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Ageing Research Reviews 13 (2014) 38–45 Contents lists available at ScienceDirect Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr Review What are the roles of calorie restriction and diet quality in promoting healthy longevity? Wanda Rizza a,b , Nicola Veronese a,c , Luigi Fontana a,d,e,∗ a Division of Geriatrics and Nutritional Science and Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA Department of Food and Human Nutrition Science, University Campus Bio-Medico, Rome, Italy Division of Geriatrics, Department of Medicine, University of Padova, Italy d Department of Medicine, University of Salerno Medical School, Salerno, Italy e CEINGE Biotecnologie Avanzate, Napoli, Italy b c a r t i c l e i n f o Article history: Received 29 August 2013 Received in revised form 12 November 2013 Accepted 19 November 2013 Available online 27 November 2013 Keywords: Calorie restriction Diet quality Health Lifespan Vegetarian diet Disease prevention a b s t r a c t Epidemiological and experimental data indicate that diet plays a central role in the pathogenesis of many age-associated chronic diseases, and in the biology of aging itself. Data from several animal studies suggest that the degree and time of calorie restriction (CR) onset, the timing of food intake as well as diet composition, play major roles in promoting health and longevity, breaking the old dogma that only calorie intake is important in extending healthy lifespan. Data from human studies indicate that long-term CR with adequate intake of nutrients results in several metabolic adaptations that reduce the risk of developing type 2 diabetes, hypertension, cardiovascular disease and cancer. Moreover, CR opposes the expected age-associated alterations in myocardial stiffness, autonomic function, and gene expression in the human skeletal muscle. However, it is possible that some of the beneficial effects on metabolic health are not entirely due to CR, but to the high quality diets consumed by the CR practitioners, as suggested by data collected in individuals consuming strict vegan diets. More studies are needed to understand the interactions among single nutrient modifications (e.g. protein/aminoacid, fatty acids, vitamins, phytochemicals, and minerals), the degree of CR and the frequency of food consumption in modulating anti-aging metabolic and molecular pathways, and in the prevention of age-associated diseases. © 2013 Elsevier B.V. All rights reserved. Contents 1. 2. 3. 4. 5. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Roles of calorie intake and diet quality in the prevention of cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Role of nutrients in the primary and secondary prevention of CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The role of CR in CVD prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. The role of specific nutrients in the pathogenesis of CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Calorie restriction, protein intake and diet quality. What roles in the prevention of cancer? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Excessive food intake, CR and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Role of protein intake on the IGF1 signaling pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Role of micronutrients in the pathogenesis of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Which is the role of calorie intake and diet composition in slowing aging? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Dietary restriction and aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Role of diet quality in modulating the biology of aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Role of dietary supplements on lifespan extension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Does calorie restriction slow the aging process in humans? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 39 39 40 40 40 40 41 41 41 41 42 42 43 ∗ Corresponding author at: Washington University School of Medicine, 4566 Scott Avenue, Campus Box 8113, St. Louis, MO 63110, USA. Tel.: +1 314 747 1485; fax: +1 314 362 7657. E-mail address: [email protected] (L. Fontana). 1568-1637/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.arr.2013.11.002 W. Rizza et al. / Ageing Research Reviews 13 (2014) 38–45 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction That nutrition plays a central role in preventing diseases and promoting health is well established. Before mechanical refrigerators became available, sailors and soldiers on long voyages eating diets rich in cured and salted meats and dried grains developed a life-threatening disease (i.e. scurvy), unless their diets were supplemented with fresh fruits and vegetables, or lemon juice loaded with vitamin C (Carpenter, 2003). Despite adequate intake of calories and protein, chronic vitamin D and iodine deficiencies causing rickets, goiter, and sometimes cretinism, were common problems in Western Europe and United States during the Industrial Revolution (Carpenter, 2003; Heimburger, 2014). Today the likelihood of developing these and other deficiency diseases (e.g. beriberi, pellagra, Keshan disease, and night blindness) in a developed country is extremely low. On the other hand, the likelihood of developing and dying of other chronic diseases (e.g. heart disease, stroke, type 2 diabetes, and certain cancers) is very high. Accumulating data from epidemiological and experimental studies suggest that calorie intake, the timing of food intake (e.g. fasting cycles), and some of the nutrients we ingest with foods are fundamentally implicated in the pathogenesis of these chronic diseases, and also in the biology of aging itself (i.e. they control the rate of aging of our body) (Fontana et al., 2010; Mattson, 2005; Eyre et al., 2004). In 1935 McCay and associates published the first paper showing that food restriction without malnutrition extends average and maximal lifespan in rats (McCay et al., 1935). Since then, several other research groups have consistently shown that restricting food intake without malnutrition slows aging, and results in a marked healthspan and lifespan extension in yeasts, fruit flies, nematode worms, fish, hamsters, and in a wide variety of mice and rat strains (Fontana et al., 2010; Weindruch and Walford, 1988; Masoro, 2005). The age when calorie restriction is started and the degree of restriction determine the magnitude of maximal lifespan extension (Fontana et al., 2010; Weindruch and Walford, 1982; Means et al., 1993). These “super-lean” animals not only live longer and healthier lives, but at any time they are physiologically younger than ad libitum fed animals (Weindruch and Walford, 1988; Masoro, 2005). Approximately, 30% of the CR rodents die at old ages without any significant pathological lesion, suggesting that in mammals aging is not inevitably linked with debilitating, painful and costly medical conditions (Shimokawa et al., 1993; Ikeno et al., 2013). Alternate day fasting and methionine restriction have also been shown to increase lifespan and prevent chronic diseases in certain species of rodents (Carlson and Hoelzel, 1946; Goodrick et al., 1982; Miller et al., 2005; Orentreich et al., 1993). This research has been reviewed previously (Mattson, 2005; Varady and Hellerstein, 2007; Cavuoto and Fenech, 2012) and need not be considered here in detail. Moreover, data from genetic and pharmacological animal models of longevity indicate that down-regulation of the PI3K/AKT and mTOR signaling pathways, which are key cellular nutrientsensing pathways controlled by energy and aminoacid availability, significantly extends both average and maximal lifespan in simple model organisms and rodents (Fontana et al., 2010). Nonetheless, because large variations exist in metabolism, life expectancy and susceptibility to diseases among yeast, worms, flies, rodents and humans, some key questions remain to be addressed: “Can human beings live a long life without ever developing chronic disease?”, “Does CR without malnutrition extend 39 43 43 43 43 healthspan and lifespan in humans?” How important are meal frequency/timing (i.e. cycles of fasting) and dietary composition (e.g. protein, aminoacid, fat, mineral, vitamin and phytochemical intake) in mediating health or longevity? This last question is particularly important because accumulating data from non-human and human primates suggest that both diet quality and calorie intake are important in modulating the metabolic and molecular pathways, and physiological processes that promote health and longevity. 2. Roles of calorie intake and diet quality in the prevention of cardiovascular disease Cardiovascular disease (i.e. coronary heart disease, stroke, heart failure) is the primary cause of morbidity, disability and mortality in both men and women in the developed countries. Around 2200 people die of CVD each day in USA, an average of 1 death every 39 s (Roger et al., 2012). Well-established, modifiable cardiometabolic risk factors are high blood pressure, hypercholesterolemia, type 2 diabetes, smoking, inflammation and excessive adiposity. In the Framingham Heart Study, men with normal cardiometabolic profiles (i.e. total cholesterol less than 180 mg/dl, blood pressure <120/80 mm Hg, fasting glucose <125 mg/dl, BMI < 25 kg/m2 , and no smoking) at age 50 have a 13 fold lower risk of developing CVD during their remaining lifetime than individuals with two or more risk factors (Lloyd-Jones et al., 2006). 2.1. Role of nutrients in the primary and secondary prevention of CVD Data from several epidemiological and interventional studies have clearly shown that individuals who are eating diets rich in fish and nutrient-dense minimally processed plant foods have a lower risk of developing cardiometabolic abnormalities and CVD than men and women who consume Western diets rich in empty calories, saturated/trans fatty acids, animal protein and salt. The Seven Countries and the Ni-Hon-San were the first population studies to suggest an interrelationship between diet and CVD (Keys et al., 1986; Kato et al., 1973). The Twenty Country and the INTERHEART studies confirmed and expanded the relationship between CVD risk and the intake of animal foods, and the potential protective role of fruit and vegetable consumption (Stamler, 1979; Yusuf et al., 2004). Several well-conducted randomized clinical trials, including the Oslo Diet Heart Study, the Los Angeles Veterans Administration Study, the Finnish Mental Hospital Study, also confirmed that replacing diets rich in animal fat with vegetable oil lowers the risk of developing CVD morbidity and mortality (Hjermann et al., 1981; Dayton et al., 1968; Turpeinen, 1979). The PRIDIMED randomized clinical trial on the cardiovascular effects of a Mediterranean diet (supplemented with extra-virgin olive oil or nuts) was stopped after a median follow-up of only 4.8 years because this diet significantly reduced the incidence of the combined cardiovascular end points and stroke (but not for myocardial infarction alone) (Estruch et al., 2013). This was a primary prevention trial in high-risk men and women who were initially free of cardiovascular disease, but the beneficial effects of an energy-unrestricted Mediterranean diet rich in alpha-linolenic acid (a main ingredient of walnuts) have also been shown in a secondary prevention trial, the Lyon Diet Heart Study. De Lorgeril and associates showed a striking reduction in 40 W. Rizza et al. / Ageing Research Reviews 13 (2014) 38–45 rates of coronary heart disease events in patients who had already suffered a first myocardial infarction (de Lorgeril et al., 1999). The traditional Mediterranean diet is rich in plant foods (grains, legumes, vegetables, fruits, tree nuts, seeds and olives), with extravergin olive oil and fish as the primary source of fat. Consumption of other animal products such as red meat, eggs, and dairy products is limited, and moderate amounts of wine are consumed mainly during meals. A similar diet, though more extreme is the Ornish diet. In a classical paper published in JAMA, Ornish and colleagues have shown that a low-fat vegetarian diet in conjunction with other lifestyle changes (i.e. smoke cessation, endurance exercise, and stress management training) is highly effective in reversing the progression of coronary atherosclerosis and in reducing cardiac events even in patients with moderate to severe coronary artery disease (Ornish et al., 1998), reinforcing the importance of diet in the primary and secondary treatment of atherosclerotic cardiovascular disease, the leading cause of both death and disability in North America, Europe and many developing countries. 2.2. The role of CR in CVD prevention Reducing the risk of CVD progression in metabolically abnormal individuals or diseased patients by lowering for example salt or saturated fat intakes or by taking drugs (e.g. lipid lowering, antihypertensive or anti-diabetic medications), is not the same as preventing the development of any clinically relevant CVD by maintaining optimal cardiometabolic health. Accumulating data show that men and women practicing long-term severe CR with adequate intake of nutrients are simultaneously protected against abdominal obesity, type 2 diabetes, hypertension, dyslipidemia, inflammation and atherosclerosis (Fontana et al., 2004). These individuals, who call themselves CRONIes (i.e. Calorie Restriction with Optimal Nutrition), are extremely lean with an average body mass index of 19.6 ± 1.9 kg/m2 and total body fat of ∼12%. Total serum cholesterol, LDL cholesterol, total cholesterol/HDL cholesterol ratio, and triglyceride values all fall in the lowest 10% for people in their age groups (Fontana et al., 2004). Even in the elderly CRONies, blood pressure is extremely low with a systolic blood pressure of ∼110 mm Hg and a diastolic blood pressure of ∼70 mm Hg, fasting glucose concentration in the 80 mg/dl range and very low C-reactive protein concentrations. Accordingly, the intima-media thickness of the common carotid arteries was ∼40% lower in the CRONies than in age- and sex-matched controls eating Western diets (Fontana et al., 2004). However, it is possible that some of the beneficial effects on the cardiometabolic risk factors are not entirely due to CR, but to the high quality diets consumed by the CR practitioners. All of the CRONies have eliminated from their diets refined and processed foods containing salt, trans-fatty acids, dietary glycotoxins and high-glycemic-index foods (e.g. refined carbohydrates, potato, white rice, sucrose- and fructose-enriched foods). They consume, instead, a wide variety of vegetables, low-glycemic-index fruits, nuts, low-fat dairy products, egg whites, wheat and soy proteins, fish, and lean meat. Interestingly, we found that men and women consuming energy unrestricted strict vegan diets also have extremely low blood pressure, LDL cholesterol, triglycerides and fasting glucose concentrations, suggesting that the quality of the diet plays a major role in modulating blood pressure, lipid and glucose metabolism (Fontana et al., 2007). Nevertheless, unlike in the CRONies, serum HDL-cholesterol and adiponectin concentrations were not significantly increased in these vegetarians and serum concentration of fasting insulin, TNF-alpha and triiodothyronine were higher than in age- and sex-matched individuals practicing CR. Short-term alternate day fasting has also been shown to result in some beneficial cardiometabolic adaptations in obese individuals eating typical Western diets during the no-fasting days, including a reduction in body weight, blood pressure, and serum cholesterol and triglycerides concentrations, but high-density lipoprotein cholesterol (HDL-C), C-reactive protein, and homocysteine concentrations did not change (Varady et al., 2009; Bhutani et al., 2010). 2.3. The role of specific nutrients in the pathogenesis of CVD Because classical cardiometabolic risk factors do not fully explain the risk of developing CVD (i.e. 10–20% of patients with CVD lack any of the conventional risk factors), more studies are needed to understand the role of macro- and micronutrients in modulating alternative metabolic pathways that regulate cardiovascular health and disease (Khot et al., 2003). For example, data from several experimental studies suggest that excessive intake of salt and partially hydrogenated trans fatty acids play an independent role in promoting the progression of atherosclerotic CVD (Dickinson and Havas, 2007; Mozaffarian et al., 2006). In contrast, consumption of omega-3 fatty acids, and certain phytochemicals such as olecanthal may have protective effects because of their anti-inflammatory and anti-thrombotic effects (De Caterina, 2011; Beauchamp et al., 2005). Recently, it has been shown that the intestinal microbiota convert dietary phosphatidylcholine and l-carnitine (a trimethylamine abundant in red meat) into a metabolite, trimethylamine-N-oxide (TMAO), which promotes atherosclerosis and increases the risk of developing major adverse cardiovascular events independently of traditional cardiovascular risk factors (Tang et al., 2013; Koeth et al., 2013). Data from metabonomic studies in humans indicate that individuals with high-meat consumption have elevated concentrations of TMAO, creatine, carnitine, and acetylcarnitine, and a vegetarian or high-fiber diet can reduces phosphatidylcholine intake (Stella et al., 2006). 3. Calorie restriction, protein intake and diet quality. What roles in the prevention of cancer? In both men and women cancer is the second most important cause of death. It has been estimated that approximately 1600 people die of cancer each day in USA, an average of 1 death every 60 s (Siegel et al., 2013). The lifetime probability of being diagnosed with an invasive tumor is high: 38% for women and 45% for men. Prostate, lung, and colon–rectum are the most common cancers in men, whereas breast, lung, colon, and uterine corpus are the most frequent in women (Siegel et al., 2013). 3.1. Excessive food intake, CR and cancer The importance of a healthy diet in reducing the risk of developing some of the most common types of cancer in the Western world is supported by several experimental and epidemiological studies (Eyre et al., 2004; Longo and Fontana, 2010). Calorie restriction without malnutrition is the most potent physiological intervention for protecting against spontaneous, chemicallyand radiation-induced cancers in experimental animals (Longo and Fontana, 2010; Weindruch and Walford, 1988). Young-onset 30% CR has, so far, completely prevented cancer in the NIA CR monkey study, while adult-onset 30% CR reduced cancer incidence by 50% in the Wisconsin monkey study (Mattison et al., 2012; Colman et al., 2009). In contrast, excessive food intake has been associated with increased cancer risk (Longo and Fontana, 2010). Excessive energy and protein intake before puberty, by stimulating the insulin/IGF/mTOR pathway, causes rapid growth rates, and early menarche, which is a well-established risk factor for breast cancer (Berkey et al., 2000). Whether or not overstimulation of anabolic/mitogenic pathways by excessive nutrition during childhood influences the development of other cancer types (e.g. prostate, colon, and endometrial cancer) remain to be tested. W. Rizza et al. / Ageing Research Reviews 13 (2014) 38–45 There is also consensus that a positive energy balance during adulthood, by increasing adiposity, contributes to an increased risk of developing several cancer types, including cancer of the colon, breast, prostate, endometrium, pancreas, liver and kidney, and weight loss lowers this risk (Longo and Fontana, 2010; Calle and Kaaks, 2004). In a prospective, controlled study involving 4047 obese patients, bariatric surgery-induced weight loss was associated with a 40% reduction in cancer mortality (Sjöström et al., 2007). Reductions in growth factors/anabolic hormones (such as insulin, testosterone, estradiol, leptin), inflammatory cytokines and oxidative stress are probably responsible in part for the lower risk of death associated with weight loss (Longo and Fontana, 2010; Calle and Kaaks, 2004). Data from studies conducted in lean and weight stable men and women practicing long-term CR also show a significant reduction in serum levels of insulin, sex hormones, inflammatory cytokines (Fontana et al., 2010a; Cangemi et al., 2010). 3.2. Role of protein intake on the IGF1 signaling pathway Whether or not the quality of diet plays a key role in cancer prevention independently of energy intake in non-obese individuals is still under debate. For example, what is the role of chronic excessive protein intake in the pathogenesis of cancer? In other words, what are the biological implications of consuming high-protein low-carbohydrate diets in lean physically active individuals with a family history of breast, prostate or colon cancer? It is known that high concentrations of IGF-1 and essential amino acids stimulate the PI3K/AKT/mTOR pathway, which promotes cell proliferation and inhibits apoptosis of mutated cells (Pollak, 2004). Individuals eating an energy-unrestricted plant-only diet have significantly lower concentrations of total and free IGF-1 than extremely lean individuals practicing long-term CR or regular endurance exercise training (Fontana et al., 2008, 2006). Daily protein intake in the vegan group was ∼0.75 g/kg of body weight (i.e. 10% calories from protein), whereas the CRONies and the master athletes consumed a relatively high protein diet (i.e. ∼1.6 g/kg, 23% calories from protein). A 3-week isocaloric reduction of protein intake from ∼1.6 g/kg to 1 g/kg in the CRONies resulted in a 25% reduction in serum IGF-1 concentration (from 194 ± 34 to 152 ± 41 ng/ml), suggesting that in humans, protein intake is more important than calorie intake in modulating IGF-1 concentrations (Fontana et al., 2008). Interestingly, many patients with prostate and breast cancer have at least one component of the IGF-1/mTOR signaling pathway activated (Ma et al., 2011; Dai et al., 2009). Consistently, several epidemiological studies have found a strong association between serum IGF-1 concentration and the risk of developing colon, breast (in premenopausal women) and prostate cancer in humans (Renehan et al., 2004). Interestingly, the inhabitants of Okinawa, who until 1960 were eating moderate CR diets with 9% calories from protein, had 80% lower rates of breast, prostate, and colon cancer mortality than the average U.S. population, and one of the highest numbers of centenarians in the world (Willcox et al., 2007). More studies are needed to understand the effects of protein intake and dietary aminoacid composition (e.g. methionine intake) in regulating IGF/mTOR activity, cancer risk, and aging, independently of other risk factors modulated by caloric intake/energy expenditure (e.g. insulin, leptin, sex hormones, and inflammation). 41 intake. In a population-based, prospective study involving 22,043 Greek adults, increasing adherence to a Mediterranean diet has been shown to be associated with a significant reduction in cancer mortality (adjusted HR, 0.76 [95% C.I., 0.59 to 0.98]) and total mortality (adjusted HR, 0.75 [95% C.I., 0.64 to 0.87]), independently of body-mass index, waist-to-hip ratio, level of physical activity and smoking status (Trichopoulou et al., 2003). Accumulating data suggest that certain food constituents may modulate DNA repair processes, genome stability, epigenetic regulation of DNA, metabolic activation of carcinogens, cell proliferation and differentiation, and angiogenesis (Kris-Etherton et al., 2012; de Kok et al., 2010). For example, data from in vitro studies have shown that folic acid, vitamin A, vitamin B12, vitamin D, calcium, iron, zinc, allyl sulphide, n-3 fatty acids, genistein and other phenolic compounds are important regulators of cell cycle progression and cell proliferation (Kris-Etherton et al., 2012; de Kok et al., 2010; Stan et al., 2008). Moreover, several phytochemicals extracted from plant foods (i.e. isothiocyanates, curcumin, resveratrol, EGCG, genistein, indole-3-carbinol, lycopene, capsaicin, and organosulphur compounds) have been shown to induce apoptosis of cultured cancer cells (Kris-Etherton et al., 2012; de Kok et al., 2010; Stan et al., 2008). Some of these effects can be synergistic, as it has been shown in an animal model of chemically induced gastric cancer. Supplementation with lycopene and S-allylcysteine from garlic in combination was more effective in inhibiting N-methyl-N’-nitroN-nitroso-guanidine induced stomach cancer than when these bioactive compounds were administered in isolation (Velmurugan et al., 2005). Similarly, administration of calcitriol with dietary soy resulted in substantially greater inhibition of tumor growth in a human xenograft model of prostate cancer (Wang et al., 2012). However, because these are the result of cell culture and animal studies using xenograft models in immunosuppresed or transgenic mice, well performed randomized clinical trials are needed to assess the independent effects of these compounds in the primary and secondary prevention of cancer in humans. So far despite the promising data obtained from cell culture and animal studies, randomized clinical trials have failed to show a beneficial effect of vitamin C, vitamin E, beta-carotene, selenium and fiber supplementation on cancer morbidity or mortality, and 2 large randomized clinical trials have shown an increased lung cancer mortality in smokers that received beta-carotene supplementation (Lippman et al., 2009; Omenn et al., 1994, 1996; The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group, 1994; Alberts et al., 2000). Furthermore, data from a meta-analysis suggests that supplementation with a high-dose of vitamin E may increase all-cause mortality in men and women living in developed countries (Miller 3rd et al., 2005). On the other hand, supplementation with beta carotene, vitamin E, and selenium has been shown to reduce deaths due to esophageal or stomach cancer in a Chinese rural population with a micronutrient-poor diet (Blot et al., 1993). Finally, data from both the Women’s Healthy Eating and Living and the Women’s Health Initiative studies suggest that a reduction of fat intake does not reduce breast cancer risk, but it may reduce the incidence of ovarian cancer among postmenopausal women (Pierce et al., 2007; Prentice et al., 2006, 2007). 4. Which is the role of calorie intake and diet composition in slowing aging? 3.3. Role of micronutrients in the pathogenesis of cancer 4.1. Dietary restriction and aging Data from epidemiological and experimental cell and animal studies suggest that other nutrients (e.g. fat, vitamins, phytochemicals, and minerals) may play a role in modulating cancer initiation and progression independently of calorie and protein The importance of diet (i.e. CR, intermittent fasting and methionine restriction) in slowing aging and extending lifespan in simple model organisms and rodents is well established (Fontana et al., 2010; Weindruch and Walford, 1988; Masoro, 2005; Goodrick et al., 42 W. Rizza et al. / Ageing Research Reviews 13 (2014) 38–45 Poor health Decreased survival Good health Increased survival Poor health Decreased survival Fat and muscle wasting Metabolic dysfunction: Insulin resistance Amenorrhea Infertility Immune dysfunction Cardiac dysfunction Optimal tissue & organ function Decreased risk of chronic disease Excess adipose tissue Metabolic dysfunction: Insulin resistance Amenorrhea Infertility Immune dysfunction Cardiac dysfunction Cancer Potential lifespan/ Life expectancy Activation of PI3K/AKT/mTOR pathway Calorie & Protein intake/Adiposity Fig. 1. Relationship between healthy longevity and calorie-protein intake and adiposity. 1982; Mattson, 2005; Miller et al., 2005; Arum et al., 2009). In many strains of rats and mice a monotonic linear relationship between CR and lifespan extension exists. A 10–50% reduction in calorie intake below usual ad libitum intake causes a proportionate increase in maximum life span, whereas CR exceeding 50% typically causes starvation and increases mortality (Fontana et al., 2010; Weindruch and Walford, 1988; Masoro, 2005). However, this relationship between CR and life extension seems not to be universal. Some mice strains undergoing 40% CR do not live longer, or even live shorter, than ad libitum fed control mice (Harper et al., 1987; Harrison and Archer, 1987; Forster et al., 2003; Liao et al., 2010). A possible explanation for these experimental findings is that 40% CR in these mice strains is excessive, and that lower degree of CR would be beneficial. In fact, in both wild-caught and C57BL/6J mice 40% CR shortened lifespan when started early in life, but increased lifespan when started later in life, suggesting that 40% CR was too extreme in these growing animals (Harper et al., 1987; Harrison and Archer, 1987). The same may be true for humans. A certain degree of CR that may be optimal for some individuals, may be excessive and cause harm in others (Fig. 1). Biomarkers of optimal calorie intake that define the threshold between optimal health and starvation/malnutrition are needed to guide dietary prescriptions. 4.2. Role of diet quality in modulating the biology of aging The apparently contradictory data from the two ongoing CR monkey studies suggest that diet quality plays a major role in modulating longevity independently of caloric intake. One study, the Wisconsin National Primate Research Center (WNPRC), has found that long-term 30% CR results in a significant increase in lifespan (when considering only age-associated deaths), in a 50% reduction of cancer and cardiovascular disease morbidity, and in the prevention of sarcopenia and neurodegeneration of some brain regions (Colman et al., 2009, 2012). In contrast, data from the National Institute of Aging (NIA) monkey study suggest that long-term CR does not increase lifespan in Rhesus monkeys, even though CR markedly reduces cancer, obesity and type 2 diabetes incidences (Mattison et al., 2012). A potential problem is that the WNPRC diet is a semipurified diet rich in dairy proteins, corn oil, and refined and processed carbohydrates such as sucrose and cornstarch, which resembles the typical Western diet (Colman et al., 2009). Conversely, the NIA study is a healthier diet rich in fish and minimally processed plant foods (i.e. ground wheat and corn, soy, and alfalfa meal) (Mattison et al., 2012). Fat intake is 10% (mainly from corn oil) in the WNPRC, and only 5% (mainly from soy oil, fish, and alfalfa) in the NIA study. Sucrose intake is 28.5% and 3.9% respectively in the WNCRP and NIA study. Furthermore, unlike in the WNPRC study, the NIA natural ingredient-based diets are rich in phytochemicals and fish omega3 fatty acids. Therefore, it is possible that the slightly restricted (i.e. control monkeys were not freely fed, but received a controlled allotment of food each day to avoid obesity) pesco-vegetarian diet of the NIA control monkeys, that resembles the traditional Mediterranean diet, exerts a sub-maximal effect in extending lifespan, reducing the statistical power of the NIA study in detecting statistical differences in survival between groups. Accordingly, in both the NIA control and CR male monkeys average lifespan was ∼45% longer than in Rhesus monkeys kept in captivity (Mattison et al., 2012). Moreover, 4 CR and 1 control NIA monkeys have lived more than 40 years, which is an extraordinary long life for a Rhesus monkey (Mattison et al., 2012). 4.3. Role of dietary supplements on lifespan extension Several studies were performed to understand the effects of supplementation with supposedly anti-aging dietary additives (e.g. resveratrol, green tea extract, curcumin, oxaloacetic acid, mediumchain triglyceride oil) on lifespan and healthspan extension in genetically heterogeneous mice. None of the compounds tested so far in the National Institute on Aging Interventions Testing Program (ITP), with the exception of rapamycin, have resulted in a statistically significant effect on maximal lifespan of male or female mice (Strong et al., 2013; Miller et al., 2011). However, supplementation with nordihydroguaiaretic acid and aspirin increased average but not maximal lifespan in the ITP genetically heterogeneous male mice (Strong et al., 2008). Smaller studies suggest that treatment with metformin and beta-blockers, but not with a range of phytonutrients which have been reported to extend lifespan in Caenorhabditis elegans and Drosophila (e.g. blueberry, pomegranate, green and black tea, cinnamon, sesame, French maritime pine bark, curcumin, morin, and quercetin), may increase average but not maximal lifespan in some selected strains of male mice (Spindler et al., 2013, 2013a; Martin-Montalvo et al., 2013). Data from a recent randomized clinical trial indicate that supplementation with combinations of supplements (i.e. resveratrol, green, black, and white tea extract, pomegranate extract, quercetin, acetyl-l-carnitine, lipoic acid, curcumin, sesamin, cinnamon bark W. Rizza et al. / Ageing Research Reviews 13 (2014) 38–45 43 extract, and fish oil), each of which has been shown to have antioxidant and/or anti-inflammatory effects in cell culture or animal studies, do not exert any cardiovascular or metabolic effect in nonobese men and women (Soare et al., 2013). Rapamycin, is a powerful immunosuppressive drug, that inhibits the activity of mTOR, which controls key cellular responses to energy and aminoacid availability (Sengupta et al., 2010). Data from dietary and genetic animal models of longevity indicate that inhibition of the IGF/mTOR pathway plays a crucial role in slowing down aging and increasing lifespan, whereas increased activity of the IGF pathway markedly accelerates aging and shortens life expectancy (Fontana et al., 2010; Bartke et al., 2002). 5. Does calorie restriction slow the aging process in humans? Whether or not CR slows aging and extends maximal lifespan in humans is not known yet. However, data collected on humans practicing long-term CR without malnutrition (i.e. CRONies) indicate that CR opposes the expected age-associated changes in myocardial stiffness and autonomic function. Both left ventricular diastolic function and heart rate variability indexes, two well accepted markers of cardiovascular aging, are significantly improved by CR, and resemble those of individuals 20 years younger on a typical Western diet (Meyer et al., 2006; Stein et al., 2012). Recent data also suggest that CR counters the typical age-dependent gene expression derangements in the human skeletal muscle. Indeed, the skeletal muscle transcriptional profile of the CR practitioners resembles that of much younger individuals (Mercken et al., 2013). Despite their genetic heterogeneity, CR resulted in a dramatic transcriptional reprogramming of molecular pathways in skeletal muscle, which shifts cellular metabolism from growth to maintenance and repair functions. In particular, several inflammatory genes, a number of transcripts along the IGF-1/insulin/FOXO pathway, and akt phosphorylation were down-regulated by CR in skeletal muscle (Mercken et al., 2013). However, the independent or additive role of protein/aminoacid, vitamin and phytochemical intakes in modulating these and other anti-aging molecular pathways is not known yet. Finally, long term CR in humans is associated with significant reductions in serum levels of triiodothyronine and core body temperature independently of adiposity (Fontana et al., 2006a; Soare et al., 2011). The importance of a low body temperature in extending lifespan has been supported by data obtained from CR mice, dwarf and growth hormone receptor knock-out mice, the HcrtUCP2 mice and the Baltimore Longitudinal Study of Aging (Rikke et al., 2003; Schonholz and Osborn, 1949; Hauck et al., 2001; Conti et al., 2006; Roth et al., 2002). Indeed, in the Baltimore Longitudinal Study of Aging men with a lower core body temperature lived significantly longer (Roth et al., 2002). 6. Conclusions Several factors have been hypothesized to play a key role in mediating healthy longevity (Fig. 2). However, more studies are needed to understand the interactions among single nutrient modifications, CR and regular exercise in the prevention of CVD, cancer, cognitive impairment/dementia, inflammatory diseases, sarcopenia and immune senescence, in both experimental animals and humans. The discovery of early predictive biomarkers of cancer, dementia, sarcopenia/osteoporosis, and biological aging is essential to design new clinical trials and accelerate the acquisition of the knowledge required to prescribe personalized dietary/life style modifications based on the individual’s genetic profile. The discovery of biomarkers of optimal caloric and protein intake are also Fig. 2. 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