Naked Mole Rats Maintain High Levels of Autophagy

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.

Link: http://dx.doi.org/10.1016/j.bbadis.2015.08.002

Comments

One thing to note is that many age related degenerative diseases are actually characterized by significantly higher than normal levels of autophagasome proteins such as LC3 and Beclin1. Lipofuscin stops autophagy at the point where the lysosome and the autophagasome normally fuse, which can lead to the appearance of a buildup of autophagasomes which cannot be broken down. I doubt that this is the case here, but results can be misleading.

Posted by: Kris Barnes at August 13th, 2015 8:38 AM

What do we know about what usually ends up killing NMRs after the end of a normal lifespan?

Posted by: Seth at August 13th, 2015 6:13 PM

@Seth - Probably just the same things that end up killing regular mice and humans - heart disease, stroke, organ failure, infection due to a weakened immune system etc (with the notable exception being cancer).

Perhaps the differences in lifespan between mice, naked mole rats, humans, and bow head whales are just down to how much autophagey each species gets around to doing and the cancer resistance thing is a bit of a red herring?

"One of the most interesting over-expressed genes in the naked mole-rat is the serum pan-protease inhibitor, alpha2-macroglobulin (A2m). While A2m is expressed at a low level in wild-derived mouse liver (1,307 reads out of 8.8 M), we detected almost 202,500 (out of 9.0 M) reads in naked mole-rat liver which makes it among the top 20 most over-expressed genes. Interestingly, A2m is listed as a candidate protein relevant to the human ageing process in GenAge, a database of ageing- and longevity-associated genes [24]. A2m is also known to interact with longevity-associated ApoE (apolipoprotein E) and is associated with Alzheimer's disease [25]. Furthermore, A2m was determined to be a biomarker for ageing in vivo as its mRNA expression level showed positive correlation with age [26]. The function of A2m as a proteinase inhibitor may also be of interest in the context of protein turnover regulation in naked mole-rats, which PĂ©rez et al. (2009) argue to be a key contributor to their extreme longevity."

Posted by: Jim at August 16th, 2015 11:09 AM

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