Requirement of NAD and SIR2 for Life-Span Extension by Calorie Restriction in Saccharomyces cerevisiae

Abstract

Calorie restriction extends life-span in a wide variety of organisms. Although it has been suggested that calorie restriction may work by reducing the levels of reactive oxygen species produced during respiration, the mechanism by which this regimen slows aging is uncertain. Here, we mimicked calorie restriction in yeast by physiological or genetic means and showed a substantial extension in life-span. This extension was not observed in strains mutant for SIR2 (which encodes the silencing protein Sir2p) or NPT1 (a gene in a pathway in the synthesis of NAD, the oxidized form of nicotinamide adenine dinucleotide). These findings suggest that the increased longevity induced by calorie restriction requires the activation of Sir2p by NAD.

SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol

“…In small model organisms, Sir2 orthologues have been reported to promote lifespan extension (Kaeberlein et al, 1999;Tissenbaum and Guarente, 2001;Rogina and Helfand, 2004) and to be required for calorie restriction (CR) to extend lifespan (Lin et al, 2000;Rogina and Helfand, 2004). We have recently reported evidence that the orthologue of Sir2 in mammals, SirT1, is also required for many of the physiological effects of CR (Boily et al, 2008).…”

Low Sirt1 expression, which is upregulated by fasting, in human adipose tissue from obese women

“…2 This increase in lifespan has been associated with an increase in SIR2 activity in yeast. 3 In mammals, the SIR2 ortholog Sirt1 (Sirtulin 1) also seems to play a role for the changes in fat metabolism observed after calorie restriction. 4 Recently, small molecules capable of stimulating SIR2 in yeast were characterized.…”

Pathophysiology of the aging kidney and therapeutic interventions

“…8 Recent evidence reveals that several anti-aging molecules are active in the human body and that these molecules are regulated by multiple factors through individual behaviors. 9,10 These results indicate that kidney aging could in fact be delayed and even reversed with the appropriate intervention.…”

“…9,74 The health benefits of calorie restriction have also been demonstrated in primates; calorie restriction in rhesus monkeys blunts aging and significantly delays the onset of age-related disorders, including cancer, diabetes, cardiovascular disease and brain atrophy. 75 Numerous molecules may mediate the beneficial effects of calorie restriction.…”