title: Reciprocal Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Kinase with Age Are a Determinant of Aging in Caenorhabditis elegans.
abstract: Aging involves progressive loss of cellular function and integrity, presumably caused by accumulated stochastic damage to cells. Alterations in energy metabolism contribute to aging, but how energy metabolism changes with age, how these changes affect aging, and whether they can be modified to modulate aging remain unclear. In locomotory muscle of post-fertile Caenorhabditis elegans, we identified a progressive decrease in cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), a longevity-associated metabolic enzyme, and a reciprocal increase in glycolytic pyruvate kinase (PK) that were necessary and sufficient to limit lifespan. Decline in PEPCK-C with age also led to loss of cellular function and integrity including muscle activity, and cellular senescence. Genetic and pharmacologic interventions of PEPCK-C, muscle activity, and AMPK signaling demonstrate that declines in PEPCK-C and muscle function with age interacted to limit reproductive life and lifespan via disrupted energy homeostasis. Quantifications of metabolic flux show that reciprocal changes in PEPCK-C and PK with age shunted energy metabolism toward glycolysis, reducing mitochondrial bioenergetics. Last, calorie restriction countered changes in PEPCK-C and PK with age to elicit anti-aging effects via TOR inhibition. Thus, a programmed metabolic event involving PEPCK-C and PK is a determinant of aging that can be modified to modulate aging.
authors.affiliation: From the Departments of Pharmacology.
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Departments of Biochemistry and.
authors.forename: Parvin
authors.initials: P
authors.lastname: Hakimi
authors.affiliation: From the Departments of Pharmacology.
authors.forename: Clara
authors.initials: C
authors.lastname: Kao
authors.affiliation: From the Departments of Pharmacology.
authors.forename: Allison
authors.initials: A
authors.lastname: Kao
authors.affiliation: From the Departments of Pharmacology.
authors.forename: Ruifu
authors.initials: R
authors.lastname: Liu
authors.affiliation: the Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195.
authors.forename: Allison
authors.initials: A
authors.lastname: Janocha
authors.affiliation: From the Departments of Pharmacology, Physiology and Biophysics, and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Boyd-Tressler
authors.affiliation: From the Departments of Pharmacology, the School of Pharmacy, Suzhou Health College, Suzhou, Jiangsu 215009, China, and.
authors.forename: Xi
authors.initials: X
authors.lastname: Hang
authors.affiliation: Departments of Biochemistry and.
authors.forename: Hanna
authors.initials: H
authors.lastname: Alhoraibi
authors.affiliation: Departments of Biochemistry and.
authors.forename: Erin
authors.initials: E
authors.lastname: Slater
authors.affiliation: From the Departments of Pharmacology.
authors.forename: Kevin
authors.initials: K
authors.lastname: Xia
authors.affiliation: From the Departments of Pharmacology.
authors.forename: Pengxiu
authors.initials: P
authors.lastname: Cao
authors.affiliation: From the Departments of Pharmacology.
authors.forename: Quinn
authors.initials: Q
authors.lastname: Shue
authors.affiliation: the Departments of Internal Medicine, Division of Geriatric Medicine, and.
authors.forename: Tsui-Ting
authors.initials: TT
authors.lastname: Ching
authors.affiliation: the Departments of Internal Medicine, Division of Geriatric Medicine, and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Ao-Lin
authors.initials: AL
authors.lastname: Hsu
authors.affiliation: the Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195.
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.affiliation: From the Departments of Pharmacology, Physiology and Biophysics, and.
authors.forename: George R
authors.initials: GR
authors.lastname: Dubyak
authors.affiliation: Departments of Biochemistry and Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Berger
authors.affiliation: Departments of Biochemistry and.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Hanson
authors.affiliation: From the Departments of Pharmacology, john.feng@case.edu.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Feng
mesh_terms: D000375:Aging; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D031204:Caloric Restriction; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D004734:Energy Metabolism; D018507:Gene Expression Regulation, Developmental; D006019:Glycolysis; D063154:Mitochondrial Dynamics; D009154:Mutation; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D016019:Survival Analysis
chemical_list: D029742:Caenorhabditis elegans Proteins; D011770:Pyruvate Kinase; D019764:Phosphoenolpyruvate Carboxykinase (ATP)
keywords: Calorie restriction; aging; energy metabolism; mitochondria; phosphoenolpyruvate carboxykinase; physical activity; pyruvate kinase