Review
Resveratrol, sirtuins, and the promise of a DR mimetic

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Abstract

Dietary restriction (DR) delays or prevents age-related diseases and extends lifespan in species ranging from yeast to primates. Although the applicability of this regimen to humans remains uncertain, a proportional response would add more healthy years to the average life than even a cure for cancer or heart disease. Because it is unlikely that many would be willing or able to maintain a DR lifestyle, there has been intense interest in mimicking its beneficial effects on health, and potentially longevity, with drugs. To date, such efforts have been hindered primarily by our lack of mechanistic understanding of how DR works. Sirtuins, NAD+-dependent deacetylases and ADP-ribosyltransferases that influence lifespan in lower organisms, have been proposed to be key mediators of DR, and based on this model, the sirtuin activator resveratrol has been proposed as a candidate DR mimetic. Indeed, resveratrol extends lifespan in yeast, worms, flies, and a short-lived species of fish. In rodents, resveratrol improves health, and prevents the early mortality associated with obesity, but its precise mechanism of action remains a subject of debate, and extension of normal lifespan has not been observed. This review summarizes recent work on resveratrol, sirtuins, and their potential to mimic beneficial effects of DR.

Introduction

Although genetic manipulations that extend rodent lifespan are being reported with increasing frequency, none have yet exceeded the benefit of dietary restriction (DR), a simple reduction in caloric intake in the absence of malnutrition. This regimen was first described as a means to extend lifespan by McCay and colleagues in 1935 (McCay et al., 1935). By way of comparison, single-gene mutations were first shown to extend lifespan in worms in 1988 (Friedman and Johnson, 1988), and in rodents in 1996 (Brown-Borg et al., 1996). Whereas most genetic manipulations in rodents have been tested only once, with limited phenotypic assessment, the effects of DR have been tested in hundreds of labs, and its effects on nearly every age-related change have been documented (Baur, 2009, Masoro, 2005, Weindruch and Walford, 1988). The overwhelming conclusion is that DR affects something very fundamental to the aging process, as determined by its effects on disparate age-related diseases, as well as detailed analyses of mortality rates (Yen et al., 2008). Among DR's beneficial effects are the delay or prevention of major causes of morbidity and mortality such as cancer, heart disease, neurodegenerative diseases, sarcopenia (age-related loss of muscle mass), and diabetes. While there are some initial trade-offs in terms of fertility and bone density, and nagging questions about the ultimate effects on the immune system (Ritz et al., 2008), the available evidence suggests that there may be some long-term benefits even on these parameters (Dixit, 2008, McShane and Wise, 1996, Tatsumi et al., 2008). In contrast, there is little information available, and much reason to be concerned about potential trade-offs in long-lived genetically manipulated mice. For example, Snell dwarf mice, which carry a recessive mutation in the Pit-1 gene that affects anterior pituitary development, are long-lived. However, these mice also develop increased adiposity (Flurkey et al., 2001) that might be harmful in humans, and are quite frail, to the point where lifespan is shortened if special care is not taken to provide a protective environment (Flurkey et al., 2002). Similarly, telomerase-overexpressing mice are long-lived on a tumor-suppressing background (Tomas-Loba et al., 2008), but in wild type mice this manipulation increases early cancer-related deaths (Gonzalez-Suarez et al., 2005). Because of examples like this, the study of DR remains the most promising approach to discovering a safe and effective way to slow age-related decline in humans.

Studies in monkeys and humans have shown that DR improves parameters relevant to health (Anderson and Weindruch, 2006, Lefevre et al., 2009), and in monkeys this translates into a delay in age-related mortality (Colman et al., 2009). Although there are theoretical arguments to suggest that effects on human longevity will be smaller based on evolutionary forces (Phelan and Rose, 2005), or on comparisons between populations with different caloric intakes (Everitt and Le Couteur, 2007), the potential effect of DR is enormous as compared to other factors that can influence lifespan (Fig. 1). Moreover, the effects on health that have already been demonstrated could significantly improve the quality of life for many individuals (Lefevre et al., 2009, Weiss et al., 2006). Because it is viewed as unlikely that a large proportion of the population would be willing or able to maintain a DR lifestyle, there has been growing interest in mimicking the effects of DR with drugs (Ingram et al., 2006). These efforts raise important questions about the nature of the DR effect and highlight our ignorance of the mechanisms involved. For example, if one proposes the simple passive hypothesis that caloric input drives metabolic rate, which determines the amount of damage, which is the cause of aging, then it would seem that reproducing the effect without manipulating caloric intake would not be possible. However, this model is clearly not correct, since a number of mutations block the ability of caloric intake to influence lifespan (Anderson et al., 2003, Bonkowski et al., 2006, Panowski et al., 2007), indicating the involvement of an active signaling mechanism. Moreover, the assertion that long-term DR decreases metabolic rate (e.g. Sohal et al., 2009) has been called into question (Hempenstall et al., 2010), and some interventions, such as fat-specific deletion of the insulin receptor (Bluher et al., 2003), appear to simultaneously increase longevity and metabolism. To side-step many of these issues, Lane et al. (1998) selected 2-deoxyglucose, a glycolysis inhibitor, as the first candidate DR mimetic. Impressively, this relatively non-specific approach to mimicking energy stress recapitulates the increase in insulin sensitivity and decrease in core body temperature observed in DR animals. However, toxicity near the therapeutic doses has prevented studies on longevity, or further development of the molecule for use in humans. A second approach was based on the ability of metformin to promote insulin sensitivity, which is a hallmark of DR (Roth et al., 2001). Strikingly, metformin mimicks a large proportion of the transcriptional changes induced by DR in liver (Dhahbi et al., 2005), and inhibits tumor development (Anisimov et al., 2005). Although the effects of metformin on oxidative metabolism are complex and incompletely understood (Leverve et al., 2003), activation of AMP-activated protein kinase (AMPK), a sensor of energy stress, is thought to play a central role (Zhou et al., 2001). In addition, a related compound, phenformin, was shown in 1980 to extend mouse lifespan, albeit in a tumor-prone strain (Dilman and Anisimov, 1980). However, the precise role of AMPK in DR has been debated (Gonzalez et al., 2004), and phenformin has been pulled off the market as a human drug due to fatal cases of lactic acidosis (Kwong and Brubacher, 1998). While metformin remains an interesting candidate DR mimetic (and as an anti-diabetic, remains one of the most widely prescribed drugs), it is clear that the rational design of interventions to mimic DR will require a better understanding of the underlying mechanisms.

Section snippets

Sirtuins as mediators of DR in lower organisms

In 2000, Lin et al. proposed that sirtuins, homologues of the yeast Sir2 protein, are critical mediators of the effects of DR. This hypothesis was based in part on the observation that SIR2 copy number determines yeast lifespan, but was prompted most directly by the discovery that the enzymatic activity of all sirtuins is dependent on the co-substrate nicotinamide adenine dinucleotide (NAD+) (Imai et al., 2000, Smith et al., 2000). Since the reduced form of the molecule, NADH, is a competitive

Resveratrol in lower organisms and in vitro

Based on the hypothesis that sirtuins are critical mediators of DR, Howitz et al. (2003) performed an in vitro screen for small molecule activators of the closest mammalian Sir2 homolog, SIRT1. Their most potent hit was resveratrol, a small polyphenol that was already suspected to be cardioprotective and have cancer chemopreventive activity, supporting the hope that compounds identified in this manner would mimic beneficial aspects of DR. Subsequently, resveratrol was shown to extend yeast,

Does resveratrol mimic dietary restriction in rodents?

At the phenotypic level the assertion that resveratrol mimics DR in lower organisms relies heavily on lifespan extension. This raises an important question about what constitutes a DR mimetic. In the broadest sense, a DR mimetic could be considered any compound that produces a beneficial effect of DR through the same mechanism without the need to restrict energy intake. By this definition, lifespan extension in lower organisms makes resveratrol a DR mimetic, as long as activation of Sir2 (or

Is SIRT1 the critical target of resveratrol in vivo?

Resveratrol treatment leads to deacetylation of SIRT1 targets in vivo, supporting its proposed mechanism of action (Baur et al., 2006, Lagouge et al., 2006). In some cases, these effects have the potential to directly explain observed changes in physiology. For example, SIRT1 deacetylates PGC-1α (Rodgers et al., 2005), which directly activates mitochondrial biogenesis and most likely explains the increase in mitochondria observed in resveratrol-treated animals. However, resveratrol has many

Other sirtuins

Another important question is whether other mammalian sirtuins (SIRT2-7) are critical mediators of DR. While SIRT1 is the closest mammalian homolog to the enzymes associated with lifespan in lower organisms, and has been the focus of drug discovery efforts, other sirtuins also use NAD+ as a co-substrate and may respond to DR. Resveratrol is thought to act mainly on SIRT1, but may also activate SIRT7 (Vakhrusheva et al., 2008), while SRT1720 is currently considered to be specific for SIRT1,

Conclusion

There is compelling evidence that resveratrol can ameliorate many of the negative health consequences associated with obesity in rodents, and provides some benefit even in lean animals. Overexpression studies, and novel small molecule activators support a role for SIRT1 in many of these effects, however the poor phenotype of SIRT1 null mice has thus far precluded a more definitive experiment. Based on transcriptional profiling, resveratrol mimics a striking number of the changes induced by

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