The role of epigenomics in the slow and social status-dependent aging of mole-rats

• Applicant: Professor Dr. Arne Sahm
• Subject Area: Evolution, Anthropology ; Bioinformatics and Theoretical Biology ; Biogerontology and Geriatric Medicine
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 536363525

African mole-rats (Bathyergidae) are exceptionally long-lived animals reaching lifespans of more than 30 years. Remarkably, this is five times longer than would be expected based on the body-mass-to-lifespan-ratio model. Of all land-dwelling mammals, only humans display a more substantial upward divergence in this ratio. In addition, the species naked mole-rat and Micklem’s mole-rat exhibit a social hierarchy separating two groups: reproductive animals of a colony (breeders) and non-reproductive animals (workers). Most strikingly, breeders live twice as long as workers – a social status-based difference in life expectancy that is unparalleled in any other known group of vertebrates. Recently, we investigated the transcriptome of 636 samples of 15 tissues from both groups and uncovered that the most pronounced expression differences affected upregulation of stress-associated pathways in shorter-lived workers. These findings indicate that mole-rats may be a powerful model to study how stress-induced poorer health can lead to accelerated aging. To examine the molecular mechanisms underlying this intriguing association, our project aims at answering the following questions: 1) How do the breeders manage to live considerably longer than the workers based on their reduced stress levels? 2) Why are even the shorter-lived workers of social mole-rats living twice as long as their closest relatives and most other rodents? 3) What are the molecular and evolutionary links between these two phenomena? To this end, we have a comprehensive collection of organs sampled from naked mole-rats, Micklem's mole-rats and guinea pig as a short-lived outgroup readily available. On this basis, we will identify the epigenetic switches that are flipped when workers ascend to breeder status, resulting in a permanent and lifespan-prolonging change in gene expression. Integrating this new epigenomic data with our existing transcriptomic data will enable us to investigate how stress-dependent gene expression patterns are regulated that affect health and lifespan. Based on our previous findings, we will particularly focus on the steroid hormone biosynthesis and glucocorticoid receptor pathways, the GH/IGF1 axis, and proteasome-related processes. In addition, we will apply evolutionary models recently developed by us to examine how the interplay of genomic and epigenomic evolution has resulted in the long and healthy life of the mole-rats compared to their short-lived relatives.

• DFG Programme: Research Grants