ИСТИНА

Lifespan of an organism is a variable demonstrating significant variation both across- and within the species. Indeed, maximum lifespan of mammals ranges between 3.2 years in Etruscan shrew to more than 200 years in bowhead whale. Within the species, lifespan can also be shortened and most importantly extended by some environmental and genetical interventions, resulting in up to 10-fold increase in longevity in certain animal models. However, molecular signatures and mechanisms responsible for such lifespan variation remain unclear. Here, we examined this problem by performing high-throughput analysis of both across- and within-species models. We performed RNA sequencing of fibroblasts of exceptionally long-lived naked mole rat (NMR) and mouse in response to DNA damage, induced by γ-irradiation. We then identified and experimentally validated gene expression signatures associated with high resistance of the NMR to DNA damage. We further extensively characterized DNA methylation changes occurring during aging in mice, using 141 individuals representing 16 age groups. We identified general trends and pathways associated with these changes along with the effect of lifespan-extending intervention (caloric restriction) on them. Finally, we performed RNA sequencing of 8 lifespan-extending interventions in mouse and aggregated this data with publicly available gene expression data, resulting in the coverage of 17 different healthspan- and lifespan-extending interventions. We characterized similarity of gene expression profiles across interventions and examined their feminizing effect in males. We then identified common signatures of longevity interventions along with the signatures associated with the degree of lifespan extension. We further applied these signatures for the identification of new lifespan-extending conditions and estimation of differences in lifespan across mouse strains. We observed common and distinct signatures associated with lifespan extension across- and within-species models. We note the importance of NRF2-regulated acute stress response and antioxidative defense along with apoptosis as a mechanism of NMR resistance to DNA damage and lifespan extension by interventions. Other processes, such as oxidative phosphorylation, glucose metabolism and immune response seem to be uniquely associated with interventions while autophagy appears to be distinctive for response in NMR. Notably, gene expression signatures obtained from the analysis of lifespan-extending interventions were shown to properly predict the effect of other conditions on longevity based on gene expression profile, pointing to a possibility of their application for the identification of new lifespan-extending interventions, facilitating the development of novel antiaging therapies.