants, whales, and turtles have such low incidence rates of cancer could point to ways to shut down human cancers. This remains a hypothesis, as comparative biology research has not yet advanced to the point at which technology demonstrations of transferring biochemistry between species are commonplace, or at which any of the discoveries seem easily used as a basis for the development of therapies. It may just be a matter of time, or it may be that this is a project for a more distant future in which engineering significant changes in human biochemistry is an easier undertaking.

Turtles occupy the extremes of biology, but perhaps are best known for their longevity: even the shortest-lived species (the chicken turtle, Deirochelys reticularia) exceed 20 years, whereas others, such as Galapagos and Aldabra giant tortoises, can live well over 150 years. Turtles also exhibit remarkable variation in adult body size. Theoretically, organisms with more cells and higher lifetime cellular turnover should face greater cancer risk. Therefore, large, long-lived species must have evolved mechanisms to mitigate this increased risk. On the basis of their considerable variation in both body mass and lifespan, turtles are a promising group for studying the evolution of natural cancer resistance. However, cancer reports in turtles remain exceedingly rare - far less common than in mammals, birds, or even other reptiles.

To build on previous studies, we analyzed 290 additional necropsies from 64 turtle species across eight zoos in Europe, the United Kingdom, and the United States, representing nine taxonomic families. Despite extensive taxonomic and geographic coverage - from the tiny black-breasted leaf turtle (Geoemyda spengleri; 150 grams) to the Galapagos giant tortoise (Chelonoidis spp.; less than 300 kilograms) - we found only one case of neoplasia, in the mata mata (Chelus fimbriata), with no malignancies detected. This corresponds to neoplasia and cancer prevalence estimates of 0.34% and 0%, respectively. These values are similar to those reported by other groups. Taken together, this data reinforces the conclusion that cancer is very uncommon in turtles. When cancer does occur, it rarely metastasizes, suggesting that turtles may possess biological or evolutionary traits contributing to their low cancer prevalence.

Genomic analyses of large, long-lived species such as Galapagos and Aldabra giant tortoises, have revealed positive selection and duplications in key tumor suppressor genes, metabolic regulators, immune response genes, and pathways involved in genome maintenance. Moreover, comparative studies indicate that Galapagos tortoises exhibit enriched expression of tumor suppressors, proteostasis regulators, and metabolic pathways associated with growth control, potentially contributing to their reduced cancer susceptibility. Functional assays in Galapagos giant tortoise cell lines further suggest an enhanced ability to trigger apoptosis to mitigate endoplasmic reticulum stress, which may help clear damaged cells before tumorigenesis can occur.

Link: https://doi.org/10.1093/biosci/biaf100