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 antiaging 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.Aging is characterized by the progressive decline in cellular function and integrity that leads to disease vulnerability and eventually death of organisms (1). The leading proposed cause of decline in cellular function and integrity with age is the accumulation of stochastic damage of molecules and organelles by reactive molecules, such as reactive oxygen species (ROS). Whether ROS are detrimental to organisms and whether ROS limit lifespan, however, are in debate (2).Energy metabolism supplies ATP for cellular function and maintenance. Alterations in energy metabolism are linked to the aging process and aging-associated diseases (3). In model organisms, environmental and genetic factors that change energy metabolism, such as calorie restriction (CR) (4), inhibition of target of rapamycin (TOR) (5), and 5Ј AMP kinase (AMPK) (6) are determinants of longevity. A large body of aging research has been focusing on the signaling of CR, TOR inhibition, and AMPK in regulating longevity. The exact alterations in energy metabolism that occur with age, how these changes impact aging, and whether they can be modified to modulate aging are understudied and remain poorly understood, largely due to the intrinsic complexity of energy metabolism, and the indirect impact of these longevity paradigms on energy metabolism. This impedes the understanding of aging mechanisms and the development of mechanism-based strategies to modulate aging.A key regulation of energy metabolism at the cellular level is the reciprocal changes of PK and PEPCK-C (7). Whether this regulation of cellular energy metabolism contributes to organismal aging is...

PCK1Deficiency Shortens the Replicative Lifespan ofSaccharomyces cerevisiaethrough Upregulation ofPFK1

“…PCK1 is a multifunctional gene that is closely related to gluconeogenesis, obesity, and diabetes. Previous studies have reported that PCK1 was evidently downregulated in skeletal muscle and liver of aged mammals, and overexpression of PCK1 significantly prolonged the lifespan of nematodes and mice [13][14][15][16]34]. Our demonstration that PCK1 deficiency dramatically shortened the lifespan of S. cerevisiae further verified the crucial effect of PCK1 in aging process, which was consistent with the above published literature.…”

Reprogramming of energy metabolism as a driver of aging

“…Although oxidative damage of mitochondrial DNA accumulates with age [ 8 , 9 ] and leads to reduced gene expression [ 10 , 11 ], it is inconclusive whether oxidative damage is the cause of aging-associated decline in mitochondrial function or aging [ 12 , 13 ]. Recently, we have reported that the aging of C. elegans , a genetic model of aging that lives about three weeks, is highlighted by a progressive decline in cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) after the reproductive peak, and a reciprocal increase in pyruvate kinase (PK) [ 4 ]. While PK is an enzyme of glycolysis, PEPCK-C is a metabolic enzyme associated with longevity [ 4 , 14 , 15 ].…”

“…It has been long thought that age-dependent accumulation of stochastic damage of molecules drives aging [ 3 ]. Current evidence demonstrate that a programmed event of energy metabolism is a determinant of aging that can be modified to modulate aging [ 4 ].…”

Erythropoietin ameliorates hyperglycemia in type 1-like diabetic rats

“…Counteracting changes in PEPCK and AMPK have been reported during cell aging. 35 In addition, the natural product caffeamide also enhanced p-AMPK in liver to reduce the mRNA levels of PEPCK. 36 However, the molecular mechanism(s) for this integration is still unknown and needs to be investigated in the future.…”