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Aging is an intrinsic feature of human life whose manipulation has fascinated humans ever since becoming conscious of their own existence. Several long-term experimental interventions (e.g., resveratrol, rapamycin, spermidine, and metformin) may open doors for corresponding pharmacological strategies. Surprisingly, most of the effective aging interventions proposed converge on only a few molecular pathways: nutrient signaling, mitochondrial proteostasis, and the autophagic machinery.
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Life span is inevitably accompanied by functional decline, steady increase of a plethora of chronic diseases, and ultimately death. For millennia, it has been a dream of mankind to prolong both life span and health span. Developed countries have profited from the medical improvements and their transfer to public health care systems—as well as from better living conditions derived from their socioeconomic power—to achieve remarkable increases in life expectancy during the last century. In the United States, the percentage of the population aged ≥65 years is projected to increase from 13% in 2010 to 19.3% in 2030. However, old age remains the main risk factor for major life-threatening disorders, and the number of people suffering from age-related diseases is anticipated to almost double over the next two decades. The prevalence of age-related pathologies represents a major threat as well as an economic burden that urgently needs effective interventions.
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Molecules, drugs, and other interventions that might decelerate aging processes continue to raise interest among both the general public and scientists of all biological and medical fields. Over the past two decades, this interest has taken root in the fact that many of the molecular mechanisms underlying aging are interconnected and linked with pathways that cause disease, including cancer, cardiovascular and neurodegenerative disorders. Unfortunately, among the many proposed aging interventions, only a few have reached a certain age themselves. Results often lack reproducibility because of a simple inherent problem: interventions in aging research take a lifetime to assess. Experiments lasting the lifetime of animal models are prone to develop artifacts, increasing the possibilities and time windows for experimental discrepancies. Some inconsistencies in the field arise from overinterpreting life span-shortening models and scenarios as being accelerated aging.
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Many substances and interventions have been claimed to be antiaging throughout history and into the present. In the following sections, interventions will be restricted to those that meet the following highly selective criteria: (1) promotion of life span and/or health span, (2) validation in at least three model organisms, and (3) confirmation by at least three different laboratories. These include: (1) CR and fasting regimens, (2) some pharmacotherapies (resveratrol, rapamycin, spermidine, and metformin), and (3) exercise.
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One of the most important and robust interventions that delays aging is CR. This outcome has been recorded in rodents, dogs, worms, flies, yeasts, monkeys, and prokaryotes. CR is defined as a reduction in the total caloric intake, usually of about 30% and without malnutrition. CR reduces the release of growth factors such as growth hormone, insulin, and IGF-1, which are activated by nutrients and have been shown to accelerate aging and enhance the probability for mortality in many organisms. Yet the effects of CR on aging were first discovered by McCay in 1935 long before the effects of such hormones and growth factors on aging were recognized. The cellular pathways that mediate this remarkable response have been explored in many experimental models. These include the nutrient sensing pathways (mTOR, AMPK, insulin/IGF-1, and sirtuins) as well as transcription factors (FOXO in D. melanogaster and daf-16 in C. elegans). The transcription factor Nrf2 appears to confer most of the anticancer properties of CR in mice, even though it is dispensable for life span extension.
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The effects of CR in monkeys have been assessed in two studies with different outcomes: one study observed prolonged life while the other did not. However, both studies confirmed that CR increases health span by reducing the risk for diabetes, cardiovascular disease, and cancer. In humans, CR is associated with increased life and health span. This is most convincingly demonstrated in Okinawa, Japan, where one of the most long-lived human populations resides. In comparison to the rest of the Japanese population, Okinawan people usually combine an above-average amount of daily exercise with a below-average food intake. However, when Okinawan families move to Brazil, they adopt a Western lifestyle that affects both exercise and nutrition, causing a rise in weight and a reduction in life expectancy by nearly two decades. In the Biosphere II project, where volunteers lived together for 24 months undergoing an unforeseen severe CR, there were improvements in insulin, blood sugar, glycated hemoglobin, cholesterol levels, and blood pressure—all outcomes that would be expected to benefit life span. CR changes many aspects of human aging that might influence life span such as the transcriptome, hormonal status (especially IGF-1 and thyroid hormones), oxidative stress, inflammation, mitochondrial function, glucose homeostasis, and cardiometabolic risk factors. Epigenetic modifications are an emerging target for CR.
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It must be noted that maintaining CR and avoiding malnutrition is not only arduous in humans but is also linked with substantial side effects. For instance, prolonged reduction of calorie intake may decrease fertility and libido, impair wound healing, reduce the potential to combat infections, and lead to amenorrhea and osteoporosis.
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While extreme obesity (body mass index [BMI] >35) leads to a 29% increased risk of dying, people with BMI in the overweight range seem to have reduced mortality, at least in population studies of middle-aged and older subjects. People with a BMI in the overweight range seem more able to counteract and respond to disease, trauma, and infection, whereas CR impairs healing and immune responses. On the other hand, BMI is an insufficient denominator of body and body fat composition. A well-trained athlete may have an equivalent BMI compared to a fat person because of the higher muscle mass density. The waist:hip ratio is a much better indicator for body fat and an excellent and stringent predictor for the risk to die from cardiovascular disease: the lower the waist:hip ratio, the lower the risk.
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How can CR be translated to humans in a socially and medically feasible way? A whole series of periodic fasting regimens are asserting themselves as suitable strategies, among them the alternate-day fasting diet, the “five:two” intermittent fasting diet, and a 48-h fast once or twice each month. Periodic fasting is psychologically more viable, lacks some of the negative side effects and is only accompanied by minimal weight loss.
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It is striking that many cultures implement periodic fasting rituals, for example Buddhists, Christians, Hindus, Jews, Muslims, and some African animistic religions. It could be speculated that a selective advantage of fasting versus nonfasting populations is conferred by health-promoting attributes of religious routines that periodically limit caloric intake. Indeed, several lines of evidence indicate that intermittent fasting regimens exert antiaging effects. For example, improved morbidity and longevity were observed among Spanish home nursing residents who underwent alternate-day fasting. Even rats subjected to alternate-day fasting live up to 83% longer than normally fed control animals and one 24-h fasting period every 4 days is sufficient to generate life span extension.
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Repeated fasting and eating cycles may circumvent the negative side effects of sustained CR. This strategy may even yield effects despite extreme overeating during the nonfasting periods. In a spectacular experiment, mice fed a high-fat diet in a time-restricted manner, i.e., with regular fasting breaks, showed reduced inflammation markers, no fatty liver and were slim in comparison to mice with equivalent total calorie consumption but ad libitum. From an evolutionary point of view, this kind of feeding pattern may reflect mammalian adaptation to food availability: overeating in times of nutrient availability (e.g., after a hunting success) and starvation in between. This is how some indigenous peoples who have avoided Western lifestyles live today; those who have been investigated show limited signs of age-induced diseases such as cancer, neurodegeneration, diabetes, cardiovascular disease, and hypertension.
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Fasting exerts beneficial effects on health span by minimizing the risk of developing age-related diseases including hypertension, neurodegeneration, cancer, and cardiovascular diseases. The most effective and rapid repercussion of fasting is reduction in hypertension. Two weeks of water-only fasting resulted in a blood pressure below 120/80 mmHg in 82% of subjects with borderline hypertension. Ten days of fasting cured all hypertensive patients who had been taking antihypertensive medication previously.
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Periodic fasting dampens the consequences of many age-related neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and frontotemporal dementia but not amyotrophic lateral sclerosis in mouse models). Fasting cycles are as effective as chemotherapy against certain tumors in mice. In a combination with chemotherapy, fasting protected mice against the negative side effects of chemotherapeutic drugs, while it enhances their efficacy against tumors. Combining fasting and chemotherapy rendered 20–60% mice cancer-free when inoculated with highly aggressive tumors like glioblastoma or pancreatic tumors, which have 100% mortality even with chemotherapy.
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Pharmacological Interventions to Delay Aging and Increase Life Span
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Virtually all obese people know that stable weight reduction will reduce their elevated risk of cardiometabolic disease and enhance their overall survival, yet only 20% of overweight individuals are able to lose 10% weight for a period of at least 1 year. Even in the most motivated people (such as the “Cronies” who deliberately attempt long-term CR in order to extend their lives), long-term CR is extremely difficult. Thus, focus has been directed at the possibility of developing medicines that replicate the beneficial effects of CR without the need for reducing food intake (“CR-mimetics,” Fig. 463-5):
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Resveratrol. Resveratrol, an agonist of SIRT1, is a polyphenol that is found in grapes and in red wine. The potential of resveratrol to promote life span was first identified in yeast, and it has gathered fame since, at least in part because it has been suggested to be responsible for the so-called French paradox whereby wine reduces some of the cardiometabolic risks of a high fat diet. Resveratrol has been reported to increase life span in many lower order species such as yeast, fruit flies, worms as well as mice on high-fat diets. In monkeys fed with a diet high in sugar and fat, resveratrol had beneficial outcomes related to inflammation and cardiometabolic parameters. Some studies in humans have also shown improvements in cardiometabolic function while others have not. Gene expression studies in animals and humans reveal that resveratrol mimics some of the metabolic and gene expression changes of CR.
Rapamycin. Rapamycin, an inhibitor of mTOR, was originally discovered on the Easter Island (Rapa Nui, hence its name) as a bacterial secretion with antibiotic properties. Before its immersion in the antiaging field, rapamycin was known as an immunosuppressant and cancer chemotherapeutic in humans. Rapamycin extends life span in all organisms tested so far, including yeast, flies, worms, and mice. However, the potential utility of rapamycin for human life span extension is likely to be limited by adverse effects related to immunosuppression, wound healing, proteinuria, and hypercholesterolemia, among others. An alternative strategy may be intermittent rapamycin feeding, which was found to increase mouse life span.
Spermidine. Spermidine is a physiological polyamine that induces autophagy-mediated life span extension in yeast, flies, and worms. Spermidine levels decrease during life of virtually all organisms including humans, with the stunning exception of centenarians. Oral administration of spermidine or upregulation of bacterial polyamine production in the gut both lead to life span extension in short-lived mouse models. Spermidine has also been found to have beneficial effects on neurodegeneration probably by increasing transcription of genes involved in autophagy.
Metformin. Metformin, an activator of AMPK, is a biguanide first isolated from the French lilac that is widely used for the treatment of type 2 diabetes mellitus. Metformin decreases hepatic gluconeogenesis and increases insulin sensitivity. Metformin has other actions including inhibition of mTOR and mitochondrial complex I, and activation of the transcription factor SKN-1/Nrf2. Metformin increases life span in different mouse strains including female mouse strains predisposed to high incidence of mammary tumors. At a biochemical level, metformin supplementation is associated with reduced oxidative damage and inflammation and mimics the some of the gene expression changes seen with CR.
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Exercise and Physical Activity
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In humans and animals, regular exercise reduces the risk of morbidity and mortality. Given that cardiovascular diseases are the dominant cause of aging in humans but not in mice, the effects on human health may be even stronger than those seen in mouse experiments. An increase in aerobic exercise capacity, which declines during aging, is associated with favorable effects on blood pressure, lipids, glucose tolerance, bone density, and depression in older people. Likewise, exercise training protects against aging disorders such as cardiovascular diseases, diabetes mellitus, and osteoporosis. Exercise is the only treatment that can prevent or even reverse sarcopenia (age-related muscle wasting). Even moderate or low levels of exercise (30 min walking per day) have significant protective effects in obese subjects. In older people, regular physical activity has been found to increase the duration of independent living.
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While clearly promoting health and quality of life, regular exercise does not extend life span. Furthermore, the combination of exercise with CR has no additive effect on maximal life span in rodents. On the other hand, alternate-day fasting with exercise is more beneficial for the muscle mass than single treatments alone. In nonobese humans, exercise combined with CR has synergistic effects on insulin sensitivity and inflammation. From the evolutionary perspective, the responses to hunger and exercise are linked: when food is scarce, increased activity is required to hunt and gather.
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The term hormesis describes the, at first sight paradoxical, protective effects conferred by the exposure to low doses of stressors or toxins (or as Nietzsche stated “What does not kill me makes me stronger”). Adaptive stress responses elicited by noxious agents (chemical, thermal, or radioactive) precondition an organism rendering it resistant to subsequent higher and otherwise lethal doses of the same trigger. Hormetic stressors have been found to influence aging and life span presumably by increasing cellular resilience to factors that might contribute to aging such as oxidative stress.
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Yeast cells that have been exposed to low doses oxidative stress exhibit a marked antistress response that inhibits death following exposure to lethal doses of oxidants. During ischemic preconditioning in humans, short periods of ischemia protect the brain and the heart against a more severe deprivation of oxygen and subsequent reperfusion-induced oxidative stress. Similarly, the lifelong and periodic exposure to various stressors can inhibit or retard the aging process. Consistent with this concept, heat or mild doses of oxidative stress can lead to life span extension in C. elegans. CR can also be considered as a type of hormetic stress that results in the activation of antistress transcription factors (Rim15, Gis1, and Msn2/Msn4 in yeast and FOXO in mammals) that enhance the expression of free radical-scavenging factors and heat shock proteins.