In the near future, human aging and age-associated diseases will become one of the biggest challenges faced by developed and developing countries. Life expectancy has markedly increased in most developed countries in the last century, from about 45 years at the beginning of the 20th Century to about 77 years today . This increase is due primarily to reduced death in infancy, but also to improved sanitation and working conditions, the development of antibiotics and vaccines, and better healthcare. However, the overall increase in average life span is far greater than that for healthy life expectancy, as evidenced by the incremental burden of age-associated diseases, including cardiovascular disease, diabetes, hypertension and cancer . The financial burden caused by these chronic diseases is already overwhelming and, if present trends continue, is likely to become unbearable in the next few decades. One of these trends involves the consumption of diets rich in empty calories and poor in nutrients, and a sedentary lifestyle leading to a marked increase in age-associated chronic diseases. In contrast to these harmful effects of overeating unhealthy foods, restriction of calorie intake with adequate intake of nutrients has a wide range of benefits. Moderate calorie restriction with optimal nutrition can prevent and reverse the harmful effects of obesity, type 2 diabetes, hypertension and other age-associated metabolic alterations and diseases. Studies on laboratory animals and preliminary studies on humans have shown that more severe calorie restriction without malnutrition has additional benefits on the aging process itself. The purpose of this article is to succinctly review the current knowledge on the biology of aging, and on the effect of calorie restriction on disease risk and life expectancy, which have important clinical implications for clinicians and healthcare providers.
What is aging?
Aging is a complex biological process characterized by progressive functional and structural deterioration of multiple organ systems that eventually cause death. Primary or intrinsic aging is the physiological decline in biological functions and physical structure that occurs with advancing age independently of disease. As we get older, our skin becomes thinner and wrinkled, our hair becomes white and falls out, and we develop presbyopia and presbycusis. Regional atrophy of subcutaneous tissue, increased deposition of fat in the abdominal region, progressive loss of bone and muscle mass are some of the body composition modifications that invariably occur with aging [3–7]. Internally, the replacement of functional parenchyma with fibroconnective tissue in the heart and arteries, lungs, and kidneys results in a progressive deterioration of heart function and rhythm, increased blood pressure, reductions in maximal breathing and vital capacity, and glomerular filtration rate [8–13,14•,15]. In contrast, secondary or extrinsic aging is caused by an interaction between harmful environmental factors (e.g. unhealthy diets, physical inactivity, smoking, pollution, radiation) and genetic factors that causes serious and debilitating diseases (e.g. obesity, diabetes, hypertension, coronary heart disease, stroke, cancer) that accelerate the aging process and cause suffering, disability and premature death. Heart disease, cancer, stroke and diabetes are the four leading causes of death, accounting for approximately 70% of all deaths in developed and developing countries .
Is primary or intrinsic aging preventable?
There are currently no interventions or gene manipulations that can prevent, stop or reverse the aging process. However, there are a number of interventions that can slow down aging and prolong maximal lifespan up to 60% in experimental animals. The most robust intervention known to increase maximal lifespan and healthspan is calorie restriction, defined as a reduction in calorie intake below usual ad libitum intake, without malnutrition [17•]. In 1935, McCay et al. published the first paper showing that calorie restriction with adequate nutrition extends maximal lifespan in rats. Since then hundreds of studies have consistently shown that calorie restriction slow down aging in yeast, worms, insects, fishes and rodents [19,20]. Alternate-day fasting and methionine restriction also prolong maximal lifespan in rodents [21,22]. Recently, it has been shown that maximal lifespan can also be extended by a small number of spontaneous or induced genetic alterations, including reduced function mutations of genes encoding proteins of the insulin/IGF-1 pathway [23–28,29••] and of other pathways regulating hormonal and mitogenic signals (e.g. type 5 adenylyl cyclase, p66shc) [30••,31]. Transgenic mice overexpressing klotho, a protein that inhibits insulin and IGF-1 signaling, and mice overexpressing catalase targeted to mitochondria, an antioxidant protein, are also living significantly longer than wild-type mice [32,33].
Is secondary aging preventable? Are chronic diseases associated with aging preventable?
Aging and chronic diseases are often viewed as inextricably linked. We now know that this is not true, because in mammals it is possible to prevent the development of chronic diseases. Data from postmortem pathological studies have demonstrated that many calorie restricted and long-lived mutant rodents die without evidence of organ pathology severe enough to be recorded as a probable cause of death. In one experimental study, chronic calorie restriction without malnutrition prevented the development of chronic diseases in approximately one third of the animals, which died without any lethal pathological lesion when they were very old . In contrast, only 5% of the ‘ad-libitum’ fed animals died without any pathological lesion, and most of them when they were young . In another series of studies, 25 to 47% of the long-lived Ames and Snell dwarf mice died without obvious evidence of lethal pathological lesions, whereas only 0 to 7% of their normal siblings died without any pathological lesion [35,36]. Furthermore, approximately 50% of the long-lived growth hormone receptor knockout mice have no obvious evidence of lethal pathology at death .
Delayed incidence, progression, or both, of both neoplastic and nonneoplastic lesions, and reduced disease burden are also common pathological findings in calorie restrictied rodents and long-lived mutant rodents. Calorie restriction prevents or delays a wide range of chronic diseases, including cancer, atherosclerosis, diabetes, cardiomyopathy, kidney disease, autoimmune and neurodegenerative diseases in rodents [19–21,34,38–40]. Snell dwarf mice also show lower incidence, delayed progression and reduced severity of both neoplastic (fibrosarcoma, hemangiosarcoma, mammary adenocarcinoma) and nonneoplastic (glomerulonephritis) lesions [35,36]. In humans, calorie restriction with adequate nutrition protects against obesity, type 2 diabetes, dyslipedemia, hypertension, inflammation and atherosclerosis, which are major risk factors for myocardial infarction, stroke, heart failure and chronic kidney disease [41–47]. Data on the long-term effects of calorie restriction on factors implicated in the pathogenesis of cancer, the second leading cause of death, are accumulating. Excessive adiposity, chronic hyperinsulinemia, increased plasma free insulin-like growth factor-1 (IGF-1) concentration, increased bioavailability of sex steroid hormones, and systemic inflammation are some of the metabolic-risk factors that have been associated with several common cancers, such as breast, colon, endometrial, pancreas and kidney cancer . Long-term calorie restriction in humans prevents the accumulation of excessive body fat, reduces circulating insulin levels and inhibits inflammation [41–47].
Does excessive adiposity play a role in aging?
Excessive adiposity and its associated metabolic alterations play a key role in the pathogenesis of many chronic diseases, including diabetes, hypertension, cardiovascular disease and some type of cancers [48,49]. These chronic diseases accelerate the aging of multiple organ systems and often cause premature death. In obese individuals long-term total mortality after sustained weight loss is significantly reduced, particularly deaths from diabetes, heart disease, and cancer [50••,51••]. Nonetheless, low adiposity does not play the key role in modulating primary aging and maximal life span extension. In fact, only average lifespan but not maximum lifespan increases in rats that maintain a low body fat mass by performing regular exercise (high-energy flux), whereas both average and maximal lifespan do increase in sedentary rats that are food-restricted (low-energy flux), even though the exercising animals were leaner and more insulin sensitive than the calorie restricted animals [52,53]. Moreover, maximum lifespan is longer in calorie restricted genetically obese (ob/ob) mice than in ad libitum-fed, genetically-normal lean mice, even though body fat in the calorie restricted ob/ob mouse is more than twice that of the ad-libitum fed genetically normal lean mouse . More studies in both rodents and humans are needed to elucidate the metabolic and molecular mechanisms responsible for the different effects of calorie restriction (low-energy flux) and exercise (high-energy flux) on aging and longevity. Recent data demonstrate that calorie restricted mice have significantly lower serum fasting IGF-1 and insulin concentrations and tissue stress-related proteins levels than weight matched exercising mice, suggesting that the failure of exercise to extend maximal lifespan may be due to an inability to fully mimic the metabolic/hormonal response to calorie restriction . In humans, for example, serum triiodothyronine concentration was approximately 30% lower in individuals practicing long-term calorie restriction than in the endurance athletes, even though percentage body fat was low and similar in these two groups .
The biological mechanism of aging: is it still a mystery?
The exact mechanism by which calorie restriction has such a dramatic effect on primary aging is not yet known. Many interrelated and overlapping factors have been proposed to play a role. The four most important calorie restriction-induced antiaging mechanisms are thought be: neuroendocrine systems adaptations, prevention of inflammation, hormetic response, and protection against oxidative stress damage.
Numerous studies have consistently demonstrated that long-term calorie restriction without malnutrition and reduced function mutations in the insulin/IGF-1 signaling pathway are the most robust interventions known to increase maximal lifespan in rodents [17•,19,20,24–28,29••]. Calorie restriction decreases serum IGF-1 concentration by approximately 40% in rodents, and this calorie restriction-mediated reduction in IGF-1 levels is believed to play a key role in mediating its antiaging and anticancer effects [57,58]. Growth hormone (GH)-deficient and GH receptor-deficient mice also have low circulating IGF-1 levels and increased maximal lifespans [24–26]. In addition, decreased IGF-1 signaling is involved in the delayed aging phenotype of IGF-1 receptor-deficient mice and klotho transgenic mice [27,32]. Other important calorie restriction-mediated metabolic adaptations, that have been shown to play an important role in mediating the antiaging effects of calorie restriction, are: increased insulin sensitivity , reduced levels of anabolic hormones (e.g. insulin, testosterone, leptin) [59,60], reduced levels of hormones that regulate thermogenesis and cellular metabolism (e.g. triiodothyronine, norepinephrine) [61,62] and finally increased levels of hormones that suppress inflammation (e.g. cortisol, adiponectin, ghrelin) [63,64].
Protection against inflammation is another key calorie restriction-mediated antiaging mechanism. Chronic inflammation causes tissue damage, fibrosis, and organ dysfunction, and is implicated in the pathogenesis of many age-associated chronic diseases and in the aging process itself . Calorie restriction animals have low levels of circulating inflammatory cytokines, low blood lymphocyte levels, and reduced production of inflammatory cytokines by the white blood cells in response to stimulation, and cortisol levels in the high normal range [63,66,67]. In addition, recent data demonstrate that calorie restriction also exerts a powerful anti-inflammatory effect in humans [41,42]. Multiple metabolic and neuroendocrine mechanisms are responsible for this calorie restriction-mediated anti-inflammatory effect, including low adiposity and reduced secretion of proinflammatory adipokines and cytokines, reduced plasma glucose and advanced glycation end-product concentrations, increased cortisol and ghrelin production and increased parasympathetic tone. The developments in this area are summarized in a recent review article .
Hormesis, defined as a beneficial biological process by which a low-intensity stressor increases resistance to another more intense stressor, has been proposed to play a role in mediating some of the antiaging effects of chronic calorie restriction and alternate day fasting. For example, it is well known that exposing mice to low doses of ionizing radiation shortly before irradiating them with very high levels of ionizing radiation actually decreases the likelihood of developing cancer . Similarly, chronic calorie restriction has been hypothesized to be a hormetic agent, because it acts as a chronic low-grade stressor that provokes a survival response in the organism, helping it to endure adversity by activating longevity pathways . This theory explains why calorie restriction animals are more resistant to a wide range of stresses (e.g. surgery, radiation, acute inflammation, exposure to heat, and oxidative stress) [70–73]. In fact, chronic calorie restriction results in functional moderate hyperadrenocorticism and enhanced expression of heat shock proteins in response to stress, that help the animal to cope with a broad array of acute stressors and noxious agents [63,71,72]. Moreover, calorie restriction has been shown to enhance DNA repair systems , promote the removal of damaged proteins and oxidized lipids  and upregulate endogenous enzymatic and nonenzymatic antioxidative defense mechanisms .
Accumulating free-radical damage to biomolecules is currently one of the most accepted explanations for how aging occurs in mammals. It is well known that oxidative damage and mtDNA point mutations induced by oxidative stress dramatically increases during aging . In addition, calorie restriction has been shown to protect against the age-associated accumulation of molecular oxidative damage. Calorie restricted animals have lower levels of oxidative damage to proteins, lipids and DNA . However, most of the evidence in support of this theory is correlative, and preliminary data do not support the theory that oxidative stress under normal conditions is a key determinant of lifespan in mammals. Indeed, administration of several antioxidants to laboratory animals failed to increase lifespan [79,80]. Moreover, rodents with genetic deletion of several antioxidant enzymes (e.g. Sod2+/−, Prxd1+/−, and Sod1+/− mice) do not have a shorter lifespan, despite having elevated oxidative stress markers and tumor burden. It remains to be seen whether the reduction in oxidative damage observed in calorie restricted rodents, p66shc knockout and IGF-1 signaling deficient mice is just an epiphenomenon rather than the causal link [81••].
Does calorie restriction extend maximal lifespan in nonhuman primates?
Although it has been suggested that the slowing of aging by calorie restriction is a general phenomenon that applies to all species, there is currently no evidence that calorie restriction may extend maximal lifespan in nonhuman primates. There are two longevity studies (one at the University of Wisconsin, the other at the National Institute on Aging in USA), which are examining the long-term effects of calorie restriction on aging in rhesus monkeys. Up to now, the experimental data have shown that many of the metabolic, hormonal and structural adaptations that take place in calorie restriction rodents happen also in calorie restricted monkeys. Calorie restricted monkeys have approximately 70% lower body fat, higher insulin sensitivity, lower serum triiodothyronine concentration and core body temperature, and reduced inflammation, glycation and oxidative damage of several tissues [75,82–87]. They are protected against dyslipidemia and type 2 diabetes . In addition, immune senescence and sarcopenia are attenuated in calorie restricted monkeys [89,90]. However, as rhesus monkeys have an average and maximum lifespan of 27 and 40 years respectively, it may be another 10 years before maximal lifespan data become available on these primates.
Does calorie restriction work in humans?
Although it is currently not known if long-term calorie restriction with adequate nutrition extends maximal lifespan in humans, we do know that long-term calorie restriction without malnutrition results in some of the same metabolic and hormonal adaptations related to longevity in calorie restricted rodents, including reduced body temperature and resting metabolic rate, and reduced markers of oxidative stress [91,92]. Calorie restriction reduces fasting insulin levels, several growth factors, profibrotic molecules and cytokines, including serum concentration of PDGF, TGF-α and TNF-α [41,42,45,46,93]. Long-term calorie restriction with adequate nutrition is also associated with sustained low serum T3 concentration, similar to that found in calorie restricted rodents and monkeys [56,91,94]. This effect is likely due to calorie restriction itself, rather than a decrease in body fat mass, and could be involved in slowing the rate of aging in humans as well. Finally, calorie restriction improves diastolic function, a marker of primary aging of the heart . More studies are needed to determine whether humans develop the full range of metabolic and functional adaptive responses to calorie restriction that occur in rodents, and whether cardiovascular, pulmonary and kidney aging are slowed down by calorie restriction in humans.
Data are accumulating on the beneficial effects of calorie restriction in humans. We know that calorie restriction with adequate nutrition protects against obesity, type 2 diabetes, hypertension and atherosclerosis, which are leading causes of morbidity, disability and mortality. Preliminary data suggest that calorie restriction with adequate nutrition may also protect against cancer, the second leading cause of death. Nonetheless, nothing is known about the effects of calorie restriction on the risk of developing autoimmune disease and dementia, and on the rate of aging in humans. More studies are needed to elucidate the molecular mechanisms underlying the beneficial effects of calorie restriction in humans and to characterize new markers of aging/longevity that can assist clinicians in predicting mortality and morbidity of the general population.
Financial Disclosures: There are no conflicts of interests.
Funding/Support: Supported by NIH General Clinical Research Center Grant RR00036, Istituto Superiore di Sanità/National Institutes of Health Collaboration Program Grant, a grant from the Longer Life Foundation (an RGA/Washington University Partnership) and a donation from the Scott and Annie Appleby Charitable Trust.
Role of the Sponsor: The funding agency had no role in the analysis or interpretation of the data or in the decision to submit the report for publication.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 170).
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