title: Molecular mechanisms underlying genotype-dependent responses to dietary restriction.
abstract: Dietary restriction (DR) increases lifespan and attenuates age-related phenotypes in many organisms; however, the effect of DR on longevity of individuals in genetically heterogeneous populations is not well characterized. Here, we describe a large-scale effort to define molecular mechanisms that underlie genotype-specific responses to DR. The effect of DR on lifespan was determined for 166 single gene deletion strains in Saccharomyces cerevisiae. Resulting changes in mean lifespan ranged from a reduction of 79% to an increase of 103%. Vacuolar pH homeostasis, superoxide dismutase activity, and mitochondrial proteostasis were found to be strong determinants of the response to DR. Proteomic analysis of cells deficient in prohibitins revealed induction of a mitochondrial unfolded protein response (mtUPR), which has not previously been described in yeast. Mitochondrial proteotoxic stress in prohibitin mutants was suppressed by DR via reduced cytoplasmic mRNA translation. A similar relationship between prohibitins, the mtUPR, and longevity was also observed in Caenorhabditis elegans. These observations define conserved molecular processes that underlie genotype-dependent effects of DR that may be important modulators of DR in higher organisms.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schleit
authors.forename: Simon C
authors.initials: SC
authors.lastname: Johnson
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Bennett
authors.forename: Marissa
authors.initials: M
authors.lastname: Simko
authors.forename: Natalie
authors.initials: N
authors.lastname: Trongtham
authors.forename: Anthony
authors.initials: A
authors.lastname: Castanza
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hsieh
authors.forename: Richard M
authors.initials: RM
authors.lastname: Moller
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wasko
authors.forename: Joe R
authors.initials: JR
authors.lastname: Delaney
authors.forename: George L
authors.initials: GL
authors.lastname: Sutphin
authors.forename: Daniel
authors.initials: D
authors.lastname: Carr
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Murakami
authors.forename: Autumn
authors.initials: A
authors.lastname: Tocchi
authors.forename: Bo
authors.initials: B
authors.lastname: Xian
authors.forename: Weiyang
authors.initials: W
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.forename: Sarani
authors.initials: S
authors.lastname: Goswami
authors.forename: Sean
authors.initials: S
authors.lastname: Higgins
authors.forename: Mollie
authors.initials: M
authors.lastname: Holmberg
authors.forename: Ki-Soo
authors.initials: KS
authors.lastname: Jeong
authors.forename: Jin R
authors.initials: JR
authors.lastname: Kim
authors.forename: Shannon
authors.initials: S
authors.lastname: Klum
authors.forename: Eric
authors.initials: E
authors.lastname: Liao
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lin
authors.forename: Winston
authors.initials: W
authors.lastname: Lo
authors.forename: Hillary
authors.initials: H
authors.lastname: Miller
authors.forename: Brady
authors.initials: B
authors.lastname: Olsen
authors.forename: Zhao J
authors.initials: ZJ
authors.lastname: Peng
authors.forename: Tom
authors.initials: T
authors.lastname: Pollard
authors.forename: Prarthana
authors.initials: P
authors.lastname: Pradeep
authors.forename: Dillon
authors.initials: D
authors.lastname: Pruett
authors.forename: Dilreet
authors.initials: D
authors.lastname: Rai
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ros
authors.forename: Minnie
authors.initials: M
authors.lastname: Singh
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Spector
authors.forename: Helen
authors.initials: H
authors.lastname: Vander Wende
authors.forename: Elroy H
authors.initials: EH
authors.lastname: An
authors.forename: Marissa
authors.initials: M
authors.lastname: Fletcher
authors.forename: Monika
authors.initials: M
authors.lastname: Jelic
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.forename: Michael J
authors.initials: MJ
authors.lastname: MacCoss
authors.forename: Jing-Dong J
authors.initials: JD
authors.lastname: Han
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
mesh_terms: D000332:Aerobiosis; D000818:Animals; D001343:Autophagy; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics* / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D031204:Caloric Restriction; D004032:Diet; D005838:Genotype; D000091402:Prohibitins; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics*; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D000091402:Prohibitins; C000717338:prohibitin 2, C elegans
keywords: aging; dietary restriction; longevity; mitochondria; mitochondrial unfolded protein response; replicative lifespan; yeast