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PRESCRIPTION FOR LONGEVITY: FADS AND REALITY INTRODUCTIONAt a workshop held on November 21-23, 1997 and co-sponsored by the International Longevity Center and Canyon Ranch in Tucson, AZ, 14 leading gerontologists and other health scientists met to discuss what we currently know about how diet, dietary supplements, exercise and other interventions contribute to better health and increased longevity in older people.This group particularly addressed the question: Which of the much hyped dietary supplements are truly effective AND safe? The purpose of these workshop discussions was to write a rational prescription with respect to effectiveness and safety, and to develop a research agenda for future work in order to provide facts to replace fads. ExerciseAmericans on the average do not get enough exercise, according to our current understanding of optimal levels for longevity. Although it is not known whether there is an exercise threshold below which little benefit would be provided, a minimum increase of at least 1000 kcal per week above sedentary baseline levels is recommended. A level of 2000-3000 kcal is preferable, but may not be possible for the very frail old. Both endurance and resistance training are recommended, but the optimal amount of exercise may vary among individuals based on illness, age, physical limitations, etc. Heavy exercise should be avoided in the early morning for people at risk for myocardial infarction, and in the late evening, because it may interfere with the ability to fall asleep. The optimal time is usually the late afternoon for most people.DietThe following practices are recommended: Calcium should be supplemented, if necessary, to ensure a daily intake of 1200 mg for men and 1500 mg for women. Include at least 2 to 4 helpings of fruits and 3 to 5 helpings of vegetables per day, Include one multi-vitamin tablet per day to ensure adequate intake of vitamins B6, B12, C, D, E, and folic acid, but for the elderly, containing no or low amounts of iron,* Reduce fat to 30% or less of total caloric intake. * A diet rich in fruits and vegetables is preferred over dietary supplements, but the diets of many older Americans are deficient in one or more of these micronutrients, and may not supply the optimal amount of some micronutrients, e.g. vitamin E. Hormone replacement therapy Estrogen replacement therapy is justified for many post-menopausal women (after consultation with a physician, and in the absence of contra-indications). No other hormone intervention is recommended at this time.SleepOlder people with sleeping problems should be evaluated and treated accordingly, including the possible use of melatonin or light exposure to reset the sleep-wake cycle. OtherFUTURE RESEARCHAdditional research is needed to:ExerciseWith increasing age, the muscles atrophy and become weaker and more fatiguable. Superficially, these changes that occur with age appear similar to the changes that occur at any age when a decrease in physical activity occurs. The difference is that the loss in muscle mass and the decreases in strength and endurance associated with inactivity are totally reversible with subsequent conditioning, whereas the changes associated with aging are observed in both highly conditioned and sedentary people. Importantly, the rate of change is much more rapid when aging is coupled with decreasing physical activity. Under these circumstances, the cumulative losses in muscle mass and function may lead to a loss in mobility, an increased susceptibility to falls and ultimately severe disabilities for older persons. Although under certain conditions growth hormone may increase muscle mass of elderly males, the increase depends on continuing the treatment, which is both expensive and may be accompanied by adverse health effects. Regular physical activity and adequate nutrition provide a much more effective intervention strategy for the elderly to maintain not only an adequate muscle mass, but also muscles that function properly. Skeletal muscles are capable of performing three types of contractions: miometric contractions when the muscle shortens, isometric when the muscle remains at the same length, and pliometric when the muscle is stretched. For normal function of muscles to be maintained in the elderly, the muscles of the upper and lower limbs and of the trunk must perform each type of contraction frequently and regularly. If muscles do not perform each type of contraction frequently and regularly the muscle fibers that make up the muscle undergo changes that make them more susceptible to injury, and subsequent physical activity is even more difficult. The fibers in the muscles of old people are more easily injured by their own contractions than those in young or adult people. Consequently, regular strength conditioning of muscles is even more important for the elderly than for younger people. The only way to acquire and maintain strength conditioned muscles is to exercise with a diversity of tasks of lifting and lowering activities with light weights that involve the muscles of the arms, legs and trunk. Each individual task for a specific muscle group should be performed 10 times at about 80% of a maximum effort and then repeated 3 times with rests in between. The second requirement of total body fitness for the elderly is to maintain a reasonable level of total body endurance. Total body endurance which loads the cardiovascular and respiratory systems is achieved most easily and effectively by a total body activity such as walking, jogging, crosscountry skiing, skating, or cycling. For a 70 kg person, walking is about 200 kcal/hour above baseline, and slow jogging is about 500 kcal/hour above baseline. These activities involve the moving of the body mass; consequently, the caloric cost will go up or down proportionately with greater or lesser body masses.Oxidative Damage and Age-related DiseaseAll living cells are exposed to oxidative stress in the form of oxygen radicals. In most eukaryotic cells this occurs primarily during the metabolism of oxygen by the electron transport system in the mitochondria. Because of this continuous exposure to oxygen radicals, living organisms have developed robust antioxidant defenses and systems to repair damaged proteins, DNA and unsaturated lipids. Failure to adequately deal with these oxygen radicals is a risk factor for a variety of age-related diseases such as cancer, neurodegenerative diseases, atherosclerosis, and cataract. The antioxidant defense systems include both non-specific dietary antioxidants such as vitamins C (ascorbic acid) and E, as well as specific enzymes for destroying oxygen entities such as superoxide anion and hydrogen peroxide. Thus, dietary antioxidants provide one possible opportunity for intervention. Ascorbic acid is particularly protective in smokers, and has been shown to reduce DNA damage in sperm. Very recent data suggest that ascorbic acid accumulates in neutrophils during infection, possibly to protect the neutrophils against the very oxygen radicals they generate to kill bacteria. Another opportunity, as yet largely unexploited, would be to attenuate the rate of production of oxygen radicals by mitochondria. One possible approach is to preserve as much as possible the structural integrity of mitochondria during aging of the cell. Early results in this area of research suggest that maintaining: 1) cardiolipin levels in mitochondrial membranes, and 2) acetyl carnitine synthesis in mitochondria by carnitine supplementation, may both be effective. Lipoic acid and radical scavengers such as phenyl butyl nitrone (PBN) have also been shown to reduce oxygen radical generation by mitochondria. Diet Dietary deficiencies are a well-known risk factor for many diseases, including age-related diseases such as cancer, cardiovascular disease, and osteoporosis. Epidemiological data on dietary intakes indicate that in persons whose diet is rich in fruits and vegetables, the risk of a variety of cancers is lowered by one-half. Epidemiological health data also indicate that overweight becomes an increasing problem in both men and women 40 years of age and greater, but especially in women. The percentage of individuals who are overweight reaches as high as 60% in black women in their 50s and 60s. Hypertension also increases steadily across the decades, with up to 60% of men and 80% of women being mildly to moderately hypertensive by their 6th decade. The workshop participants discussed what is currently known about the role of both micronutrients and macronutrients in human health. Particular emphasis was placed on micronutrients which may be deficient in the diet of older persons. There was consensus that dietary intakes of the following micronutrients may be inadequate in at least 10% of individuals over 70 years of age:TABLE 1SUGGESTED DAILY INTAKES OF MICRONUTRIENTS NUTRIENT RECOMMENDED TOTAL DAILY INTAKE
TABLE 2COMPOSITION OF A MULTI-VITAMIN (SPECIALIZED FOR ADULTS OVER 50) AVAILABLE AT A MAJOR GROCERY CHAIN FOR LESS THAN 10c/TABLETNUTRITION FACTS SERVING SIZE 1 TABLET EACH TABLET CONTAINS % DAILY VALUE SUGGESTED USE: ADULTS, AS A DIETARY SUPPLEMENT, ONE TABLET DAILY There is no evidence that this would be harmful, and it is an inexpensive (5- 10c/day/person) and simple approach (see Table 2 for the composition of a multi-vitamin tablet currently available). It can be argued that the wide variations among individuals, especially among older adults, requires an individualized assessment of dietary deficiencies. The data available to date indicate that use of dietary supplements is greater in women than in men, and that both increase with increasing age in the American population. Other dietary supplements such as chromium ion (Cr+3), melatonin and dehydroepiandrosterone (DHEA) were also discussed. The use of Cr+3 in reducing blood sugar levels, blood pressure and lipid peroxidation in individuals with glucose intolerance and insulin resistance is based mainly on animal experiments. Recent human studies from China show that giving trivalent chromium to type 2 diabetics lessened the glucose intolerance and reduced the levels of circulating glycated hemoglobin significantly. Many multi-vitamin pills may not contain adequate levels of absorbable Cr+3. The participants agreed that the data in support of including melatonin as a supplement are very weak, and probably flawed. The data for DHEA are also unconvincing, and several laboratories have been unable to replicate some of the published positive results about restoring immune function in mice; DHEA also does not extend life span in mice. Epidemiological data on macronutrient intake were also discussed. Restriction of caloric intakes is the only known intervention which reliably extends life span and delays age-related disease in a variety of animal species. However, this intervention has yet to be adequately tested for either effectiveness or safety in humans. Although countries in which total caloric intake is high tend to have longer-lived populations, this cannot be construed to mean that caloric restriction would not work in humans. It is more likely an expression of the better overall health and better socioeconomic status of these populations. Modest reduction of total dietary fat (to no more than 30% of total calories), saturated fat (less than 10% of total calories), and cholesterol (less than 300 mg daily), consistent with the Dietary Guidelines for Americans and the Food Guide Pyramid, is important for achieving and maintaining healthy weight and reducing the risk of heart disease and certain cancers. Additional research is needed to clarify the health benefits and potential adverse effects of aggressive fat reduction beyond these targets. Additional data are also needed on the effects of modifying fat composition, i.e. saturated vs. monounsaturated and polyunsaturated fatty acids, and altering carbohydrate intake. Excessive reduction of dietary fat, with a concomitant increase in dietary carbohydrate, has been associated in some population groups with adverse effects on biomarkers of chronic disease risk, including decreased HDL-cholesterol, increased LDL-cholesterol and triglycerides, and insulin resistance. These findings may necessitate a shift in paradigm away from the central focus on dietary fat reduction, to consider the role of dietary fat and carbohydrate composition. Endocrine FactorsBecause hormones are produced in one part of the body and utilized at some other place, and because many hormone levels decrease with age, hormone replacement therapy is an appealing anti-aging intervention (see Table 3). The most successful example so far is estrogen replacement therapy following menopause. This therapy has proven to be not only efficacious and relatively inexpensive in lowering the risk of cardiovascular disease and osteoporosis, but also to have unanticipated consequences, such as a possible lowering of the risk of Alzheimer’s disease. A useful intervention, but one less successful over the long term includes the use of dopamine for treatment of Parkinson disease. Some success in reforming muscle mass has also been reported using growth hormone.Growth hormone levels dramatically decrease with age. Reducing the symptoms of Alzheimer’s disease with anti-inflammatory agents and/or regulation of the level of the neurotransmitter acetylcholine, has also been reported. A profound difficulty with these approaches is that it would be extremely difficult to mimic the cyclical changes in blood level for hormones such as growth hormone. This difficulty can lead to undesirable side effects. A conceptual complication is that just because serum concentrations of any circulating hormone decrease with age, this does not mean that restoring it to levels found in younger individuals will be beneficial. Furthermore, many of the therapies of this kind are likely to require individual assessment and surveillance, and thus be expensive and not available to the general population. Thus, only a few of these TABLE 3POTENTIAL HORMONE REPLACEMENT THERAPIES HORMONE TARGET KNOWN KNOWN EFFICACY SIDE EFFECTSSleepWell-documented sleep problems for many older adults are insomnia, sleep apnea, and changes in sleep cycles. These problems have different causes, and need to be treated differently. In the case of insomia which delays sleep until the early morning hours, taking melatonin in the late evening may advance the 24 hour biological clock sufficiently to be useful. However, melatonin is not useful for general insomnia, such as may be caused by sleep apnea. In those individuals who tend to fall asleep early in the evening, bright light in the evening may be useful for delaying the time of sleep-onset and waking. Amino acid supplements, e.g. tryptophan, do not appear to be a useful therapy, may actually contain dangerous contaminants, and are not encouraged.Sleep is also associated with growth hormone production, and good sleep cycling may improve growth hormone cyclicity. Thus, this issue is a significant quality of life concern in older adults. Genetics and Gene TherapyWhile it is obvious that differences in life span among animal species have a strong genetic basis, it has been estimated that only about 30-35% of individual differences in human longevity depend on genetic factors.However, with the possible exception of the gene for Werner’s syndrome, little is known about which human genes play critical roles in these differences. It can be assumed that longevity is an extremely polygenic trait, and that small differences such as single nucleotide polymorphisms (SNPs) in many genes are partially responsible for individual differences in aging.
Until the existence and frequency of SNPs
in the human genome and their impact on
aging can be evaluated, an alternate approach
is to try to identify and characterize
candidate aging genes in genetically-pliable
model systems such as yeast (S. cerevisiae),
fruit flies (Drosophila), nematodes (C. elegans),
and mice. |