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Editorial: Antiaging Medicine

The Good, the Bad, and the Ugly

^a Department of Medicine, Division of Geriatrics, University of California, San Francisco
^b Geriatric Research Education and Clinical Center, VA Medical Center, and Division of Geriatric Medicine, Saint Louis University, St. Louis, Missouri

John E. Morley, Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104 E-mail: morley{at}slu.edu.

THROUGHOUT the centuries, humans have looked for magical ways to extend the lifespan and improve the quality of old age. In the 13th century, Roger Bacon suggested that rejuvenation required good nutrition, regular exercise, and receiving "the breath of a virgin" ⁽¹⁾. Many of the modern claims of the antiaging medicine gurus are, like Bacon's virgin's breath, unlikely to rejuvenate but are couched in pseudoscientific terminology to appeal to those desperate to find the mythical fountain of youth.

The double Nobel Prize winner Linus Pauling touted the antiaging effects of megadoses of vitamin C. Vitamin C is involved in multiple oxidation-reduction reactions. Despite the extraordinary zeal for the therapeutic properties of vitamin C, neither epidemiological nor intervention studies have demonstrated any major efficacy of this vitamin in pharmacological dose in being protective against atherosclerotic disease or cancer ⁽²⁾. In addition, there is some evidence that vitamin C may produce oxidative damage to DNA, as levels of 8-oxoadenine are increased in persons taking vitamin C ⁽³⁾.

Excess oxidative stress remains a major theory of aging ⁽⁴⁾. Experiments in the worm C. elegans have demonstrated that mutations that activate an antioxidant pathway prolong life ⁽⁵⁾. Similarly, Drosophila strains that have extended longevity have higher antioxidant activity ⁽⁵⁾⁽⁶⁾. In contrast, transgenic mice that overproduce Cu-Zn superoxide dismutase do not have an increased lifespan ⁽⁷⁾. These animal studies have led, in part, to nearly half of older persons using vitamin and mineral supplements ⁽⁸⁾. The use of these supplements is not associated with dietary deficiencies in most people using them.

Vitamin E supplementation in controlled trials in humans showed a reduction in morbidity and mortality from atherosclerosis in the Cambridge Heart Antioxidant Study ⁽⁹⁾, but failed to find a beneficial effect in the Primary Prevention Project ⁽¹⁰⁾, the Alpha-Tocopherol and Beta-Carotene Cancer Prevention Study ⁽¹¹⁾, the Heart Outcomes Prevention Evaluation Study ⁽¹²⁾, and the Italian Gizzi-Prevenicone Study ⁽¹³⁾. In addition, progression of carotid atherosclerosis is not prevented by vitamin E ^(14)(15). In the HDL-atherosclerosis trial, an antioxidant cocktail including vitamin E resulted in inhibition of the ability of niacin and simvastatin to increase high-density lipoprotein (HDL) ⁽¹⁶⁾. Overall, these studies are not supportive of the ability of vitamin E to prevent or treat atherosclerosis. Vitamin E has been shown to have some benefit in delaying Alzheimer's disease progression, specifically time to nursing home placement, but only after the data were statistically manipulated to account for baseline mental status ⁽¹⁷⁾. Similarly, trials examining the efficacy of beta-carotene for atherosclerosis and cancer prevention have been disappointing ^(15)(18). Vitamin A should only be taken with caution because of its propensity to produce hypercalcemia and hip fracture in postmenopausal women ⁽¹⁹⁾. Alpha-lipoic acid, a more potent antioxidant, has been shown to be able to reverse memory impairment in the SAMP8 mice, an animal model of Alzheimer's disease ^(20)(21). Alpha-lipoic acid is modestly effective in treating diabetic neuropathy ⁽²²⁾. Overall, at present, there is little evidence that free radical scavengers have positive antiaging effects.

Caloric restriction has been shown to extend lifespan in a variety of animal species ^{(23)(24)(25)(26)}. Recently, a study in Ethiopian baboons has suggested that dietary restriction as practiced in animal colonies in the United States may purely be preventing excess obesity seen in these animals ⁽²⁷⁾. Caloric restriction reduces visceral fat, reduces fasting glucose and improves insulin sensitivity, reduces serum triglycerides, lowers blood pressure, and reduces growth hormone and thyroid hormones ^(28)(29). Many of the hormonal changes of caloric restriction are similar to the changes seen with aging, raising the question of whether or not caloric restriction is a form of "premature" aging or slowing of the organism. An important negative effect of caloric restriction is a reduction in bone mineral density ⁽²⁸⁾. A caloric restriction in humans, sponsored by National Institute on Aging, has recently been started ⁽²⁴⁾. While the enthusiasm for a reasonable level of caloric restriction in humans is reasonable, it is important to remember that the anorexia of aging and its subsequent weight loss represents one of the major clinical problems of older persons ^(30)(31)(32). Roberts and colleagues ⁽³³⁾ have shown that older persons fail to regain weight lost during caloric restriction after the restriction is removed. Depending on the percentage of fat versus muscle regained following caloric restriction, caloric restriction could lead over time to an increase of the number of "fat frail" in the older population ⁽³⁴⁾. These concerns need to be kept in mind as the caloric restriction studies go forward. An important developing area of antiaging research is in the development of caloric restriction mimetics ⁽³⁵⁾. This includes further understanding of antioxidants, the role of agents that inhibit glycosylation, the effect of agents that regulate intermediary metabolism and energy metabolism, and the effects of agents that enhance activation of cytotoxic T cells ^(35)(36).

There has been much enthusiasm for the discovery of a "hormonal fountain of youth" ⁽³⁷⁾. The levels of many hormones decline with aging. At present, it is uncertain whether replacement of these hormones will extend life and improve its quality or decrease lifespan. Estrogen replacement in women at menopause is perhaps the best example of this. Clearly, estrogen can prevent the unpleasant effects of menopause and delay the rapid decline in bone mineral density that occurs following menopause ⁽³⁸⁾. However, despite the salutary effects of estrogen on lipids and endothelial function, the Heart Estrogen Replacement Study and Women's Health Initiative Memory Study have suggested that estrogen replacement may increase early cardiovascular deaths in some women taking estrogen ^(38)(39)(40). Selective estrogen receptor modulators, such as raloxifene, need further study before they can be recommended in place of estrogen.

Testosterone levels decline with aging in men ^(41)(42). A number of studies, including some published in the Journal, have shown that testosterone replacement in older hypogonadal men increases muscle mass, strength, bone mineral density, cognition, and function while having minimal deleterious effects ^{(41)(43)(44)(45)(46)(47)(48)(49)}. It is possible that testosterone loss with aging plays a major role in the development of sarcopenia ^(34)(50) and, therefore, in frailty ⁽⁵¹⁾. There are, however, minimal safety studies demonstrating the long-term effects of testosterone, and an old study in the Journal of Gerontology suggested a protective effect of castration in persons with developmental disabilities ⁽⁵²⁾, though a similar effect was not found in the "castrati" ⁽⁵³⁾. At present, it would seem reasonable to replace testosterone in older men who are hypogonadal and symptomatic ^(41)(54). Testosterone levels decline dramatically in women from 20 to 50 years of age, and free testosterone declines further when estrogen is replaced ⁽⁵⁵⁾. The role of testosterone replacement in women is clearly in need of further study.

Antiaging aficionados have evinced a major interest in two steroid precursor hormones, dehydroepiandrosterone (DHEA) and pregnenolone. Both of these hormones decline dramatically with aging ⁽⁵⁶⁾. A number of studies have examined the effects of DHEA replacement with aging. In low doses, DHEA has minimal effects in older persons ⁽⁵⁷⁾. In doses of 100 mg daily, Morales and colleagues ⁽⁵⁸⁾ found an increase in muscle mass in men, but not in women. Pregnenolone is the true "mother hormone," being made from cholesterol and being the precursor of all steroid hormones. In mice, pregnenolone is the most potent known memory enhancer ^(59)(60). In humans, pregnenolone improves attention and decreases arthritic pain but fails to improve memory ⁽⁶¹⁾. At present, there is not evidence to support the use of DHEA or pregnenolone as antiaging hormones.

Both growth hormone and insulin-like growth factor-1 levels decline with aging ⁽⁶²⁾. These declines are more dramatic in malnourished persons ⁽⁶³⁾. Rudman and colleagues suggested the existence of a growth hormone "menopause" ⁽⁶⁴⁾. Studies on growth hormone replacement have unfortunately provided minimal positive effects of growth hormone and a plethora of unpleasant side effects ^(65)(66). A recent study in the Journal did find positive effects of a combination of growth hormone and testosterone ⁽⁶⁷⁾. However, animal and epidemiological studies have failed to support a role for growth hormone as an antiaging hormone ⁽⁶⁸⁾. A recent animal study found that growth hormone excess resulted in a decline in superoxide dismutase and glutathione peroxidase ⁽⁶⁹⁾. These findings of a decline in free radical defenses were suggested as one of the mechanisms of early mortality produced by growth hormone excess.

Numerous herbals are touted to improve quality of life or as longevity agents. Of these, some scientific evidence for the utility of ginkgo biloba for memory disorders, glucosamine and chondroitin for arthritis, and saw palmetto for benign prostatic hypertrophy exists ⁽⁷⁰⁾. A recent controlled trial failed to show evidence for efficacy of St. John's Wort in the treatment of moderately severe depression ⁽⁷¹⁾. Of note, these results need to be viewed with caution as the selective serotonin reuptake inhibitor sertraline was also not statistically more effective than placebo. Garlic has minimal effects on lowering cholesterol and no effect on blood pressure ⁽⁷²⁾. Garlic supplements containing 1.3% allicin have not been shown to prevent cancer ⁽⁷³⁾. Thus, it would appear that garlic's use should be limited to those who expect to meet a vampire or wish to ward off other evil spirits by its pungent odor. Shark cartilage contains some agents that are active against cancer in vitro, but there is little evidence for in vivo activity ⁽⁷⁴⁾.

At the beginning of the 20th century, Ellie Metchnikoff ⁽⁷⁵⁾ taught that lactobacilli-containing yogurt reduced gut toxins and thus would prolong life. Subsequently, it was believed that populations who ingested yogurt, such as Bulgarian peasants, were often long-lived, but eventually it turned out that their longevity was more related to their inability to correctly count their chronological age. In modern times, there has been a resurgence in the concept of probiotics (Greek meaning "for life"). These are agents secreted by microorganisms that modulate the growth of other microorganisms. Schaafsma ⁽⁷⁶⁾ felt that these living organisms could "exert health effects beyond inherent basic nutrition." There is reasonable evidence to support the use of probiotics for Clostridium difficile diarrhea prevention in persons receiving antibiotics, for the management of lactose insufficiency, and for protection against urogenital infections ⁽⁷⁷⁾. Less substantial data suggest their use in colon cancer prevention and in lowering blood pressure ⁽⁷⁸⁾. Prebiotics, such as oligofructoses, are nonbacterial agents that enhance the growth of positive gut flora. Much further research is required to establish a role of either pre- or probiotics as antiaging agents.

Four studies have examined the use of complementary and alternative medicine by older adults ^{(79)(80)(81)(82)}. The usage in the United States varied from 30% to 64%. Physicians are often unaware of their patients' usage of these therapies. Usage of complementary and alternative medicine is higher in Japan than in the United States ⁽⁸²⁾.

Perhaps the best antiaging medicine is exercise ^(83)(84). Resistance exercise seems to be particularly useful as it not only improves strength ^{(85)(86)(87)(88)} but also enhances cognition ^(89)(90)(91) and decreases depression ⁽⁹²⁾. Despite these positive effects, Keysor and Jette ⁽⁹³⁾ have pointed out that it is very difficult to demonstrate long-term functional effects of exercise programs.

While the concept of antiaging therapies is intriguing, there is clearly little evidence-based medicine to support most of the generally touted approaches. While research needs to go forward, it is important that gerontologists do not provide support for the large number of inappropriate antiaging therapies ^(94)(95).

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