Calorie restriction extends yeast life span by lowering the level of NADH

Abstract

Calorie restriction (CR) extends life span in a wide variety of species. Previously, we showed that calorie restriction increases the replicative life span in yeast by activating Sir2, a highly conserved NAD-dependent deacetylase. Here we test whether CR activates Sir2 by increasing the NAD/NADH ratio or by regulating the level of nicotinamide, a known inhibitor of Sir2. We show that CR decreases NADH levels, and that NADH is a competitive inhibitor of Sir2. A genetic intervention that specifically decreases NADH levels increases life span, validating the model that NADH regulates yeast longevity in response to CR. Received October 27, 2003; revised version accepted November 26, 2003. Calorie restriction (CR) extends life span in a wide spectrum of organisms and for decades was the only regimen known to promote longevity in mammals (Weindruch and Walford 1998;Roth et al. 2001). CR has also been shown to delay the onset or reduce the incidence of many age-related diseases including cancer and diabetes (Weindruch and Walford 1998;Roth et al. 2001). Although it has been suggested that CR may work by reducing the levels of reactive oxygen species through a slowing in metabolism (Weindruch and Walford 1998), the mechanism by which CR extends life span is still uncertain. To study the mechanism by which CR extends life span, we established a model of CR in the budding yeast Saccharomyces cerevisiae. In this system, life span can be extended by limiting glucose content in the media from 2% to 0.5% or by reducing the activity of the glucose-sensing cAMP-dependent kinase (PKA; Lin et al. 2000).The benefit of CR requires NAD (nicotinamide adenine dinucleotide, oxidized form) and Sir2 , a key regulator of life span in both yeast and animals (Kaeberlein et al. 1999;Tissenbaum and Guarente 2001). Sir2 is an NAD-dependent histone deacetylase and is required for chromatin silencing and life-span extension (Imai et al. 2000;Landry et al. 2000;Smith et al. 2000). The requirement of NAD for Sir2 deacetylase activity suggested CR may activate Sir2 by increasing the available pool of NAD for Sir2 (Guarente 2000).Our previous studies suggested that there was a second mechanism to activate Sir2 and extend the life span in yeast-osmotic stress . This stress mechanism was genetically distinguishable from CR. Mutations knocking out electron transport prevented CR from extending life span, but had no effect on the longevity conferred by osmotic stress Lin et al. 2002). This requirement for electron transport during CR is because of a shunting of carbon metabolism from fermentation to the mitochondrial TCA cycle. The concomitant increase in respiration is necessary and sufficient for the activation of Sir2-mediated silencing and extension in life span . The fact that respiration produces NAD from NADH (Bakker et al. 2001), reinforces the idea that changes in the NAD/NADH ratio regulate Sir2 during CR.A recent report, however, challenged this model by claiming that both stress and CR activated Sir2 by a different mechanism, namely, by ...

Genes that may modulate longevity in C. elegans in both dauer larvae and long-lived daf-2 adults

“…Indeed, the respiration rate in some long-lived mutants of C. elegans is not reduced relative to wild-type animals (Braeckman et al, 2002), and the longevity-enhancing effect of caloric restriction has been associated with a higher than normal rate of oxygen consumption (Barros et al, 2004;Lin et al, 2004). As we observed a decrease in tags for TCA cycle enzymes, a question arose about possible alternative sources of the NADH required for the membrane-associated ATP-generating mitochondrial complex.…”

Bivalve models of aging and the determination of molluscan lifespans

“…It is important to note that both, depression of metabolic rate in hypoxia tolerant animals as much as CR, which after an initial transition phase is completely aerobic (Lin et al, 2008), could result in prolongation of life expectancy. Buick and Ivany (2004) proposed that one of the processes conferring an extension of lifespan in bivalves from high latitudes could be the seasonal limitations of light and food availability.…”

Role of dietary amino acid balance in diet restriction‐mediated lifespan extension, renoprotection, and muscle weakness in aged mice

“…Dietary restriction (DR) can extend lifespan in numerous species, including mammals, and prevent age‐related impairment in organ function, including kidney dysfunction (Colman et al., 2014; Kume et al., 2010; Lin, Ford, Haigis, Liszt, & Guarente, 2004; Shimokawa et al., 2015). In contrast, DR has only one principal negative effect: muscle weakness due to protein wasting (Lopes, Russell, Whitwell, & Jeejeebhoy, 1982; Thomas, 2007), which also represents a health problem in both elderly subjects and patients with kidney disease (Goodpaster et al., 2006; Workeneh & Mitch, 2010).…”

“…Of particular note is that, in a study conducted in Drosophila , recovering dietary EAA, but not NEAA, prevented DR‐induced lifespan extension (Grandison, Piper, & Partridge, 2009). Given that the beneficial effect of simple DR on lifespan is observed in most living organisms (Colman et al., 2014; Kume et al., 2010; Lin et al., 2004), the distinct effects of dietary EAA and NEAA on DR‐mediated longevity may be conserved across species. We therefore hypothesized that the balance between the dietary content of EAAs and NEAAs would affect DR‐induced lifespan extension and modify age‐related organ dysfunction in mammals, with implications for the design of an improved dietary regimen aimed at extending healthy lifespan.…”