Reciprocal changes in phosphoenolpyruvate carboxykinase and pyruvate kinase with age are a determinant of aging in Caenorhabditis elegans

Yiyuan Yuan, Parvin Hakimi, Clara Kao, Allison Kao, Ruifu Liu, Allison Janocha, Andrea Boyd-Tressler, Xi Hang, Hanna Alhoraibi, Erin Slater, Kevin Xia, Pengxiu Cao, Quinn Shue, Tsui Ting Ching, Ao Lin Hsu, Serpil C. Erzurum, George R. Dubyak, Nathan A. Berger, Richard W. Hanson, Zhaoyang Feng*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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 antiaging effects via TOR inhibition. Thus, a programmed metabolic event involving PEPCK-C and P Kis a determinant of aging that can be modified to modulate aging.

Original languageEnglish
Pages (from-to)1307-1319
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number3
DOIs
StatePublished - 15 Jan 2016

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