title: Determinants of rodent longevity in the chaperone-protein degradation network.
abstract: Proteostasis is an integral component of healthy aging, ensuring maintenance of protein structural and functional integrity with concomitant impact upon health span and longevity. In most metazoans, increasing age is accompanied by a decline in protein quality control resulting in the accrual of damaged, self-aggregating cytotoxic proteins. A notable exception to this trend is observed in the longest-lived rodent, the naked mole-rat (NMR, Heterocephalus glaber) which maintains proteostasis and proteasome-mediated degradation and autophagy during aging. We hypothesized that high levels of the proteolytic degradation may enable better maintenance of proteostasis during aging contributing to enhanced species maximum lifespan potential (MLSP). We test this by examining proteasome activity, proteasome-related HSPs, the heat-shock factor 1 (HSF1) transcription factor, and several markers of autophagy in the liver and quadriceps muscles of eight rodent species with divergent MLSP. All subterranean-dwelling species had higher levels of proteasome activity and autophagy, possibly linked to having to dig in soils rich in heavy metals and where underground atmospheres have reduced oxygen availability. Even after correcting for phylogenetic relatedness, a significant (p < 0.02) positive correlation between MLSP, HSP25, HSF1, proteasome activity, and autophagy-related protein 12 (ATG12) was observed, suggesting that the proteolytic degradation machinery and maintenance of protein quality play a pivotal role in species longevity among rodents.
authors.affiliation: Sam and Anne Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX, 78229, USA.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Rodriguez
authors.affiliation: Sam and Anne Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX, 78229, USA.|Department of Cellular and Structural Biology, UTHSCSA, San Antonio, TX, 78229, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Valentine
authors.affiliation: Department of Medicine, UTHSCSA, San Antonio, TX, 78229, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Kramer
authors.affiliation: Department of Epidemiology and Biostatistics, UTHSCSA, San Antonio, TX, 78229, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Gelfond
authors.affiliation: Department of Biological Sciences, California State University San Marcos, San Marcos, CA, 92096, USA.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Kristan
authors.affiliation: Institute of Evolution, University of Haifa, Haifa, 3498838, Israel.
authors.forename: Eviatar
authors.initials: E
authors.lastname: Nevo
authors.affiliation: Sam and Anne Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX, 78229, USA. rbuffen@gmail.com.|Department of Physiology, UTHSCSA, San Antonio, TX, 78229, USA. rbuffen@gmail.com.|Calico, 1170 Veterans Blvd, San Francisco, CA, 94080, USA. rbuffen@gmail.com.
authors.forename: Rochelle
authors.initials: R
authors.lastname: Buffenstein
mesh_terms: D000375:Aging / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071192:Autophagy-Related Protein 12 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D000076249:Heat Shock Transcription Factors; D008099:Liver / Q000378:metabolism; D008136:Longevity / Q000235:genetics* / Q000502:physiology; D051379:Mice; D019577:Mole Rats / Q000235:genetics / Q000502:physiology; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D010802:Phylogeny; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D059748:Proteolysis; D052097:Quadriceps Muscle / Q000378:metabolism; D051381:Rats; D012377:Rodentia; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000071192:Autophagy-Related Protein 12; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D018832:Molecular Chaperones; D014157:Transcription Factors; D046988:Proteasome Endopeptidase Complex
keywords: Aging; Chaperones; Naked mole rat; Proteasome; Proteostasis