title: Long-lived crowded-litter mice have an age-dependent increase in protein synthesis to DNA synthesis ratio and mTORC1 substrate phosphorylation.
abstract: Increasing mouse litter size [crowded litter (CL)] presumably imposes a transient nutrient stress during suckling and extends lifespan through unknown mechanisms. Chronic calorically restricted and rapamycin-treated mice have decreased DNA synthesis and mTOR complex 1 (mTORC1) signaling but maintained protein synthesis, suggesting maintenance of existing cellular structures. We hypothesized that CL would exhibit similar synthetic and signaling responses to other long-lived models and, by comparing synthesis of new protein to new DNA, that insight may be gained into the potential preservation of existing cellular structures in the CL model. Protein and DNA synthesis was assessed in gastroc complex, heart, and liver of 4- and 7-mo CL mice. We also examined mTORC1 signaling in 3- and 7-mo aged animals. Compared with controls, 4-mo CL had greater DNA synthesis in gastroc complex with no differences in protein synthesis or mTORC1 substrate phosphorylation across tissues. Seven-month CL had less DNA synthesis than controls in heart and greater protein synthesis and mTORC1 substrate phosphorylation across tissues. The increased new protein-to-new DNA synthesis ratio suggests that new proteins are synthesized more so in existing cells at 7 mo, differing from 4 mo, in CL vs. controls. We propose that, in CL, protein synthesis shifts from being directed toward new cells (4 mo) to maintenance of existing cellular structures (7 mo), independently of decreased mTORC1.
authors.affiliation: Health and Exercise Science Department, Colorado State University, Fort Collins, Colorado; and josh.drakewv@gmail.com.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Drake
authors.affiliation: Health and Exercise Science Department, Colorado State University, Fort Collins, Colorado; and.
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Bruns
authors.affiliation: Health and Exercise Science Department, Colorado State University, Fort Collins, Colorado; and.
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Peelor
authors.affiliation: Health and Exercise Science Department, Colorado State University, Fort Collins, Colorado; and.
authors.forename: Laurie M
authors.initials: LM
authors.lastname: Biela
authors.affiliation: Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.affiliation: Health and Exercise Science Department, Colorado State University, Fort Collins, Colorado; and.
authors.forename: Karyn L
authors.initials: KL
authors.lastname: Hamilton
authors.affiliation: Health and Exercise Science Department, Colorado State University, Fort Collins, Colorado; and.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Miller
mesh_terms: D000375:Aging; D000465:Algorithms; D000818:Animals; D000833:Animals, Suckling; D003433:Crosses, Genetic; D004247:DNA / Q000096:biosynthesis; D015536:Down-Regulation; D005260:Female; D006321:Heart / Q000254:growth & development; D006614:Hindlimb; D008098:Litter Size; D008099:Liver / Q000254:growth & development / Q000378:metabolism; D008136:Longevity; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D046912:Multiprotein Complexes; D004247:DNA; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: crowded litter; deuterium; mTORC1; proteostasis; slowed aging