Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat

Abstract

The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. Surprisingly, data from the longest-living rodent known, naked molerats [MRs; mass 35 g; maximum lifespan (MLSP) > 28.3 years], when compared with mice (MLSP 3.5 years) exhibit higher levels of lipid peroxidation, protein carbonylation, and DNA oxidative damage even at a young age. We hypothesize that age-related changes in protein structural stability, oxidation, and degradation are abrogated over the lifespan of the MR. We performed a comprehensive study of oxidation states of protein cysteines [both reversible (sulfenic, disulfide) and indirectly irreversible (sulfinic/sulfonic acids)] in liver from young and old C57BL/6 mice (6 and 28 months) and MRs (2 and >24 years). Furthermore, we compared interspecific differences in urea-induced protein unfolding and ubiquitination and proteasomal activity. Compared with data from young mice, young MRs have 1.6 times as much free protein thiol groups and similar amounts of reversible oxidative damage to cysteine. In addition, they show less urea-induced protein unfolding, less protein ubiquitination, and higher proteasome activity. Mice show a significant age-related increase in cysteine oxidation and higher levels of ubiquitination. In contrast, none of these parameters were significantly altered over 2 decades in MRs. Clearly MRs have markedly attenuated age-related accrual of oxidation damage to thiol groups and age-associated up-regulation of homeostatic proteolytic activity. These pivotal mechanistic interspecies differences may contribute to the divergent aging profiles and strongly implicate maintenance of protein stability and integrity in successful aging.cysteine oxidation ͉ Heterocephalus glaber ͉ mechanisms of aging ͉ proteasome activity ͉ protein homeostasis

Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species

“…Combined with marginally lower TrxR and Grx activities in brain tissue from Snell dwarf, relative to normal mice, it would appear that maintenance of constitutively high protein repair activities does not contribute to longevity. These results are similar to those reported by Perez et al (2009a), showing that neither glutaredoxin nor methionine sulfoxide reductase A protein levels are higher in naked mole rat liver compared to mouse (though this conclusion is limited by potential between-species differences in amino acid sequences, which were not known, in this study). Thus, longevity is not associated with enhanced protein repair activities in the major oxidative tissues.…”

“…Protein oxidative damage could also be prevented in longer-lived species by the systematic evolutionary replacement of cysteine residues with amino acids less susceptible to oxidative modification (as Moosmann and Behl (2008) demonstrated for mitochondrial DNA-encoded proteins); however, there is no evidence that this has occurred in nuclear DNA-encoded proteins that function either in the mitochondria or cytosol (Moosmann and Behl 2008). Similarly, proteins of naked mole rats actually have higher cysteine content than shorter-lived mice (Perez et al 2009a). On the other hand, proteins in crude liver homogenates of some long-lived species, such as bats or naked mole rats, have been shown to resist urea-induced denaturation, which suggests some inherent stabilizing property (Perez et al 2009a;Salmon et al 2009).…”

“…Similarly, proteins of naked mole rats actually have higher cysteine content than shorter-lived mice (Perez et al 2009a). On the other hand, proteins in crude liver homogenates of some long-lived species, such as bats or naked mole rats, have been shown to resist urea-induced denaturation, which suggests some inherent stabilizing property (Perez et al 2009a;Salmon et al 2009). Perez et al (2009a) report that this is not attributable to differences in heat shock protein-70 levels.…”

“…On the other hand, proteins in crude liver homogenates of some long-lived species, such as bats or naked mole rats, have been shown to resist urea-induced denaturation, which suggests some inherent stabilizing property (Perez et al 2009a;Salmon et al 2009). Perez et al (2009a) report that this is not attributable to differences in heat shock protein-70 levels. While this between-species immunodetection approach requires validation for conservation of amino acid sequence, it is nonetheless in agreement with the observation that HSP70 levels are also lower in stress-resistant fibroblasts of long-lived Snell dwarf mice compared to those from normal littermates (Maynard and Miller 2006).…”

Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity

“…( Pérez et al 2009), the longest living rodent known, and another on two long-lived bats ), suggest that an optimization of protein oxidation and turnover mechanisms may have been responsible for their exceptional longevity when compared to closely related species.…”