Status-dependent aging rates in long-lived, social mole-rats are shaped by HPA stress axis

Background: Mole-rat families of the genus Fukomys consist of social categories that differ considerably in their life expectancy. In a typical family, only one pair is reproductively active. These animals, called breeders, reach twice the lifespan of non-breeders in captivity. Results: We used RNA-seq to compare breeders9 gene expression profiles across 15 tissues from both sexes in two Fukomys species against those of age-matched non-breeders. The gene found to be most affected was SULT2A1, whose gene product is well known to deactivate DHEA - a repeatedly proposed "anti-aging hormone". The second most affected gene - again strongly down-regulated in breeders - was MC2R, which codes for the adrenocorticotropic hormone (ACTH) receptor, the primary inducer of glucocorticoid production. In line with this, we found the expression of the target genes of the glucocorticoid receptor substantially altered, breeders exhibited lower weight gain, higher bone density, and stronger use of the IGF1/GH axis. In addition to the latter, several anabolic processes such as protein synthesis, myogenesis, and oxidative phosphorylation, were found to be up-regulated in breeders. Also, apoptosis, P53-signaling, proteasome activity, and the immune defense were elevated in breeders. While coagulation was down-regulated, steroid hormone biosynthesis shifted from glucocorticoid to sex steroid production. Conclusions: Our results highlight the role of the hypothalamic-pituitary-adrenal stress axis in aging, confirm already known promising targets of aging research, and suggest new ones. The observed up-regulation of the IGF1/GH axis in longer-living breeders questions the extent to which findings from short-lived species can be transferred to longer-lived ones.