Giant Mole-Rats Exhibit Greater Gene Expression Stability with Aging than Rats
A number of African mole-rat species live significantly longer than similar-sized rodents, and show very little age-related decline until very late life. Where examined in detail, their biochemistry is an odd mix. In some respects they exhibit the usual signs of damage and dysfunction associated with mammalian aging, such as raised oxidative stress and the presence of senescent cells, but don't appear all that affected by it. Elsewhere they exhibit clearly superior mechanisms, such as improved protein quality control, a layered set of anti-cancer mechanisms that provide near immunity to cancer, and - the topic of this paper - a well preserved pattern of gene expression. This latter case may be something of a tautology: dysregulation of gene expression, or changes in gene expression that are reactions to underlying damage, are a downstream consequence of the causes of aging. When an organism ages more slowly, or exhibits only a lesser degree of aging until very late life, then one would naturally expect gene expression patterns to remain more stable over time.
Compared to short-lived mammals, long-lived mammals have repeatedly been shown to exhibit fewer age-associated changes in numerous physiological parameters related to the functional decline during aging. Recent RNA-seq studies have suggested that much of the remarkable lifespan diversity among mammals is based on interspecies differences in gene expression. However, those studies focused on identifying particular genes and pathways that are differentially expressed between species with divergent longevities. Whether short-lived and long-lived species differ at the transcript level with respect to their amount of differentially expressed genes (DEGs) during aging (hereinafter referred to as "gene expression stability") has, to the best of our knowledge, not been explored yet.
Here, we examined age associated transcriptome changes in two similarly sized rodent species with different longevities: the laboratory rat (Rattus norvegicus), which has a maximum lifespan of 3.8 years, and the giant mole-rat (Fukomys mechowii), which has a maximum lifespan of more than 20 years. In giant mole-rats, longevity is significantly correlated with the reproductive status. Breeding animals outlive non-breeders by far. In the current study, we examined only non-breeding males. Male non-breeding giant mole-rats have a maximum lifespan of approximately 10 years and an average lifespan of approximately 6 years, still clearly exceeding the life expectancy of the laboratory rat.
For both species, we performed RNA-seq on tissue samples from five organs (blood, heart, kidney, liver, and skin; hereinafter called simply tissues) of young and elderly adults. The tissues were collected from young and elderly cohorts of laboratory rats (0.5 and 2.0 years) and giant mole-rats (young: approximately 1.5 years at average; elderly: approximately 6.8 years at average). For each species, we determined DEGs between the two respective time points and searched for enriched functional categories.
Our findings show that giant mole-rats exhibit higher gene expression stability during aging than rats. Although well-known aging signatures were detected in all tissue types of rats, they were found in only one tissue type of giant mole-rats. Furthermore, many differentially expressed genes that were found in both species were regulated in opposite directions during aging. This suggests that expression changes which cause aging in short-lived species are counteracted in long-lived species. Taken together, we conclude that expression stability in giant mole rats (and potentially in African mole-rats in general) may be one key factor for their long and healthy life.