THE ROLE OF THE SMALL MOLECULAR CHAPERONE HSP25 IN LONGEVITY AND HEALTHY AGING

Proteostasis is an integral component of healthy aging. In most metazoans, protein quality declines during aging, resulting in accrual of damaged or self-aggregating cytotoxic proteins, linked to several age-associated diseases (e.g., Alzheimer's Disease, Parkinson's Disease) and pathology (e.g., sarcopenia, cataracts). The mouse-sized naked mole-rat [NMRs] lives ~5 times longer than expected based on body size, and despite detected high levels of oxidative damage even at a young age, maintain good health for most of their long lives. Like other long-lived animal models, both in vivo and in vitrostudies reveal that NMRs are resistant to a broad spectrum of environmental stressors. Collectively these findings suggest that NMRs possess efficient mechanisms to maintain protein quality. Our research has previously shown that this is attributed in part to altered proteasome forms and subcellular location. However, changes in proteasome-related molecular chaperone activity that assists in the transport of damaged proteins into the proteasome may also play a role in this decline. Here we examine key proteasome-related molecular chaperones [HSPs] and the heat-shock factor 1 [HSF1] transcription factor in the brain, heart, liver, spleen, kidney,testes, and quadriceps leg muscle in mice and NMRs. HSP25 both showed higher levels of protein in NMRs compared to mice in all the tissues examined. Hence we measured HSP25 protein content in seven rodents with ages ranging from four to 32 years in both liver and muscle. This comparison resulted in a significant correlation with longevity suggesting that HSP25 may play a key role in age-related maintenance of protein homeostasis in long-lived animals. A review of the literature suggested that HSP25 was involved in a number of cellular systems or responses including heat stress, proteasome activity, autophagy, inflammatory response, and cell structure stabilization all to prevent apoptosis in the cell. Thus, we test the overall hypothesis that HSP25 mediates the trafficking of proteins to different protein degradative pathways based upon the 'stress-state' of the cell to maintain homeostasis, and this action is an integral component responsible for increasing longevity and healthspan in long-lived species.