RESUMEN
CONTEXT: Nicotinamide adenine dinucleotide (NAD) levels decline with aging and age-related decline in NAD has been postulated to contribute to age-related diseases. OBJECTIVE: We evaluated the safety and physiologic effects of NAD augmentation by administering its precursor, ß-nicotinamide mononucleotide (MIB-626, Metro International Biotech, Worcester, MA), in adults at risk for age-related conditions. METHODS: Thirty overweight or obese adults, ≥ 45 years, were randomized in a 2:1 ratio to 2 MIB-626 tablets each containing 500 mg of microcrystalline ß-nicotinamide mononucleotide or placebo twice daily for 28 days. Study outcomes included safety; NAD and its metabolome; body weight; liver, muscle, and intra-abdominal fat; insulin sensitivity; blood pressure; lipids; physical performance, and muscle bioenergetics. RESULTS: Adverse events were similar between groups. MIB-626 treatment substantially increased circulating concentrations of NAD and its metabolites. Body weight (difference -1.9 [-3.3, -0.5] kg, P = .008); diastolic blood pressure (difference -7.01 [-13.44, -0.59] mmHg, P = .034); total cholesterol (difference -26.89 [-44.34, -9.44] mg/dL, P = .004), low-density lipoprotein (LDL) cholesterol (-18.73 [-31.85, -5.60] mg/dL, P = .007), and nonhigh-density lipoprotein cholesterol decreased significantly more in the MIB-626 group than placebo. Changes in muscle strength, muscle fatigability, aerobic capacity, and stair-climbing power did not differ significantly between groups. Insulin sensitivity and hepatic and intra-abdominal fat did not change in either group. CONCLUSIONS: MIB-626 administration in overweight or obese, middle-aged and older adults safely increased circulating NAD levels, and significantly reduced total LDL and non-HDL cholesterol, body weight, and diastolic blood pressure. These data provide the rationale for larger trials to assess the efficacy of NAD augmentation in improving cardiometabolic outcomes in older adults.
Asunto(s)
Resistencia a la Insulina , Sobrepeso , Persona de Mediana Edad , Humanos , Anciano , NAD/metabolismo , NAD/uso terapéutico , Mononucleótido de Nicotinamida/uso terapéutico , Obesidad , Peso Corporal , ColesterolRESUMEN
BACKGROUND: Nicotinamide adenine dinucleotide (NAD) precursors, nicotinamide mononucleotide (NMN), or nicotinamide riboside (NR) extend healthspan and ameliorate some age-related conditions in model organisms. However, early-phase trials of NAD precursors have yielded varying results and their pharmacokinetics remain incompletely understood. Here, we report the pharmacokinetics and pharmacodynamics of MIB-626, a microcrystalline unique polymorph ßNMN formulation. METHODS: In this double-blind, placebo-controlled study, 32 overweight or obese adults, 55-80 years, were block-randomized, stratified by sex, to 1 000-mg MIB-626 once daily, twice daily, or placebo for 14 days. NMN, NAD, and NAD metabolome were measured using liquid chromatography-tandem mass spectrometry. RESULTS: Participant characteristics were similar across groups. MIB-626 was well tolerated and frequency of adverse events was similar across groups. Blood NMN concentrations on Day 14 in MIB-626-treated groups were significantly higher compared to placebo (1.7-times and 3.7-times increase above baseline in 1 000 mg once-daily and twice-daily groups in mean AUClast, respectively). MIB-626 treatment was associated with substantial dose-related increases in blood NAD levels. Blood levels of NAD metabolites were higher in NMN-treated participants on Days 8 and 14 than at baseline. Changes in NMN or NAD levels were not related to sex, body mass index, or age. Very little unmodified NMN was excreted in the urine. CONCLUSION: MIB-626 1 000 mg once-daily or twice-daily regimens were safe and associated with substantial dose-related increases in blood NAD levels and its metabolome. These foundational data that were obtained using a pharmaceutical-grade ßNMN, standardized sample collection, and validated liquid chromatography-tandem mass spectrometry assays, should facilitate design of efficacy trials in disease conditions.
Asunto(s)
NAD , Mononucleótido de Nicotinamida , Humanos , Persona de Mediana Edad , Anciano , NAD/metabolismo , Mononucleótido de Nicotinamida/metabolismo , Mononucleótido de Nicotinamida/farmacología , Metaboloma , Espectrometría de Masas , Índice de Masa CorporalRESUMEN
The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.
Asunto(s)
Descubrimiento de Drogas , Pirimidinas/química , Pirimidinas/farmacología , Sirtuinas/antagonistas & inhibidores , Humanos , Modelos Moleculares , Conformación Proteica , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/química , Sirtuina 2/antagonistas & inhibidores , Sirtuina 2/química , Sirtuina 3/antagonistas & inhibidores , Sirtuina 3/química , Sirtuinas/químicaRESUMEN
AIM: SRT2104 is a novel, first-in-class, highly selective small molecule activator of the NAD + dependent deacetylase SIRT1. SRT2104 was dosed to healthy male and female volunteers in a series of phase 1 clinical studies that were designed to elucidate tolerability and pharmacokinetics associated with oral dosing to aid in dose selection for subsequent clinical trials. METHODS: In the first-in-human study, there was both a single dose phase and 7 day repeat dose phase. Doses used ranged from 0.03 to 3.0 g. A radioactive microtracer study was subsequently conducted to determine systemic clearance, bioavailability and preliminary metabolism, and a crossover study was conducted to determine the effect of gender, formulation and feeding state on SRT2104 pharmacokinetics. RESULTS: SRT2104 was well tolerated in all of these studies, with no serious adverse reactions observed. SRT2104 displayed a dose-dependent, but sub-proportional increase in exposure following single dose and repeated dose administration. Accumulation of three-fold or less occurs after 7 days of repeat dosing. The mean bioavailability was circa 14% and the mean clearance was circa 400 ml min(-1). Although there were no substantial effects on exposure resulting from gender or formulation differences, a notable food effect was observed, manifested as up to four-fold increase in exposure parameters. CONCLUSIONS: In the absence of an optimized formulation of SRT2104, the food effect can be used to maximize exposure in future clinical studies. Combined with the good tolerability of all doses demonstrated in these studies, the favourable selectivity profile of SRT2104 allows for the use of this SIRT1 modulator for target validation in the clinic.
Asunto(s)
Imidazoles/farmacocinética , Sirtuina 1/efectos de los fármacos , Tiazoles/farmacocinética , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Activación Enzimática , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Masculino , Tiazoles/administración & dosificación , Tiazoles/efectos adversosRESUMEN
BACKGROUND: Calorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD+-dependent protein deacetylase SIRT1 has been implicated as one of the key downstream regulators of CR in yeast, rodents, and humans. Small molecule activators of SIRT1 have been identified that exhibit efficacy in animal models of diseases typically associated with aging including type 2 diabetes. To identify molecular processes induced in the liver of mice treated with two structurally distinct SIRT1 activators, SIRT501 (formulated resveratrol) and SRT1720, for three days, we utilized a systems biology approach and applied Causal Network Modeling (CNM) on gene expression data to elucidate downstream effects of SIRT1 activation. RESULTS: Here we demonstrate that SIRT1 activators recapitulate many of the molecular events downstream of CR in vivo, such as enhancing mitochondrial biogenesis, improving metabolic signaling pathways, and blunting pro-inflammatory pathways in mice fed a high fat, high calorie diet. CONCLUSION: CNM of gene expression data from mice treated with SRT501 or SRT1720 in combination with supporting in vitro and in vivo data demonstrates that SRT501 and SRT1720 produce a signaling profile that mirrors CR, improves glucose and insulin homeostasis, and acts via SIRT1 activation in vivo. Taken together these results are encouraging regarding the use of small molecule activators of SIRT1 for therapeutic intervention into type 2 diabetes, a strategy which is currently being investigated in multiple clinical trials.
Asunto(s)
Restricción Calórica , Activación Enzimática/genética , Modelos Genéticos , Transducción de Señal/genética , Sirtuinas/metabolismo , Animales , Activación Enzimática/efectos de los fármacos , Perfilación de la Expresión Génica , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Ratones , Análisis por Micromatrices , Estructura Molecular , Resveratrol , Transducción de Señal/efectos de los fármacos , Sirtuina 1 , Estilbenos/química , Estilbenos/farmacologíaRESUMEN
SIRT1 is an NAD(+)-dependent protein deacetylase that appears to produce beneficial effects on metabolic parameters such as glucose and insulin homeostasis. Activation of SIRT1 by resveratrol (1) has been shown to modulate insulin resistance, increase mitochondrial content and prolong survival in lower organisms and in mice on a high fat diet. Herein, we describe the identification and SAR of a series of oxazolo[4,5-b]pyridines as novel small molecule activators of SIRT1 which are structurally unrelated to and more potent than resveratrol.
Asunto(s)
Oxazoles/síntesis química , Oxazoles/metabolismo , Piridinas/síntesis química , Piridinas/metabolismo , Sirtuinas/metabolismo , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Humanos , Ratones , Ratones Transgénicos , Oxazoles/farmacología , Piridinas/farmacología , Ratas , Ratas Zucker , Sirtuina 1 , Sirtuinas/agonistas , Relación Estructura-ActividadRESUMEN
A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.
Asunto(s)
Activadores de Enzimas/síntesis química , Hipoglucemiantes/síntesis química , Imidazoles/síntesis química , Quinoxalinas/síntesis química , Sirtuina 1/metabolismo , Tiazoles/síntesis química , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Activadores de Enzimas/química , Activadores de Enzimas/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Imidazoles/química , Imidazoles/farmacología , Ratones , Quinoxalinas/química , Quinoxalinas/farmacología , Ratas , Ratas Zucker , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
Sirtuins post-translationally modulate the function of many cellular proteins that undergo reversible acetylation-deacetylation cycles, affecting physiological responses that have implications for treating diseases of ageing. Potent small-molecule modulators of sirtuins have shown efficacy in preclinical models of metabolic, neurodegenerative and inflammatory diseases, and so hold promise for drug discovery efforts in multiple therapeutic areas. Here, we discuss current knowledge and data that strengthens sirtuins as a druggable set of enzymes for the treatment of age-associated diseases, including activation of SIRT1 in type 2 diabetes.
Asunto(s)
Envejecimiento/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/tendencias , Neoplasias/tratamiento farmacológico , Sirtuinas/metabolismo , Envejecimiento/efectos de los fármacos , Animales , Restricción Calórica/métodos , Enfermedades Cardiovasculares/enzimología , Diabetes Mellitus Tipo 2/enzimología , Sistemas de Liberación de Medicamentos/métodos , Humanos , Neoplasias/enzimología , Sirtuinas/agonistasRESUMEN
Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
Asunto(s)
Restricción Calórica , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Sirtuinas/agonistas , Acetilación , Sitio Alostérico , Animales , Glucemia/metabolismo , Dominio Catalítico , Línea Celular , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/farmacología , Modelos Animales de Enfermedad , Drosophila melanogaster , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Insulina/metabolismo , Insulina/farmacología , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Resveratrol , Sirtuina 1 , Sirtuinas/metabolismo , Estilbenos/química , Estilbenos/farmacologíaRESUMEN
Eukaryotes have evolved elaborate mechanisms to survive periods of adversity. By manipulating genes that control these mechanisms, researchers have found they can generate more stress resistant, longer-lived organisms. One of these is the PNC1 gene of Saccharomyces cerevisiae, a master "longevity regulatory gene" that translates a variety of environmental stresses into lifespan extension by activating the sirtuin family of longevity deacetylases. Master longevity genes such as PNC1 are highly adaptive because they allow organisms to respond in a concerted way to adversity and to rapidly evolve life strategies to compensate for a changing environment. Hence, they should be well conserved. We propose that there is a functional equivalent of PNC1 in mammals called Nampt (a.k.a. PBEF/Visfatin), a stress-responsive gene that would coordinately regulate metabolism, cell defenses, and resistance to diseases of aging.
Asunto(s)
Envejecimiento/fisiología , Longevidad/fisiología , Mamíferos/fisiología , Pentosiltransferasa/fisiología , Animales , Restricción Calórica , NAD/biosíntesis , Niacinamida/fisiología , Nicotinamida Fosforribosiltransferasa , Saccharomyces cerevisiae/fisiología , Sirtuinas/fisiologíaRESUMEN
In a search for potent inhibitors of class III histone/protein deacetylases (sirtuins), a series of sirtinol analogues have been synthesized and the degree of inhibition was assessed in vitro using recombinant yeast Sir2, human SIRT1, and human SIRT2 and in vivo with a yeast phenotypic assay. Two analogues, namely, 3- and 4-[(2-hydroxy-1-naphthalenylmethylene)amino]-N-(1-phenylethyl)benzamide (i.e., m- and p-sirtinol), were 2- to 10-fold more potent than sirtinol against human SIRT1 and SIRT2 enzymes. In yeast in vivo assay, these two small molecules were as potent as sirtinol. Compounds lacking the 2-hydroxy group at the naphthalene moiety or bearing several modifications at the benzene 2'-position of the aniline portion (carbethoxy, carboxy, and cyano) were 1.3-13 times less potent than sirtinol, whereas the 2'-carboxamido analogue was totally inactive. Both (R)- and (S)-sirtinol had similar inhibitory effects on the yeast and human enzymes, demonstrating no enantioselective inhibitory effect.
Asunto(s)
Benzamidas/síntesis química , Inhibidores de Histona Desacetilasas , Naftoles/síntesis química , Proteínas Reguladoras de Información Silente de Saccharomyces cerevisiae/antagonistas & inhibidores , Sirtuinas/antagonistas & inhibidores , Benzamidas/química , Benzamidas/farmacología , Diseño de Fármacos , Proteínas Fúngicas/genética , Silenciador del Gen , Histona Desacetilasas/química , Histona Desacetilasas/genética , Humanos , Naftoles/química , Naftoles/farmacología , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/genética , Proteínas Reguladoras de Información Silente de Saccharomyces cerevisiae/química , Proteínas Reguladoras de Información Silente de Saccharomyces cerevisiae/genética , Sirtuina 1 , Sirtuina 2 , Sirtuinas/química , Sirtuinas/genética , Estereoisomerismo , Relación Estructura-Actividad , Telómero/enzimologíaRESUMEN
Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.
Asunto(s)
Envejecimiento/fisiología , Caenorhabditis elegans/fisiología , Restricción Calórica , Drosophila melanogaster/fisiología , Longevidad/fisiología , Sirtuinas/agonistas , Envejecimiento/efectos de los fármacos , Alelos , Alimentación Animal , Animales , Caenorhabditis elegans/efectos de los fármacos , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Conducta Alimentaria/efectos de los fármacos , Conducta Alimentaria/fisiología , Femenino , Fertilidad/efectos de los fármacos , Fertilidad/fisiología , Flavonoides/farmacología , Flavonoles , Genotipo , Longevidad/efectos de los fármacos , Masculino , Mutación/genética , Fenoles/farmacología , Polifenoles , Resveratrol , Sirtuinas/metabolismo , Estilbenos/farmacología , Tasa de Supervivencia , Factores de TiempoRESUMEN
Apoptosis is a key tumor suppression mechanism that can be initiated by activation of the proapoptotic factor Bax. The Ku70 DNA end-joining protein has recently been shown to suppress apoptosis by sequestering Bax from mitochondria. The mechanism by which Bax is regulated remains unknown. Here, we identify eight lysines in Ku70 that are targets for acetylation in vivo. Five of these, K539, K542, K544, K533, and K556, lie in the C-terminal linker domain of Ku70 adjacent to the Bax interaction domain. We show that CBP and PCAF efficiently acetylate K542 in vitro and associate with Ku70 in vivo. Mimicking acetylation of K539 or K542 or treating cells with deacetylase inhibitors abolishes the ability of Ku70 to suppress Bax-mediated apoptosis. We demonstrate that increased acetylation of Ku70 disrupts the Ku70-Bax interaction and coincides with cytoplasmic accumulation of CBP. These results shed light on the role of acetyltransferases as tumor suppressors.
Asunto(s)
Acetiltransferasas/metabolismo , Antígenos Nucleares/metabolismo , Apoptosis/fisiología , ADN Helicasas , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Acetilación , Acetiltransferasas/antagonistas & inhibidores , Acetiltransferasas/genética , Secuencia de Aminoácidos , Animales , Antígenos Nucleares/genética , Sitios de Unión/fisiología , Proteína de Unión a CREB , Cricetinae , Proteínas de Unión al ADN/genética , Inhibidores Enzimáticos/farmacología , Células HeLa , Histona Acetiltransferasas , Humanos , Autoantígeno Ku , Lisina/metabolismo , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas Nucleares/genética , Estructura Terciaria de Proteína/fisiología , Proteínas Proto-Oncogénicas/genética , Homología de Secuencia de Aminoácido , Transactivadores/genética , Proteínas Supresoras de Tumor/genética , Proteína X Asociada a bcl-2RESUMEN
Calorie restriction (CR) slows aging in numerous species. In the yeast Saccharomyces cerevisiae, this effect requires Sir2, a conserved NAD+-dependent deacetylase. We report that CR reduces nuclear NAD+ levels in vivo. Moreover, the activity of Sir2 and its human homologue SIRT1 are not affected by physiological alterations in the NAD+:NADH ratio. These data implicate alternate mechanisms of Sir2 regulation by CR.
Asunto(s)
Proteínas Bacterianas , Histona Desacetilasas/metabolismo , NAD/metabolismo , Saccharomyces cerevisiae/fisiología , Proteínas Reguladoras de Información Silente de Saccharomyces cerevisiae/metabolismo , Sirtuinas/metabolismo , Acetaldehído/metabolismo , Aerobiosis , Factor de Unión a CCAAT/genética , Factor de Unión a CCAAT/metabolismo , Restricción Calórica , Medios de Cultivo , Proteínas de Unión al ADN , Genes Fúngicos , Genes Reporteros , Histidina/metabolismo , Hidroliasas/genética , Hidroliasas/metabolismo , Longevidad , Espectroscopía de Resonancia Magnética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Sirtuina 1 , Sirtuina 2 , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.