ReviewWhat are the roles of calorie restriction and diet quality in promoting healthy longevity?
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 nutrient-sensing 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 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.
Section snippets
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
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).
Dietary restriction and aging
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., 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
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
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
Conflicts of interest
We declare that we have no conflicts of interest.
Acknowledgements
This work was supported by grants from the Bakewell Foundation, AFAR, Glenn Foundation, the Longer Life Foundation (an RGA/Washington University Partnership), the Scott and Annie Appleby Charitable Trust, the National Center for Research Resources (UL1 RR024992), the National Institute of Diabetes And Digestive And Kidney Diseases (P30DK056341), and the European Union's Seventh Framework Programme MOPACT (“Mobilizing the potential of active ageing in Europe”; FP7-SSH-2012-1 grant agreement no.
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