Abstract
The longest-lived rodent, the naked mole-rat (Bathyergidae; Heterocephalus glaber), maintains robust health for at least 75% of its 32 year lifespan, suggesting that the decline in genomic integrity or protein homeostasis routinely observed during aging, is either attenuated or delayed in this extraordinarily long-lived species. The ubiquitin proteasome system (UPS) plays an integral role in protein homeostasis by degrading oxidatively-damaged and misfolded proteins. In this study, we examined proteasome activity in naked mole-rats and mice in whole liver lysates as well as three subcellular fractions to probe the mechanisms behind the apparently enhanced effectiveness of UPS. We found that when compared with mouse samples, naked mole-rats had significantly higher chymotrypsin-like (ChT-L) activity and a two-fold increase in trypsin-like (T-L) in both whole lysates as well as cytosolic fractions. Native gel electrophoresis of the whole tissue lysates showed that the 20S proteasome was more active in the longer-lived species and that 26S proteasome was both more active and more populous. Western blot analyses revealed that both 19S subunits and immunoproteasome catalytic subunits are present in greater amounts in the naked mole-rat suggesting that the observed higher specific activity may be due to the greater proportion of immunoproteasomes in livers of healthy young adults. It thus appears that proteasomes in this species are primed for the efficient removal of stress-damaged proteins. Further characterization of the naked mole-rat proteasome and its regulation could lead to important insights on how the cells in these animals handle increased stress and protein damage to maintain a longer health in their tissues and ultimately a longer life.
Highlights
The naked mole-rat, Heterocephalus glaber, is the longest-lived rodent on record, with a maximum lifespan greater than 30 years [1]
Cleavage of the acidic substrate was similar in both species and appeared to play a minor role in protein degradation
2) The higher proteasome activity observed in naked mole-rat tissue extracts over mouse tissue extracts was due to a higher 26S activity per unit of proteasome in the naked mole-rat
Summary
The naked mole-rat, Heterocephalus glaber, is the longest-lived rodent on record, with a maximum lifespan greater than 30 years [1] Does this animal live 8 to 10 times longer than similar-sized mice but this species shows prolonged maintenance of cancer-free good health and reproductive potential well into its third decade [2]. Despite high levels of oxidative damage even at a young age, ubiquitinylated proteins are maintained at lower levels than mice at both young and old ages [8], suggestive of less accumulation of damaged or misfolded proteins These findings may be indicative of a highly efficient ubiquitin-proteasome system (UPS) in the naked mole-rat
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