Naked mole rats live nine times longer than similarly sized rodents and show little sign of age-related decline across the majority of that span. Researchers are very interested in finding out why this is the case. Here a team is looking at levels of autophagy in the naked mole rat, a collection of cellular maintenance mechanisms that direct damaged cell structures to be engulfed by lysosomes for recycling. More active autophagy is seen in many of the methods shown to slow aging in mammals, and most likely contributes by reducing the presence and impact of forms of cellular damage such as mitochondrial DNA mutations.
Like all important cellular mechanisms autophagy falters with age, and this harms long-lived cell populations such as those of the central nervous system by allowing damage to accumulate. In mice and humans we can point to growing levels of the hardy garbage compounds known collectively as lipofuscin. These clutter up cellular lysosomes and degrade their function, providing one important cause of failing autophagy, as well as a target for efforts to produce drugs capable of breaking down lipofuscin. In naked mole rats, however, autophagy is maintained at high levels into late age, though at present the precise reasons why remain to be uncovered:
The naked mole-rat (NMR) is the longest-lived rodent and possesses several exceptional traits: marked cancer resistance, negligible senescence, prolonged genomic integrity, pronounced proteostasis, and a sustained healthspan. The underlying molecular mechanisms that contribute to these extraordinary attributes are currently under investigation to gain insights that may conceivably promote and extended human healthspan and lifespan.
The ubiquitin-proteasome and autophagy-lysosomal systems play a vital role in eliminating cellular detritus to maintain proteostasis and have been previously shown to be more robust in NMRs when compared to shorter-lived rodents. Using a proteomics approach, differential expression and phosphorylation levels of proteins involved in proteostasis networks were evaluated in the brains of NMRs in an age-dependent manner. We identified 9 proteins with significantly altered levels and/or phosphorylation states that have key roles involved in proteostasis networks. To further investigate the possible role that autophagy may play in maintaining cellular proteostasis, we examined aspects of the PI3K/Akt/mammalian target of rapamycin (mTOR) axis as well as levels of Beclin-1, LC3-I, and LC3-II in the brain of the NMR as a function of age. Together, these results show that NMRs maintain high levels of autophagy throughout the majority of their lifespan and may contribute to the extraordinary health span of these rodents. The potential of augmenting human health span via activating the proteostasis network will require further studies.