The accrual of damaged or misfolded proteins commonly occurs during aging. Indeed, protein dysfunction is a key feature of many age-associated diseases. As such maintenance of protein quality control may be central to sustained healthspan and extended longevity. The longest-lived rodents, naked mole-rats [NMRs], maintain proteostasis and robust health for most of their 32-year lifespan. NMRs also show marked resistance to environmental stressors, and efficiently preserve protein quality. Both autophagy and proteasome-mediated degradation [PMD] play critical roles in intracellular protein quality control. We focus here on PMD for it is a key player in the removal of oxidatively damaged proteins and reportedly declines with age. We hypothesize that NMRs maintain highly efficient PMD in mitotic (e.g., liver), terminally-differentiated (brain, muscle) and immune-responsive (spleen) tissues during aging and that this is due to intrinsic properties of the proteasome [PRS] and/or a cytoprotective intracellular milieu. We address this in the following specific aims:
Aim 1. To evaluate PRS structure and function, and in particular the role of the immunoproteasome [IMPR], in specific differences in PRS functional capacity, both during aging and in response to in vivo oxidative stressors. We hypothesize that the PRSs of NMRs are well-suited to effectively respond to oxidative stress and predict that this is due, in part, to the greter abundance of IMPRs. We will measure both age-related and oxidative stress-induced changes in PRS structure, functional capacity, and intracellular distribution in the various tissues. Our preliminary data reveal 2-5-fold higher rates of ChTL and TL activities, and higher diversity of PRS assemblies in NMR than in mouse livers. We expect to find similar trends in other tissues, especially in response to drug-induced oxidative stress, and predict a new role of IMPRs in preserving the efficacy of PMD.
Aim 2. To determine whether interspecies differences in PRS capacity are due to intrinsic properties of the PRS and/or the intracellular environment. Here we introduce a novel concept of cytosolic-based protection of the PRSs in NMR. We hypothesize that heat shock proteins [HSPs] play a key role in PMD, especially under oxidative stress. Our preliminary data suggest that HSPs confer resistance to PRS specific inhibitors in NMRs. We assess the molecular composition and function of the """"""""resistasome"""""""", the protein assembly that protects PRSs from inhibition/stress, in several NMR tissues during aging and drug-induced oxidative stress. We expect that NMR PRSs are universally well-protected by the resistasome. We envision future development of resistasome-inspired drugs or interventions aimed at boosting PMD efficacy. These studies use an unusually long-lived rodent to gain novel insights into mechanisms enabling the stability and maintenance of elevated PRS function. Understanding these will help foil the many age-related diseases linked to inadequate PRS-mediated degradation and the accrual of damaged proteins in the elderly.
Even among similar-sized species striking differences in both longevity and the ability to maintain good health into old age are evident;for example the naked mole-rat lives >31 years in captivity whereas the laboratory mouse lives only 2-4 years. Our long-term goal is to understand how this extraordinarily long-lived rodent maintains the ability to efficiently remove damaged or misfolded proteins well into old age, and thereby maintains protein quality during aging. Our ultimate goal is to develop novel therapies that may promote healthy aging and a good quality of life in later years.
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