Rochelle Buffenstein - US grants

DESCRIPTION (provided by applicant): 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.

DESCRIPTION (provided by applicant): We are requesting funds to support the 2014 American Aging Association (AGE) 43rd Annual Meeting to be held at the Westin Hotel, San Antonio, Texas on May 30th -June 2nd. In recent years, this meeting has grown to become one of the premier meetings for biogerontological research. The meeting theme is Slowing Aging: Signaling, Stress Resistance, Stem Cells, and Small Molecules -- Insights from Old and New Models. Dr. Rochelle Buffenstein together with the AGE Program Committee (Drs. Brown-Borg, Nelson, Nikolich-Zugich, Oddo, Tissenbaum, Thompson), Session Chairs and the AGE Executive Board organize the scientific program. The objective is to bring together scientists from multiple disciplines to create a forum for presentation and critical discussion of the latest discoveries in aging research and to stimulate forward thinking and collaboration among participants. Funds are requested for travel expenses of 1) the invited speakers and 2) meritorious junior scientists (graduate students, post-doctoral fellows and junior faculty) who can benefit from exposure to the leaders of the field, present their research findings and have the opportunity to contribute to this forum of free exchange. The specific goals of this meeting are a) to assemble a broad-based forum of basic and clinical scientists to present the latest research on mechanisms involved in slowing aging; b) to ensure coverage of a variety of well-established (e.g., yeasts, worms, flies, and both human and non-human primates) and non- traditional (e.g., turtles, bees and mole-rats) experimental animal models and state-of-the-art technologies; c) to encourage open discussion of new and old conceptual paradigms in aging; d) to emphasize integrative and translational research opportunities; and e) to evaluate experimental and lifestyle interventions that may slow human aging and develop novel avenues for potential therapeutics. The invited speakers include renowned scientists in aging as well as other disciplines selected for their science and ability to stimulate debate. A key goal of this meeting is met by inclusion o rising stars and scientists both in and outside aging research who are not regular speakers on the aging conference circuit: namely, to promote broader participation and present fresh ideas, novel experimental technologies and insightful approaches to this clinically important, multidisciplinary, and integrative field. The meeting will also focus on the convergence of protective mechanisms that contribute to the maintenance of homeostasis and its modulation in slow aging species, such as humans. Topics include- Circadian Dysregulation in Aging: Consequences, and Causes; Forgotten Metabolites, Small Molecules in Aging; Stress Resistance and Signaling; The Gut Microbiome and its Role in Immunity, Inflammation and Aging; Protective Proteins and Proteostasis; Proteostatic Dysfunction During Aging; Forever Young: Tissue Regeneration and Stem Cells; and Retarding Aging: Lifestyle Changes and Interventions. The effectiveness of this meeting in achieving its stated goals, particularly broadening the range of speakers and topics, will be evaluated by participant survey and used to guide future meetings.