Insights from the Genome of the Aldabra Giant Tortoise
The oldest land animal with an established age is an Aldabra giant tortoise, at 194 years. Researchers have sequenced the genomes of an old and young Aldabra giant tortoise to compare with other long-lived species and with less long-lived giant tortoises, part of a continuing effort to better understand aging via comparative biology. There is that hope that the comparative biology of aging can identify which mechanisms of aging are most important, as well as identify specific biochemical differences in long-lived species that may one day form the basis for therapies to slow aging in humans. We stand some way removed from that goal; only very recently have the first experiments taken place that move specific genes from long-lived species into short-lived species, and it will be years yet before those first studies could give rise to new medicine.
Recent studies on longevity have used comparative genomic analysis, focusing on long-lived animals like the naked mole rat, bowhead whale, Brandt's bat, immortal jellyfish, and long-lived variants of the African turquoise killifish. These investigations have deepened our understanding of gene markers that potentially slow aging and inhibit cancer in these species. To further explore longevity pathways, we evaluated the genome of Jonathan, an Aldabra giant tortoise (Aldabrachelys gigantea) with an estimated age of 194 years, considered the world's oldest known land animal. Giant tortoises are known for their long life spans, and some species harbor longevity-associated genetic features. Prior genomic analyses of two Aldabra giant tortoises and a Galapagos giant tortoise, Lonesome George (Chelonoidis abingdonii), identified longevity-associated nonsynonymous single-nucleotide variations (nsSNVs) in genes like IGF1R, DCLRE1B, and XRCC6. However, no existing study has assessed whether giant tortoises delay or avoid the epigenetic changes that typically accrue with aging in other vertebrate lineages or whether exceptionally long-lived individuals like Jonathan have unique epigenetic features.
Relative to other giant tortoises (A. gigantea and Chelonoidis abingdonii), Jonathan has unique gene variants in most aging pathways. Moreover, Jonathan has substantial DNA methylation and methylation entropy changes compared to four other Aldabras ranging in age from a 5-year-old juvenile to older adults. Notably, we found that lower-entropy regions in Jonathan's methylome were enriched for the promoters of genes involved in the mitochondrial electron transport chain, and RNA metabolism. This suggests that high-fidelity transcription of the genes in these pathways may be crucial for long-lived species. Our findings support a model for aging wherein the maintenance of low methylation entropy in gene promoters is coupled to efficient mitochondrial energy production, efficient RNA processing, and efficient genomic repair.