Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway

Abstract

AMP-activated protein kinase (AMPK) and the homologous yeast SNF1 complex are key regulators of energy metabolism that counteract nutrient deficiency and ATP depletion by phosphorylating multiple enzymes and transcription factors that maintain energetic homeostasis. AMPK/SNF1 also promotes longevity in several model organisms, including yeast. Here we investigate the role of yeast SNF1 in mediating the extension of chronological life span (CLS) by caloric restriction (CR). We find that SNF1 activity is required throughout the transition of log phase to stationary phase (diauxic shift) for effective CLS extension. CR expands the period of maximal SNF1 activation beyond the diauxic shift, as indicated by Sak1-dependent T210 phosphorylation of the Snf1 catalytic ␣-subunit. A concomitant increase in ADP is consistent with SNF1 activation by ADP in vivo. Downstream of SNF1, the Cat8 and Adr1 transcription factors are required for full CR-induced CLS extension, implicating an alternative carbon source utilization for acetyl coenzyme A (acetyl-CoA) production and gluconeogenesis. Indeed, CR increased acetyl-CoA levels during the diauxic shift, along with expression of both acetyl-CoA synthetase genes ACS1 and ACS2. We conclude that CR maximizes Snf1 activity throughout and beyond the diauxic shift, thus optimizing the coordination of nucleocytosolic acetyl-CoA production with massive reorganization of the transcriptome and respiratory metabolism. KEYWORDS Snf1, AMPK, aging, yeast, caloric restriction, ADP, diauxic shift, acetyl-CoA A lthough each eukaryotic species suffers from its own set of age-related maladies, characteristics of the aging process at a cellular level are well conserved, including mitochondrial dysfunction, inefficient turnover of damaged proteins and organelles, accumulated reactive oxygen species (ROS) damage, and gradual breakdown of chromatin structure (reviewed in reference 1). Given the variety of the cellular components involved, it is astounding that any single intervention can alleviate the deterioration of all these processes. Caloric restriction (CR), however, slows the onset of aging-related pathologies and extends life span in almost every model organism tested, ranging from yeast to mammals (reviewed in reference 2). Some mechanistic commonalities for CR have emerged, including upregulation of cellular autophagy, increased mitochondrial respiration, protective oxidative stress responses, and decreased protein synthesis (reviewed in reference 3). The majority of these processes are regulated by a series of highly conserved nutrient signaling pathways, including the AMP-activated protein kinase (AMPK) signaling pathway (4).AMPK is the eukaryotic cell's primary energy sensor, regulating metabolism and other downstream processes while interacting with other signaling pathways (5). Experimental evidence for AMPK as a mediator of the CR longevity response is mounting. In Caenorhabditis elegans, AMPK is activated and required for life span extension under certain CR regimens (6, 7). I...

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