Enhanced Gluconeogenesis and Increased Energy Storage as Hallmarks of Aging in Saccharomyces cerevisiae
A relationship between life span and cellular glucose metabolism has been inferred from genetic manipulations and caloric restriction of model organisms. In this report, we have used the Snf1p glucose-sensing pathway of Saccharomyces cerevisiae to explore the genetic and biochemical linkages between...
Saved in:
Published in | The Journal of biological chemistry Vol. 276; no. 38; pp. 36000 - 36007 |
---|---|
Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Biochemistry and Molecular Biology
21.09.2001
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | A relationship between life span and cellular glucose metabolism has been inferred from genetic manipulations and caloric
restriction of model organisms. In this report, we have used the Snf1p glucose-sensing pathway of Saccharomyces cerevisiae to explore the genetic and biochemical linkages between glucose metabolism and aging. Snf1p is a serine/threonine kinase
that regulates cellular responses to glucose deprivation. Loss of Snf4p, an activator of Snf1p, extends generational life
span whereas loss of Sip2p, a presumed repressor of the kinase, causes an accelerated aging phenotype. An annotated data base
of global age-associated changes in gene expression in isogenic wild-type, sip2 Î, and snf4 Î strains was generated from DNA microarray studies. The transcriptional responses suggested that gluconeogenesis and glucose
storage increase as wild-type cells age, that this metabolic evolution is exaggerated in rapidly aging sip2 Î cells, and that it is attenuated in longer-lived snf4 Î cells. To test this hypothesis directly, we applied microanalytic biochemical methods to generation-matched cells from each
strain and measured the activities of enzymes and concentrations of metabolites in the gluconeogenic, glycolytic, and glyoxylate
pathways, as well as glycogen, ATP, and NAD + . The sensitivity of the assays allowed comprehensive biochemical profiling to be performed using aliquots of the same cell
populations employed for the transcriptional profiling. The results provided additional evidence that aging in S. cerevisiae is associated with a shift away from glycolysis and toward gluconeogenesis and energy storage. They also disclosed that this
shift is forestalled by two manipulations that extend life span, caloric restriction and genetic attenuation of the normal
age-associated increase in Snf1p activity. Together, these findings indicate that Snf1p activation is not only a marker of
aging but also a candidate mediator, because a shift toward energy storage over expenditure could impact myriad aspects of
cellular maintenance and repair. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M103509200 |