title: Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice.
abstract: Combating the social and economic consequences of a growing elderly population will require the identification of interventions that slow the development of age-related diseases. Preserved cellular homeostasis and delayed aging have been previously linked to reduced cell proliferation and protein synthesis rates. To determine whether changes in these processes may contribute to or predict delayed aging in mammals, we measured cell proliferation rates and the synthesis and replacement rates (RRs) of over a hundred hepatic proteins in vivo in three different mouse models of extended maximum lifespan (maxLS): Snell Dwarf, calorie-restricted (CR), and rapamycin (Rapa)-treated mice. Cell proliferation rates were not consistently reduced across the models. In contrast, reduced hepatic protein RRs (longer half-lives) were observed in all three models compared to controls. Intriguingly, the degree of mean hepatic protein RR reduction was significantly correlated with the degree of maxLS extension across the models and across different Rapa doses. Absolute rates of hepatic protein synthesis were reduced in Snell Dwarf and CR, but not Rapa-treated mice. Hepatic chaperone levels were unchanged or reduced and glutathione S-transferase synthesis was preserved or increased in all three models, suggesting a reduced demand for protein renewal, possibly due to reduced levels of unfolded or damaged proteins. These data demonstrate that maxLS extension in mammals is associated with improved hepatic proteome homeostasis, as reflected by a reduced demand for protein renewal, and that reduced hepatic protein RRs hold promise as an early biomarker and potential target for interventions that delay aging in mammals.
authors.affiliation: Department of Nutritional Science and Toxicology, University of California at Berkeley, Berkeley, CA, 94720, USA.
authors.forename: Airlia C S
authors.identifier: http://orcid.org/0000-0003-4820-2413
authors.initials: AC
authors.lastname: Thompson
authors.affiliation: Department of Nutritional Science and Toxicology, University of California at Berkeley, Berkeley, CA, 94720, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Bruss
authors.affiliation: KineMed Inc., Emeryville, CA, 94608, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Price
authors.affiliation: KineMed Inc., Emeryville, CA, 94608, USA.
authors.forename: Cyrus F
authors.initials: CF
authors.lastname: Khambatta
authors.affiliation: KineMed Inc., Emeryville, CA, 94608, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Holmes
authors.affiliation: Department of Nutritional Science and Toxicology, University of California at Berkeley, Berkeley, CA, 94720, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Colangelo
authors.affiliation: Department of Nutritional Science and Toxicology, University of California at Berkeley, Berkeley, CA, 94720, USA.
authors.forename: Marcy
authors.initials: M
authors.lastname: Dalidd
authors.affiliation: Department of Nutritional Science and Toxicology, University of California at Berkeley, Berkeley, CA, 94720, USA.
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Roberts
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
authors.forename: Clinton M
authors.initials: CM
authors.lastname: Astle
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Harrison
authors.affiliation: Department of Nutritional Science and Toxicology, University of California at Berkeley, Berkeley, CA, 94720, USA.|KineMed Inc., Emeryville, CA, 94608, USA.
authors.forename: Marc K
authors.initials: MK
authors.lastname: Hellerstein
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D031204:Caloric Restriction; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D013006:Growth Hormone / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008136:Longevity / Q000502:physiology*; D008810:Mice, Inbred C57BL; D020543:Proteome / Q000187:drug effects / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D020543:Proteome; D013006:Growth Hormone; D020123:Sirolimus
keywords: Snell Dwarf; calorie restriction; cell proliferation; maximum lifespan extension; proteome dynamics; rapamycin