The study of large differences in longevity between otherwise similar species has produced interesting insights into how biochemical and genetic differences might contribute to species life span. As of yet, the field has failed to produce much in the way of actionable insights, however. The recent transfer of a gene from naked mole rats to mice was notable for being one of only a few such exercises conducted with increased life span as a goal. Still, the wheel turns, and we may expect to see an increasing application of what is known of the genetics of species longevity in the decades ahead.
The naked mole rat (NMR) is the longest-lived rodent, resistant to multiple age-related diseases including neurodegeneration. However, the mechanisms underlying the NMR's resistance to neurodegenerative diseases remain elusive. Here, we isolated oligodendrocyte progenitor cells (OPCs) from NMRs and compared their transcriptome with that of other mammals.
Extracellular matrix (ECM) genes best distinguish OPCs of long- and short-lived species. Notably, expression levels of CD44, an ECM-binding protein that has been suggested to contribute to NMR longevity by mediating the effect of hyaluronan (HA), are not only high in OPCs of long-lived species but also positively correlate with longevity in multiple cell types/tissues.
We found that CD44 localizes to the endoplasmic reticulum (ER) and enhances basal ATF6 activity. CD44 modifies proteome and membrane properties of the ER and enhances ER stress resistance in a manner dependent on unfolded protein response regulators without the requirement of HA. This HA-independent role of CD44 in proteostasis regulation may contribute to mammalian longevity.