Age-related changes in the proteostasis network in the brain of the naked mole-rat: Implications promoting healthy longevity

• The naked mole-rat (NMR) has an extraordinary lifespan and health span.
• Proteomics and phosphoproteomics analyses of NMR brain as a function of age were used.
• Key brain proteins identified are involved in the UPS system and autophagy pathway.
• These proteins/processes may contribute to the long and healthy lives of NMRs.
• The results potentially may provide insights into increasing the human health span.

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 health span. The underlying molecular mechanisms that contribute to these extraordinary attributes are currently under investigation to gain insights that may conceivably promote and extend human health span 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 with shorter-lived rodents. Using a 2-D PAGE 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.

Summary schematic diagram of expression proteomics and phosphoproteomics profiles of changes in proteins related to the ubiquitin–proteasomal system in the brain of the naked mole-rat (NMR) as a function of age. Proteins with significantly altered protein and/or phosphorylation levels with age in the NMR brain are labeled. Such proteins conceivably contribute to the extraordinary lifespan and health span of these rodents.Figure optionsDownload high-quality image (165 K)Download as PowerPoint slide