Wai Yan Sun and Yu Wang, The University of Hong Kong, Hong Kong, China
Aging is a complex process of functional decline at the molecular, cellular, and organ system levels. Even as human life expectancy is being prolonged, age-related diseases continue to be major obstacles for healthy aging and longevity. Evidence from different biological models ranging from yeasts, worms, flies, rodents, and primates to humans suggests a number of conserved aging mechanisms offer pathways to maintain the “youthful” states. Calorie restriction remains the most robust nongenetic approach for extending health and life span. It slows primary aging and effectively protects secondary aging in both animals and humans. Calorie restriction mimetics (CRMs) targeting the molecular aging pathways have emerged as a promising strategy for combating age-related morbidities. This chapter introduces a number of CRMs derived from functional foods and discusses their mechanisms of action in mimicking calorie restriction.
Calorie restriction; intermediary metabolites; aging; autophagy; protein acetylation; SIRT-1
The life expectancy of humans has dramatically increased over the past few centuries, which is imposing negative impacts on age-associated diseases and the medical cost of health care. Aging is a multifactorial biological process, progressively degenerative in nature and resulting in loss of physical or mental functions (or both) (Dabhade and Kotwal, 2013; Shokolenko et al., 2014). Primary aging refers to the currently inevitable process of the functional deterioration of organs as well as slowing movement, fading vision, progressive hearing loss, and increased susceptibility to infection. In contrast, secondary aging is preventable and results largely from disease processes, harmful environmental factors, and poor lifestyle decisions such as smoking and a lack of physical activity (Anstey et al., 1993). Numerous signaling pathways that are commonly or specifically involved in age-related diseases—including type 2 diabetes mellitus, cardiovascular disease, and Alzheimer’s disease (AD)—have been identified and characterized (Masri, 2015). As a result, the protections against secondary aging lead to a significant increase in the average life span (Fontana et al., 2010). However, our knowledge of the underlying causes for primary aging remain primitive. Accordingly, the maximal longevity of humans remains largely unchanged.
Calorie intake influences the rate of aging and the onset of age-related diseases in animals and humans. Calorie restriction is a dietary regimen to limit the consumption of food without causing malnutrition, which effectively slows the process of primary aging and protects secondary aging in rodents (McCay et al. 1935; Weindruch and Sohal 1997) as well as in nonhuman primates (Lane et al., 1996; Colman et al., 2009). The effects are robust as evident in mice with long-term 55% to 65% calorie restriction leading to a 65% extension of maximal life span when compared to the control group with ad libitum feeding (Weindruch, 1996). Two long-term calorie restriction studies using rhesus monkeys by the Wisconsin National Primate Research Center (WNPRC) and the National Institute on Aging (NIA) produced controversial results. The former was initiated in 1989, and its results were published in 2014 with the conclusion that a long-term approximately 30% restricted diet significantly improved age-related and all-cause survival in rhesus monkeys (Colman et al., 2014). The NIA initiated its study in 1987, and the interim report in 2012 showed that calorie restriction did not increase the median life span of rhesus monkeys (Mattison et al., 2012). Notably, WNPRC study performed 30% dietary restriction that was individualized for each monkey, whereas the monkeys of NIA study were fed with 22% to 24% reduced calories based on the standardized chart of food intake by the National Academy of Science. In addition, all monkeys in the NIA study were supplemented with minerals and vitamins above the adequate amount in order to avoid any compromising factors. However, only the calorie-restricted monkeys were supplemented in WNPRC study. The control monkeys at NIA weighed less than those at the WNPRC at all time points, suggesting an inadequate food intake (Tenenbaum, 2014).
Long-term calorie restriction reduces body weight and has beneficial effects on the health span of nonhuman primates by reducing cancer development, neurodegeneration, and metabolic disorders (Mattison et al., 2012; Libert and Guarente, 2013). Intermittent calorie restriction also shows similar benefits in improving the health span in humans, but consistent weight loss is unlikely to be seen (Heilbronn et al., 2005). In mice, calorie restriction not only reduces body weight and fat mass but also decreases insulin-like growth factor 1 (IGF-1), leptin, fasting blood glucose, and insulin levels (Mai et al., 2003; Tatar et al., 2003; Wang et al., 2013). Overall, calorie restriction enhances metabolic and anti-inflammatory profiles. Effects such as lowered blood glucose and insulin occur quickly but also diminish rapidly when calorie restriction stops (Anderson and Herman, 1972; Mitchell et al., 2015). Thus, to be beneficial, intervention must be sustained. Nevertheless, calorie restriction lowers the susceptibility of a wide spectrum of age-associated diseases. For instance, mice on a calorie-restricted diet showed attenuation of age-related neuronal loss seen in Parkinson’s disease (Duan and Mattson, 1999) and in AD (Zhu et al., 1999); improvement for the brain’s plasticity in learning (Mattson, 2000); prevention of age-associated declines in psychomotor and spatial memory tasks (Ingram et al., 1987); and reductions in autoimmune disease, kidney damage, and diabetes (Fernandes and Good, 1984). Taken together, calorie restriction protects secondary aging in rodents and nonhuman primates.
Long-term population studies of calorie restriction are hard to conduct for primary aging in humans (Holloszy and Fontana, 2007). Physiological and metabolic variables are determined as the biomarkers for secondary aging. The Biosphere 2 study initiated in 1991 with eight healthy humans (four males and four females) sealed inside a 3.15-acre enclosure began with a limited food supply. After six months, the occupants’ body weights, blood pressure, serum cholesterol, fasting glucose, and leukocyte counts were significantly reduced without any changes in physical or mental health status (Walford et al., 1992). The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy was the first random trial in free-living nonobese men and women investigating the effects of calorie restriction (Stewart et al., 2013; Romashkan et al., 2016). During the two-year study period, individuals on an 11% calorie-restricted diet exhibited 10% weight loss, whereas the body weight of the control counterparts remained unchanged (Ravussin et al., 2015). Calorie restriction significantly reduced the levels of triiodothyronine and tumor necrosis factor alpha (a marker of inflammation) (Ravussin et al., 2015). Memory and learning performance is enhanced, and insulin sensitivity is improved in healthy elderly persons subject to calorie restriction (Witte et al., 2009). Furthermore, diabetic elderly patients on calorie restriction for 12 weeks show improved blood pressure, glucose and lipid profiles, as well as liver functions, all of which contribute to low cardiovascular risks (Choi et al., 2013).
In the 1950s, Okinawan elders were consuming a calorie-restricted diet that was approximately 1800 cal/day and approximately 20% lower than the national average of Japan (Heilbronn and Ravussin, 2003). Public health care and the quality of the diet on Okinawa were sufficiently good to prevent nutritional deficiencies and infectious diseases. Thus, life expectancy was 81.2 years, significantly higher than those of European countries (e.g., 78.3 years in Italy and 78.1 years in Greece) and the United States (76.8 years) (Sohal and Weindruch, 1996). Because of poverty, however, elderly Okinawans growth was significantly stunted. In fact, long-term calorie restriction may not be a desirable dietary method for improving health span as well as longevity in humans. On the one hand, personal motivation to undergo long-term calorie restriction may be lacking. Thus, a 30% to 60% calorie restriction is not achievable by most human subjects, especially the elderly. On the other hand, the side effects of long-term calorie reduction remain unclear, but include reduced bone mineral densities, functional disability, infertility, and slow recovery from injuries (Ingram and Roth, 2011; Romashkan et al., 2016). Moreover, calorie restriction can provoke unpleasant common side effects such as reduced body temperature and libido (Ingram and Roth, 2011).
Recent decades have seen the introduction of calorie restriction mimetics (CRMs), which are also known as energy restriction mimetics, in which a class of natural or synthetic pharmacological substances are provided as food supplements to mimic the beneficial anti-aging effects of calorie restriction (Chen and Guarente, 2007; Lee and Min, 2013). The genes and pathways involved in the actions of calorie restriction are the targets for discovering and developing CRMs (Ingram et al., 2006). An effective CRM activates the same physiological and metabolic pathways as calorie restriction, triggers stress-response mechanisms for protection against cellular damage, and extends health and life span without the requirement of dietary or energy restriction. In the following sections, the mechanisms of action for CRMs derived from functional foods will be discussed with a focus on their roles in mimicking the metabolic or signaling pathways of calorie restriction.
A precise understanding of the mechanisms underlying the actions of calorie restriction is needed for identifying and generating CRMs. Starvation of cells or dietary restriction in mammals leads to a rapid reduction of intracellular acetyl coenzyme A (acetyl-CoA), which is coupled to the status of protein acetylation and deacetylation (Bao and Sack, 2010). Decreased acetyl-CoA levels occur before the reduction of adenosine triphosphate (ATP), oxidation of nicotinamide adenine dinucleotide phosphate (NADH), and the depletion of amino acids. The coordinated alterations of these metabolites trigger a number of key cellular defense mechanisms via the activation of nutrient sensors, including adenosine monophosphate (AMP)-activated protein kinase (AMPK) and silent mating type information regulation 2 homologue 1 (SIRT-1), as well as inactivation of mammalian target of rapamycin (Cetrullo et al., 2015).
In cells, glycolysis is a multistep process that utilizes energy (ATP) to break down glucose into pyruvate, which is then decarboxylated into acetyl-CoA (Akram, 2014). Glycolytic inhibition has been suggested as a strategy for developing CRMs (Roth et al., 1999) based on the rationale that reducing energy supply enhances the metabolic responses in cells, a process mimicking calorie restriction (Ingram and Roth. 2011). There are several key enzymes for targeting the glycolytic pathway. In particular, phosphoglucose isomerase, which converts glucose-6-phosphate to fructose-6-phosphate, is the target of 2-deoxy-D-glucose (2DG) (Ingram and Roth, 2011). Low doses of 2DG enhance oxidative stress protection and neuronal resistance by upregulating heat shock protein 70 (HSP-70) and glucose-regulated protein 78, resulting in neuroprotection (Lee et al., 1999). Glycolytic inhibition delays secondary aging and prevents neurodegenerative disorders.
Glyceraldehyde-3-phosphate dehydrogenase is another target of glycolytic inhibition in vitro in which administration of iodoacetate that inhibits this enzyme can upregulate the expression of HSP-70 and HSP-90 in neurons against excitotoxic and oxidative injury (Guo et al., 2001). Other glycolytic inhibitors—including glucosamine, mannoheptulose, and 3-bromopyruvate—are also candidate CRMs. The phosphorylated form of glucosamine, glucosamine-6-phosphate, is an inhibitor of hexokinase, which is involved in the first step of glycolysis (Marshall et al., 2005). Glucosamine activates autophagy, which is an important cellular mechanism for anti-aging and discussed in later (Carames et al., 2013). In antitumor studies, mannoheptulose and 3-bromopyruvate exhibit inhibitory effects on the glycolytic enzyme hexokinase activity, where this early part of the glycolytic reactions is utilized by cancer cells to generate their own energy (Pedersen, 2007; Wang et al., 2016). However, the underlying mechanisms for CRM are not fully known in vivo. When dogs were fed mannoheptulose, their fasting insulin levels were reduced in a dose-dependent manner, but the serum glucose levels did not differ (McKnight et al., 2014; Ingram and Roth, 2015). These agents can be candidates for CRM, but further studies are required to investigate their full mechanisms of action.
The citric acid cycle (also known as the Krebs cycle or tricarboxylic acid cycle) consists of a series of reactions conducted within the mitochondria of eukaryotic cells or in the cytoplasm of prokaryotic cells (Kornberg, 2000; Korla and Mitra, 2014). It is a central driver of cellular respiration and takes acetyl-CoA as the starting material. Oxaloacetate is the end product of one citric acid cycle. Supplementation with oxaloacetate has been shown to increase longevity in Caenorhabditis elegans via an increase in the ratio of nicotinamide adenine dinucleotide (NAD) to NADH and activation of the AMPK pathway (Williams et al., 2009). The conversion of oxaloacetate to malate promotes the conversion of NADH to NAD. Unlike 2DG, oxaloacetate supports glycolysis and cellular respiration (Wilkins et al., 2016). In mice, administration of oxaloacetate increases brain bioenergetic function by activating hippocampal neurogenesis and reducing neuroinflammation via the Akt signaling pathway (Wilkins et al., 2014). A recent study has revealed the safety profile of oxaloacetate in humans, but the efficacy in AD or other age-associated diseases has yet to be elucidated (Swerdlow et al., 2016).
Formation of intracellular acetyl-CoA occurs in both mitochondrial and nucleocytosolic compartments. In mammals, the mitochondrial acetyl-CoA is produced from pyruvate, fatty acid, and branched-chain amino acids via glycolysis, lipolysis, and oxidative decarboxylation (Madeo et al., 2014). Acetyl-CoA in the mitochondrial matrix is condensed with oxaloacetate into citrate, which can be exported into the cytoplasm, where it freely diffuses in and out of nucleus. The extramitochondrial acetyl-CoA is produced from citrate by ATP citrate lyase or from acetate by acetyl-CoA synthase (Choudhary et al., 2014; Marino et al., 2014; Schroeder et al., 2014). Excessive nutrient supply enhances the transportation of acetyl-CoA from mitochondria to cytosol for the synthesis of fatty acids and sterols (Wellen et al., 2009; Cai et al., 2011; Shi and Tu, 2015). Short-term removal of nutrients in human cell culture and overnight fasting of rodents rapidly reduces acetyl-CoA levels (Marino et al., 2014). Notably, when cells commit to proliferate, the intracellular levels of acetyl-CoA are substantially elevated to promote histone acetylation so the gene expression for growth can be switched on (Cai et al., 2011). This mechanism requires energy consumption and is pro-aging. Conversely, reduction of acetyl-CoA levels is observed when arresting cell growth to reserve energy, which favors anti-aging.
A number of natural compounds act as CRMs to reduce acetyl-CoA or inhibit protein acetylation. For example, hydroxycitrate (Hackenschmidt et al., 1972) and epigallocatechin-3-gallate (EGCG), one of the major active compounds in green tea (Santana et al., 2015), stimulate the activity of acetyl-CoA carboxylase, a biotin-dependent enzyme that irreversibly catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA. Anacardic acid (6-pentadecyl-salicylic acid from the nutshell of the cashew, Anacardium occidentale), garcinol (from the fruit of the kokum tree, Garcinia indica), and spermidine (a polyamine found at particular high concentrations in durian fruit, fermented soybeans, and wheat germs) reduce the overall lysine acetylation of cellular protein via inhibition of acetyltransferases, in turn inducing autophagy (Pietrocola et al., 2015).
Nucleocytosolic acetyl-CoA production is a metabolic repressor of autophagy, a self-cannibalistic pathway to eliminate damaged organelles and toxic protein aggregates, thus mobilizing energy reserves when external resources are limited (Levine and Kroemer, 2008). During this process, the unique organelle known as the autophagosome delivers the cellular components to a lysosome for degradation. A number of autophagy-related proteins (Atg) are involved in the formation of autophagosome (Ravikumar et al., 2010). Notably, the biological process of autophagy decreases with age (Cavallini et al., 2007). Deficiency or attenuation of autophagy causes premature aging and leads to various age-dependent diseases (Levine and Kroemer, 2008; Hartleben et al., 2010; Cui et al., 2013). Conversely, activation of autophagy by overexpression of Atg can increase the life span of mice (Pyo et al., 2013).
Calorie restriction is one physiological trigger for autophagy. Depletion of nucleocytosolic acetyl-CoA in yeast and knockdown of acetyl-CoA synthase in Drosophila melanogaster attenuates the global acetylation of proteins, activating autophagy to promote longevity (Eisenberg et al., 2014; Schroeder et al., 2014). Starvation-induced autophagy is associated with the reduced acetylation of Atg, tubulin, and microtubule-associated proteins (Lee and Finkel, 2009; Geeraert et al., 2010). Inhibition of endogenous E1A-binding protein p300 (EP300), an acetyl transferase and transcription coactivator, causes induction of forkhead box protein O promotor activity (Senf et al., 2011) and reduces acetylation of Atg5, Atg7, Atg8, and Atg12 (Lee and Finkel, 2009) A variety of agents that inhibit EP300 are used in traditional medicine, including curcumin (from the South Asian spice turmeric, Curcuma longa, one of the principal ingredients of curry powder), EGCG, garcinol, and spermidine (Pietrocola et al., 2015).
Spermidine belongs to the family of polyamines that can be found naturally in oranges, soybeans, rice bran, green pepper, broccoli, mushrooms, and green tea (Morselli et al., 2011). At the cellular level, polyamines interact with negatively charged molecules such as DNA, RNA, and lipids and regulate cell growth, proliferation, and death as well as lipid metabolism (Minois et al., 2011). Spermidine increases the life span in yeast Saccharomyces cerevisiae, nematode worm C. elegans, and fruit flies D. melanogaster (Eisenberg et al., 2009; Madeo et al., 2010; Minois et al., 2012). Autophagy has been identified as the main mechanism of action underlying the antiaging effects of spermidine (Minois, 2014). Administration of spermidine at low doses induces full autophagic responses and extends life span in yeast (Morselli et al., 2011). Spermidine-fed flies show enhanced autophagy and are protected from age-induced memory impairment (Gupta et al., 2013). In addition, spermidine inhibits acetyltransferases and affects global protein acetylation status by triggering deacetylation in the cytosol or acetylation in the nucleus (or both) (Eisenberg et al., 2009; Minois et al., 2012). The intracellular concentrations of polyamines decline with age in rodents and humans (Nishimura et al., 2006; Eisenberg et al., 2009). Supplementation with spermidine reduces age-associated pathology and mortality in aged mice (Soda et al., 2009; LaRocca et al., 2013). However, the evidence for spermidine to increase primate and human life spans has yet to be revealed. Recently, the endogenous levels of spermidine have been shown to be positively correlated with left ventricular ejection fraction and heart rate in humans (Meana et al., 2016). Whether supplementation of spermidine has beneficial effects for preventing age-associated diseases, especially cardiovascular diseases, needs further investigation.
Calorie restriction increases mitochondrial NAD in order to promote survival (Yang et al., 2007). The salvage pathway for NAD biosynthesis begins with either nicotinamide (NAM) or nicotinic acid (NA), collectively known as niacin or vitamin B3 (Rongvaux et al., 2003). NAM is converted to nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyltransferase (NAMPT). The production of NAD from NMN and ATP is catalyzed by a family of NMN adenylyltransferases (NMNATs). In lower eukaryotes—including S. cerevisiae, D. melanogaster, and C. elegans—no NAMPT activity has been found. NAM is converted to NA, which then enters the parallel salvage pathway found in all eukaryotic species. Alternatively, nicotinamide riboside (NR) forms a precursor for NAD synthesis, connecting to the NAM salvage pathway through NMN. While the NAM salvage biosynthesis pathway is considered the main pathway for maintaining NAD levels, the latter can also be de novo synthesized from L-tryptophan (L-Trp). Note that the three major precursors for NAD biosynthesis (NAM, NA, and L-Trp) are all approved drugs or food supplements. NA has been a treatment option for lowering circulating lipid levels for many years (MacKay et al., 2012).
The intermediary metabolites previously mentioned regulate life span in different ways. Supraphysiological concentrations of NAD and NA extend life span in a fashion that depends on SIR-2.1, the nematodal ortholog of SIRT-1 (Hashimoto et al., 2010). By contrast, high concentration of NAM decreases nematodal life span, whereas low physiological doses of NAM or its metabolite, N1-methylnicotinamide (MNA), extend life span independently of SIR-2.1 (Schmeisser et al., 2013). Supplementation with NAM reduces chronic infection in humans (Bogan and Brenner, 2008), improves cognition in mice (Green et al., 2008; Gong et al., 2013), and increases longevity in yeast (Schmeisser et al., 2013). However, excessive NAM can cause immune intolerance and cancers (Bogan and Brenner, 2008). Nicotinamide N-methyltransferase (NNMT) is the mammalian enzyme that methylates NAM using S-adenosylmethionine as a methyl donor to generate MNA. In contrast to the discovery in lower organisms, Kraus et al. (2014) reported that knocking down NNMT protects against diet-induced obesity. Moreover, increased Nnmt expression is found in obese compared to nonobese human subjects, and the urinary MNA is elevated in humans and animals with obesity and type 2 diabetes (Salek et al., 2007).
Poly(ADP-ribose) polymerases (PARPs) catalyze the polymerization of ADP–ribose units of the target proteins with donor NAD molecules, which causes the formation of linear or branched polymers (Kim et al., 2005). A strong positive correlation between longevity and the polymer synthesis capacity of PARPs has been shown in mammalian cells (Beneke et al., 2010). Mice with PARP1 genetically knocked out exhibit faster aging than their wild-type counterparts (Piskunova et al., 2008). Thus, inhibition of PARPs has been proposed to increase NAD availability to elicit the anti-aging activity (El Ramy et al., 2009). Overall, maintaining high levels of NAD can increase the life span of the lower organisms by preventing primary aging, and it promotes the health spans of higher organisms.
Sirtuins are a family of NAD-dependent protein deacetylases that exert diversified cellular functions by interacting with a wide range of signaling molecules, transcription factors, histones, and enzymes (Wang et al., 2012). Sir2 (silent information regulator 2), the first gene discovered in this family, was originally shown to extend life span in yeast and promote transcriptional silencing through deacetylation of the epsilon-amino groups of lysine in the amino-terminal domains of histones (Gottlieb and Esposito, 1989; Aparicio et al., 1991). Budding yeast cultured under low glucose conditions (i.e., calorie restriction) exhibits a significant extension of proliferative life span, which is Sir2-dependent (Kaeberlein et al., 1999). Depletion or mutation of Sir2 significantly reduces life span in yeast, worms, and flies (Longo and Kennedy, 2006; Chen and Guarente, 2007).
Over the last decade, sirtuins have attracted major attention due to their potential in expanding life span and protecting against age-associated disorders (Baur et al., 2012). Of all mammalian sirtuins, SIRT-1 is the ortholog most highly related to Sir2 (Law et al., 2009; Wang et al., 2011; Wang et al., 2012). Both proteins possess NAD-dependent deacetylase and ADP-ribosyltransferase activities and are upregulated by calorie restriction (Hassa et al., 2006; Kanfi et al., 2008). Genetic variations of SIRT-1 are associated with accelerated aging in human populations (Kuningas et al., 2007). Mice lacking SIRT-1 fail to show an increased activity and extended life span in response to calorie restriction (Chen et al., 2005; Boily et al., 2008). Small molecular activators of SIRT-1 replicate signaling pathways triggered by calorie restriction and extend life span in mice (Smith et al., 2009; Mitchell et al., 2014). In vitro overexpression of SIRT-3 shows protective benefit of calorie restriction by increasing NADPH levels against oxidative stress-induced cell death (Someya et al., 2010). Similarly, overexpression of SIRT-6 in male mice increases the maximal life span with reduced levels of IGF-1 in serum (Kanfi et al., 2012). Recent studies have shown that a genetic variant within the SIRT-1 gene promoter is not associated with longevity in elderly Italians (Albani et al., 2015), but single nucleotide polymorphisms of SIRT-3 are involved in the longevity of female elderly within the same population (Albani et al., 2014).
The anti-aging activity of SIRT-1 has been largely attributed to its role in regulating energy metabolism. The requirement of NAD as a cosubstrate implies that SIRT-1 acts as a sensor of cellular energy and reduction–oxidation status (Lin et al., 2004). SIRT-1 not only mediates the metabolic changes associated with calorie restriction but also protects against metabolic damage caused by chronic exposure to a high-fat diet (Pfluger et al., 2008). It is a principal regulator of energy homeostasis and systemic insulin sensitivity (Chang and Guarente, 2014). Mice overexpressing SIRT-1 are leaner and exhibit improved energy homeostasis (Bordone et al., 2007). Genetic variations of SIRT-1 in humans are associated with body mass index and adiposity, especially visceral obesity (Peeters et al., 2008; Shimoyama et al., 2011). Although the molecular basis underlying the antiaging functions of SIRT-1 remains to be elucidated, activators of this longevity element represent a promising class of drugs for the treatment of aging-related diseases (Imai and Guarente, 2014).
Aging is associated with a significant change of body fat composition that is characterized by a gradual decrease in fat free mass (especially skeletal muscle) and a significant increase in fat mass (especially in the abdominal cavity). These changes, referred to as sarcopenic obesity, contributes to impaired physical and psychological functions and the development of many aging-related ailments (Batsis et al., 2013). In fact, adiposity, particularly around the abdomen, is positively linked to reduced life expectancy (Bluher, 2008). While various factors such as decreased energy expenditure and alterations of hormone productions influence body fat distribution in aged individuals, as an endocrine and metabolic organ, adipose tissue per se actively participates in the aging process (Tchkonia et al., 2013). For example, accumulation of visceral fat (central obesity) leads to metabolic syndrome and shortens life span, in part by increasing the inflammatory factors and decreasing adiponectin, an insulin-sensitizing and cardiovascular protective hormone (Hanauer, 2005). In addition, fat redistribution is often associated with the dysregulation of fatty acid storage and release. The overflow of fatty acids in the form of diacylglycerols, ceramides, and long-chain acyl-coenzymes A exert adverse effects on systemic energy homeostasis and insulin sensitivity (Jensen, 2008; Jung and Choi, 2014). Since abnormal adipose tissue distribution and function are key components of a vicious cycle accelerating the aging process, adipose tissue engineering may represent an effective anti-aging approach. Indeed, many longevity modulators including calorie restriction and physical excise elicit their beneficial effects via regulating fat distribution and metabolism (Jung and Choi, 2014). Long-term calorie restriction decreases adiposity, elevates gene expression involved in energy metabolism, and reduces the expression of more than 50 proinflammatory genes in white adipose tissues (Higami et al., 2006).
Calorie restriction reduces body weight and fat mass, especially visceral fat, which is an indicator of metabolic disorders in mammals (Li et al., 2003; Ye and Keller, 2010). Calorie restriction-induced reduction of visceral fat leads to an increase in life span and reduced renal diseases in rodents (Muzumdar et al., 2008). Calorie restriction study in overweight men and women has shown that visceral fat is largely reduced in conjugation with other benefits of lowering metabolic rate, core body temperature, and insulin resistance as well as the prevention of cardiovascular diseases (Larson-Meyer et al., 2006; Lefevre et al., 2009). Specific depletion or expansion of the visceral fat depot using genetic or surgical tools in rodents have direct effects on aging-related disease risks (Huffman and Barzilai, 2009). Mice with genetically increased life spans (Ames dwarf, Snell dwarf, insulin growth hormone receptor, pregnancy-associated plasma protein A knockout mice) have substantially reduced visceral fat (Junnila et al., 2013; Menon et al., 2014). Elevated insulin sensitivity, reduced oxidative stress, augmented adiponectin production, significantly improved whole body glucose homeostasis, and lipid metabolism contribute to the increased life span in these mice.
SIRT-1 is a key mediator coordinating the physiological responses to calorie restriction. The expression and activity of SIRT-1 is dynamically regulated in major metabolic organs. Calorie restriction-induced SIRT-1 expression occurs predominantly in adipose tissues but not liver or muscle tissues (Chen et al., 2008). In fact, SIRT-1 exerts its effects on metabolism and insulin sensitivity in a tissue-specific manner (Wang et al., 2012). SIRT-1 in liver may not be the major contributor to systemic glucose homeostasis and insulin sensitivity (Rodgers et al., 2005; Erion et al., 2009; Purushotham et al., 2009) but appears to maintain hepatic lipid homeostasis and control the bile acid metabolism (Garcia-Rodriguez et al., 2014; Li et al., 2014). In skeletal muscle, SIRT-1 expression is decreased under insulin-resistant conditions (Sun et al., 2007). It regulates the differentiation and metabolism of muscle cells (Lee and Min, 2013). However, specific overexpression or knockout of SIRT-1 in skeletal muscle does not affect whole-body energy expenditure in mice on either a standard diet or energy-restricted diets (White et al., 2013).
The role of adipose SIRT-1 as an important regulator of energy metabolism and systemic insulin sensitivity has been suggested by both clinical and animal studies (Picard and Guarente, 2005; Wang et al., 2012). In humans, SIRT-1 expression is decreased in both obese and type 2 diabetic patients (Pedersen et al., 2008; Song et al., 2013). Extensive weight loss significantly increases SIRT-1 expression in adipose tissues (Moschen et al., 2013). In mice, both expression and activity of SIRT-1 in adipose tissues progressively decrease during aging but are markedly elevated by calorie restriction (Xu et al., 2013; Xu et al., 2015). SIRT-1 acts as a nutrient-dependent modulator to inhibit adipose tissue inflammation (Gillum et al., 2011; Chalkiadaki and Guarente, 2012; Kotas et al., 2013). In 3T3-L1 adipocytes, SIRT-1 promotes fat mobilization by interacting with corepressors NcoR and SMART (Picard et al., 2004). SIRT-1–dependent deacetylation of peroxisome proliferator activator receptor gamma (PPARγ) facilitates the brown remodeling of white adipose tissues (Qiang et al., 2012). Knockdown of SIRT-1 inhibits insulin-stimulated glucose uptake and GLUT4 translocation, whereas treatment of adipocytes with specific SIRT-1 activators leads to an increase in insulin-stimulated glucose uptake (Yoshizaki et al., 2009). SIRT-1 also modulates the expression and secretion of adiponectin (Qiao and Shao, 2006; Qiang et al., 2007). In mice, activation of SIRT-1 selectively in adipose tissue protects mice against metabolic deterioration during aging and facilitates energy homeostasis; these effects resemble those elicited by calorie restriction (Wang et al., 2012; Xu et al., 2013; Wang, 2014; Xu et al., 2015).
The expression and activity of SIRT-1 decline during aging and contribute to the development of age-related complications (Yuan et al., 2016). Thus, a forced SIRT-1 activation or induction represents a strategy for identifying and developing CRMs. SIRT-1 is dynamically regulated by intermediary metabolites. Its cofactor, the pyridine nucleotide NAD, metabolically acts as a hydride acceptor to form NADH (donor for oxidoreductases) and as an enzyme substrate. However, NAD usually presents at a much higher level than its Km for SIRT-1 activation, precluding this metabolite from being a rate-limiting factor for SIRT-1 functions in vivo (Sauve and Youn, 2012). On the other hand, NAD metabolites may be more dynamically involved in regulating SIRT-1 (Lee et al., 2008).
SIRT-1 activity can be increased by supplementation of NA or NAM for NAD biosynthesis (Yoshino et al., 2011) or by inhibiting the enzyme CD38 or PARP to reduce NAD consumption (Aksoy et al., 2006; de Picciotto et al., 2016). Supplementation with purine nucleotide metabolites of NAD, such as NR, enhances oxidative metabolism and protects against high-fat-diet–induced metabolic abnormalities in SIRT-1–dependent manners (Canto et al., 2012). In addition, modulating the activity of enzymes involved in NAD metabolic pathways such as NAMPT (Song et al., 2014), NNMT (Kraus et al., 2014), and PARP (Bai et al., 2011) exerts marked effects on energy metabolism in mice. Recent evidence has further expanded the scope of intermediary metabolites for SIRT-1 regulation, including various acyl-CoA donors (Feldman et al., 2012) and biotin and biotin-5ʹ-AMP (Xu et al., 2013; Wang, 2014).
The initial breakthrough of identification of Sir2 as a deacetylase with weak ADP–ribosyltransferase activity came along with the identification of the Salmonella typhimurium CobB protein as a Sir2 homolog (Tsang and Escalante-Semerena, 1998). CobB compensates for the lack of CobT mutants during vitamin B12 biosynthesis and possesses nicotinate mononucleotide (NaMN)–dependent phosphoribosyltransferase activity. Thus, CobB catalyzes the release of NA from NaMN, whereas Sir2 and SIRT-1 remove NAM from NAD. This evidence suggests that the biosynthesis or homeostasis of B vitamins [including vitamin B3 (NA/NAM) and B7 (biotin)] regulate the enzymatic activities of SIRT-1. Indeed, SIRT-1 can be potently inhibited by biotin and its metabolite biotinyl-5ʹ-AMP (Xu et al., 2013). Chronic biotin supplementation abolishes SIRT-1-mediated health benefits (Wang, 2014). In mice, biotin storage in adipose tissues increases with age, which is accompanied by a progressively decreased SIRT-1 activity (Xu et al., 2013). Calorie restriction activates SIRT-1 partly by preventing the accumulation of biotin in adipose tissue (Xu et al., 2013, 2015). In summary, the dynamic changes of endogenous intermediary metabolites that regulate SIRT-1 activity are potential pathways for rational design and development of CRMs.
Various functional foods are able to boost SIRT-1’s activity or expression (Park et al., 2016). It is implicated in mitochondrial homeostasis, autophagy regulation, protein deacetylation, and longevity induced by a number of CRMs derived from functional foods (Lee et al., 2008; Mouchiroud et al., 2013; Ou et al., 2014). Resveratrol, known as 3,4ʹ,5-trihydroxystilbene, is a natural polyphenolic compound primarily found in plants (Fremont, 2000). It presents in either trans- or cis- isomers, where the trans-resveratrol has been widely studied and found enriched in grapes and grape products, berries, peanuts, and some herbal plants (Wenzel and Somoza, 2005; Giovinazzo et al., 2012). Many health benefits of trans-resveratrol have been reported, ranging from being cardio- and neuroprotective, antioxidant, antiinflammatory, antiatherosclerotic to anti-tumorigenic (Sale et al., 2004; Das and Maulik, 2006; Kwon et al., 2011; Smoliga et al., 2011).
Resveratrol is an activator of SIRT-1 and is able to induce AMPK, both of which are involved in its antiaging functions (Diaz-Ruiz et al., 2015). Resveratrol has been reported to increase DNA stability and extension of life span in yeast (Howitz et al., 2003). However, the effects on life span failed to be observed in higher organisms such as D. melanogaster (Bass et al., 2007) and rodents (Pearson et al., 2008; Miller et al., 2011). Nevertheless, resveratrol exerts beneficial effects on secondary aging—that is, the prevention of age-associated diseases and functional loss. Resveratrol-treated mice had lower total cholesterol levels in plasma and reduced incidence of atherosclerotic lesion formation when compared to control counterparts (Do et al., 2008). Treatment with resveratrol in the aged mice activated SIRT-1 expression, where the subsequent apoptotic pathway involving forkhead box protein O3 was inhibited (Lin et al., 2014). It increases glucose uptake in response to insulin stimulation in skeletal muscle, adipocytes, and hepatocytes via activation of SIRT-1 and AMPK (Sun et al., 2007; Breen et al., 2008). Resveratrol can penetrate the blood–brain barrier to reach the central nervous system. In the animal model of Alzheimer’s disease, resveratrol-treated mice show a delayed onset as well as a slow progression of impaired memory (Kim et al., 2007; Venigalla et al., 2016) due partly at least to SIRT-1-mediated inhibition of nuclear factor kappa B (NFκB) signaling (Chen et al., 2005). Resveratrol rescued SIRT-1 activity suppressed by betaamyloid peptide 25–35 in a dose-dependent manner, which led to significant attenuation of apoptosis in mouse neurons (Feng et al., 2013; Witte et al., 2014; Zhang et al., 2014; Turner et al., 2015).
Fisetin (3, 7, 3′, 4′-tetrahydroxyflavone) is a flavonol that can be found in vegetables and fruits such as strawberries and apples (Kim et al., 2015). It increases the expression of adiponectin in a dose-dependent manner to protect obesity-related malfunctions and vascular abnormalities (Jin et al., 2014). By suppressing PPARs, it regulates cell metabolism (Kim et al., 2015). Mechanistically, fisetin not only promotes SIRT-1 activity to mediate the deacetylation of PPARγ and FOXO1 but also enhances the association of SIRT-1 with the promoter of PPARγ, which results in attenuation of adipogenesis (Kim et al., 2015). Oligonol contains catechin-type oligomers that are found in lychee fruit and grape seed (Fujii et al., 2007). Mice treated with oligonol exhibit reduced serum lipid concentration, improved kidney function, and attenuated cognitive impairment (Noh et al., 2010; Sakurai et al., 2013). By upregulation of SIRT-1 expression, oligonol attenuates mitochondrial superoxide formation and activates autophagy (Park et al., 2016).
Melatonin (known as N-acetyl 5-methoxy tryptamine) is an indole hormone that is expressed by various plants and animals (Reiter et al., 2013). Plants synthesize melatonin from the essential amino acid L-trytophan, but melatonin in animals is mainly secreted from the pineal gland but is also present in skin, the immune system, the reproductive system, and the gastrointestinal tract (Slominski et al., 2002; Acuna-Castroviejo et al., 2014; Ramis et al., 2015). However, the absorption of melatonin is low in humans because the plasma levels of melatonin after the ingestion of melatonin-rich food are far less than the amount of melatonin ingested (Kennaway, 2015). Melatonin regulates circadian cycle (Hardeland et al., 2012) and elicits antioxidant (Galano et al., 2013) and anti-inflammatory activities (Agil et al., 2013). The circadian rhythm of melatonin is disturbed and deteriorated by aging (Waller et al., 2016). The loss of melatonin rhythm in the elderly not only causes sleep disorders but also leads to desynchronization of gene expression that affects general well-being (Jung-Hynes et al., 2010). Melatonin increases the expression of SIRT-1 protein and decreases the levels of acetylated p53 and NFκB in mice prone to accelerated senescence (Gutierrez-Cuesta et al., 2008). However, melatonin exhibits anti-tumor activity by downregulating SIRT-1 and upregulating acetylated p53 in human osteosarcoma cells (Cheng et al., 2013). Whether or not melatonin-mediated SIRT-1 expressions are specific to certain cell types warrants further study.
The average life expectancy has been creeping upward in most developed countries for many years. While the ultimate goal of science and technology is to extend the life span beyond its current natural limits, the contemporary challenge of anti-aging program is to eliminate or reduce aging-associated medical burdens from the world’s leading causes of death, including cancer and cardiovascular, neurodegenerative, musculoskeletal, and metabolic diseases. To focus on molecules that mediate the beneficial effects of caloric restriction represents one of the most straightforward approaches for developing anti-aging remedies. Accordingly, a bunch of CRMs emerge for either depletion of the energy supply or targeting specific signaling pathways such as autophagy. Functional foods represent the most promising source of CRMs. In particular, those that activate the expression or function of SIRT-1 hold great potential to delay the onset of aging and age-related diseases. In this respect, actions specific to adipose tissue by SIRT-1 are directly related to the anti-aging effects of caloric restriction. Adipose tissue is the body’s largest endocrine organ that secretes inflammatory and immune mediators. During aging, the most prominent changes in our body are the loss of functional lean (fat-free) mass and the accumulation of fat, especially in the abdominal region (Jackson et al., 2012). From the ages of 40 to 79, visceral fat in men increased by 42.9% and by 65.3% in women, whereas the fat-free mass decreased by 6.6% to 23.3% in both genders (Yamada et al., 2014). This phenomenon, referred as sarcopenic obesity, is assuming a prominent role in aging-related diseases (Prado et al., 2012). The important role of adipose tissues in human aging provides a more convenient but focused strategy for discovering SIRT-1–activating compounds in functional foods.
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