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

Abstract

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 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.

Endoplasmic reticulum proteostasis impairment in aging

“…During aging, organisms gradually accumulate intracellular aggregates composed by misfolded proteins, an event that is associated with a prominent decline in the buffering capacity of the proteostasis network and a consequent decrease in tissue and cellular function (Fig. ) (Taylor & Dillin, ; Triplett et al ., ). Several studies in model organisms have uncovered the significance of UPR signaling to the aging process, associated with protection against proteotoxicity (Ben‐Zvi et al ., ; Labunskyy et al ., ).…”

Novel treatment strategies for chronic kidney disease: insights from the animal kingdom

“…Although they have a small body size and are constantly exposed to hypoxia, oxidative stress and hypercapnia, they can live >30 years and maintain a healthy cardiovascular and reproductive status as well as body composition throughout their life (5). Interestingly, the structure and function of their proteins is not affected by their substantial exposure to oxidative stress (95), and they display high levels of autophagy and efficient removal of stress-damaged proteins throughout life (96). In contrast to humans and other rodents, (97) these animals preserve normal vascular and cardiac function with ageing (98,99) and are resistant to the development of cancer (100).…”

ER stress and impaired autophagy flux in neuronal degeneration and brain injury

“…The efficiency of the macroautophagic system decreases with age and determines the cell lifespan (Bergamini, 2006). Consequently, a healthy brain that resists aging requires the maintenance of high levels of autophagy throughout the lifespan (Triplett et al, 2015). …”