title: Lifespan of mice and primates correlates with immunoproteasome expression.
abstract: There is large variation in lifespan among different species, and there is evidence that modulation of proteasome function may contribute to longevity determination. Comparative biology provides a powerful tool for identifying genes and pathways that control the rate of aging. Here, we evaluated skin-derived fibroblasts and demonstrate that among primate species, longevity correlated with an elevation in proteasomal activity as well as immunoproteasome expression at both the mRNA and protein levels. Immunoproteasome enhancement occurred with a concurrent increase in other elements involved in MHC class I antigen presentation, including β-2 microglobulin, (TAP1), and TAP2. Fibroblasts from long-lived primates also appeared more responsive to IFN-γ than cells from short-lived primate species, and this increase in IFN-γ responsiveness correlated with elevated expression of the IFN-γ receptor protein IFNGR2. Elevation of immunoproteasome and proteasome activity was also observed in the livers of long-lived Snell dwarf mice and in mice exposed to drugs that have been shown to extend lifespan, including rapamycin, 17-α-estradiol, and nordihydroguaiaretic acid. This work suggests that augmented immunoproteasome function may contribute to lifespan differences in mice and among primate species.
authors: Andrew M
authors: AM
authors: Pickering
authors: Marcus
authors: M
authors: Lehr
authors: Richard A
authors: RA
authors: Miller
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D017951:Antigen Presentation; D002478:Cells, Cultured; D004392:Dwarfism / Q000235:genetics / Q000503:physiopathology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D053612:Janus Kinases / Q000502:physiology; D008136:Longevity / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D051379:Mice / Q000502:physiology*; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D018384:Oxidative Stress; D011323:Primates / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017471:Receptors, Interferon / Q000502:physiology; D050791:STAT Transcription Factors / Q000502:physiology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013045:Species Specificity; D015854:Up-Regulation; D001613:beta 2-Microglobulin / Q000096:biosynthesis / Q000235:genetics; D000096743:Interferon gamma Receptor
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D004958:Estradiol; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma; D053612:Janus Kinases; D009637:Masoprocol; D046988:Proteasome Endopeptidase Complex; D021122:Protein Subunits; D012333:RNA, Messenger; D017471:Receptors, Interferon; D050791:STAT Transcription Factors; D020123:Sirolimus; D001613:beta 2-Microglobulin; D000096743:Interferon gamma Receptor; C490116:Ifngr2 protein, mouse; C486171:Tap1 protein, mouse; C489516:Tap2 protein, mouse; C061553:ATP dependent 26S protease