Anti-Aging Strategies: Science or Hype?

Wendy M. Kohrt, PhD; Wendolyn S. Gozansky, MD, MPH

Aging is broadly and simplistically thought of as the postmaturational decline in physiologic function. However, there is no generally accepted definition of aging among scientists, nor is there an accepted method of measuring the aging process.1 Despite the abundance of products claiming to have “anti-aging” effects, a recent overview of the current status of anti-aging medicine concluded that “there is no empirical evidence to support the claim that aging in humans can be modified by any means, nor is there evidence that it is possible to measure biological age, or that anti-aging products extend the duration of life.”2 It is important to note that the excerpt above does not state that anti-aging strategies are ineffective, but rather that there is no evidence for their effectiveness. In this article, we will define the concept of primary (presumably unavoidable) versus secondary (potentially modifiable) aging, and briefly discuss existing strategies aimed at increasing survival (average life span) and/or longevity (maximal life span). Finally, we will use the example of the menopausal transition—a primary aging event—to discuss whether treating certain consequences of menopause might be considered as anti-aging strategies, and whether there is any evidence to support an anti-aging effect of prolonging ovarian function.

Illustration of Anti-Aging

There is indisputable evidence that skeletal muscle mass declines with advancing age, and equally convincing evidence that it can be increased with appropriate exercise intervention, even in the very elderly.

Primary versus Secondary Aging

If we accept the general definition of aging as a decline in physiologic function, it is easy to understand why there are claims for the effectiveness of ‘‘anti-aging’’ strategies. As an example, there is indisputable evidence that skeletal muscle mass declines with advancing age, and equally convincing evidence that it can be increased with appropriate exercise intervention, even in the very elderly. This has sometimes led to the conclusion that the effects of aging can be attenuated by exercise. However, an alternative interpretation is that lack of exercise exaggerates the effects of aging, and that exercise training merely “restores” the rate of decline in muscle mass to that attributable to aging, per se. In other words, the decline in function with advancing age is not due solely to the aging process (ie, primary aging), but also to changes in such factors as physical inactivity, poor nutrition, and exposure to environmental toxins that also influence physiologic function (ie, secondary aging).

Figure 1

Figure 1. Theoretical decline in physiologic function with primary aging (center line), an acceleration in functional decline attributable to secondary factors of aging (leftward shift), and the postulated preservation of function with successful anti-aging strategies (rightward shift).

As illustrated schematically in Figure 1, secondary aging factors would be predicted to accelerate an individual’s decline in function (dashed line) relative to the primary aging process (solid line), thereby reducing the level of function at a given chronologic age, and potentially culminating in premature mortality. Strategies that fall under the umbrella of preventive medicine, such as adopting healthful behaviors, avoiding toxic exposures and undergoing screening exams—with the focus on disease prevention—can shift the secondary aging curve rightward, closer to the primary aging curve. In contrast, the ultimate goal of true anti-aging medicine is a rightward shift in the primary aging curve, thereby not only better preserving function, but also increasing life span beyond the theoretical limit, which is thought to be about 120 years for humans. Several strategies have been found to increase maximal life span in animals, including caloric restriction, dietary manipulation, and genetic engineering. 3-6 Determining whether such strategies are also effective in humans will likely depend on the discovery of valid markers of biological aging, because controlled studies of the longevity of humans are not feasible. It is important to recognize that a valid biomarker of aging will not simply be a parameter that changes with aging, but one that predicts longevity.

Figure 2

Figure 2. Effects of exercise versus caloric restriction on survival (average life span) and longevity (maximal life span).

Adapted from studies of rats.9,10
Average versus Maximal Life Span

Studies of the effects of exercise and caloric restriction on survival (average life span, or the age at which half the population has died) and longevity (maximal life span, or the age of the oldest members of a population) in laboratory animals provide insight to the complexities of anti-aging research. Caloric restriction, which has been proven to be an effective anti-aging strategy in organisms as simple as yeast and as complex as mammals,7 increases both average and maximal life span (Figure 2). In contrast, exercise, which is known to have benefits on multiple physiologic systems in aging, 8 has been found to increase average life span in rats, but does not extend maximal life span.9,10 Such findings suggest that, although exercise has potent beneficial effects on physiologic function, morbidity and premature mortality, it does not alter the primary aging process.

It is compelling to look at the increase in human life expectancy and at the growing percentage of older adults in the population as examples of success in the “antiaging” arena. However, the increase in human life expectancy at birth in the United States over the last century (from about age 50 to age 80) is primarily a result of decreased infant and childhood mortality. Further, although the percentage of elderly in the population continues to increase, this demographic change is tied more closely to decreasing fertility rates (ie, fewer young people) than to increased survival.11 It is important to note that the age of the oldest living humans recorded (~120 years) has remained unchanged. Thus, the prolongation of life expectancy appears to represent an increase in average human life span rather than an increase in maximal human life span. While this accomplishment of public health and modern medicine is remarkable, it should not be assumed to represent an alteration in the primary aging process.

The increase in the elderly population is tied more closely to decreasing fertility rates than to increased survival.
Treating the Consequences of Primary Aging

Even if the mechanisms underlying primary aging are not modifiable, the consequences are sometimes amenable to treatment. An example of this is presbyopia. For a 60-yearold, the risk of being unable to focus sharply on near objects is 100%12 (ie, it occurs in everyone) and there is no known means of preventing presbyopia (ie, it is inevitable). Because presbyopia has such a detrimental impact on quality of life, most individuals elect to “treat” the resulting impairment in vision with corrective lenses. However, the physiologic changes that precipitate the decline in reading vision (ie, the aging process) remain unchanged.

In contrast, other primary aging changes occur with no attempt to alter the consequences. An example is the decline in maximal heart rate. The association with age is so well characterized that maximal heart rate is predicted solely from age (ie, maximal heart rate = 220 minus age). One consequence of a decrease in maximal heart rate is the decline in exercise capacity. In fact, the decrease in maximal heart rate explains a large portion of the decline in maximal aerobic power with aging. Although exercise training can generate an increase in maximal aerobic power, it does not do so by increasing maximal heart rate. The fact that maximal heart rate declines similarly with aging in both sedentary and highly trained individuals is taken as evidence that it is a consequence of primary, rather than secondary, aging.13

Menopause and Primary Aging

Because the menopausal transition is a post-maturational, age-triggered process that occurs in all women, it meets the definition of primary aging. As discussed in the previous section, certain consequences of primary aging are routinely treated (eg, presbyopia), whereas others are essentially ignored and accepted as being inevitable (eg, decline in maximal heart rate). Two of the most prominent consequences of menopause— the decline in bone mineral density (BMD) and the increase in vasomotor symptoms—are additional examples of consequences of primary aging that are commonly treated. Extensive research on mechanisms underlying the menopausal decline in BMD has led to the development of effective therapeutic strategies—both pharmacologic (eg, estrogen-based hormone therapy [HT], bisphosphonates, parathyroid hormone) and dietary (eg, calcium and vitamin D)—for attenuating bone loss and preventing osteoporotic fractures.14 Bisphosphonate therapy has been found to increase and then maintain BMD for several years. However, whether this therapeutic approach can maintain BMD indefinitely and prevent skeletal aging is not known. In contrast, the mechanisms underlying menopausal vasomotor dysfunction remain poorly understood, and the only therapy for which there is solid evidence of efficacy is estrogen-based HT.15

Are there other consequences of menopause for which “treatment” should be considered? This question cannot be answered because there is a paucity of knowledge regarding the relationship between aging and the withdrawal of ovarian hormones, particularly with respect to disease risk.16 The lack of knowledge regarding the biology of the menopausal transition reflects the challenges posed by studying a process that occurs over several years, with consequences that may persist for many more years. At a minimum, the protracted nature of the menopausal transition makes it difficult to isolate the effects of menopause from those of aging. It becomes increasingly more challenging when the goal is to understand the consequences of changes in multiple hormones and the numerous organ systems that may be affected.

Figure 3

Figure 3. Effects of estrogen-based HT on body weight from large, randomized controlled trials, and smaller randomized (but not necessarily placebo-controlled) trials. *P < 0.05.

Menopause-Related Fat Gain: A Target for Anti-Aging Medicine?

Although there is a lack of knowledge about the physiologic changes that occur during the menopausal transition, randomized controlled trials of estrogen-based HT have provided some intriguing insights into the potential metabolic actions of estrogens in postmenopausal women. One example is the regulation of body weight by estrogens. The longstanding dogma, in both the medical and lay communities, has been that estrogen-based HT causes weight gain. However, the available evidence indicates that just the opposite is true. Figure 3 illustrates the changes in body weight that occurred in several large randomized trials of estrogen-based HT.17-22 Across all of these studies, the average gain in weight was 20%- 30% less in women on HT than in those not on therapy. In studies that measured changes in body composition and/or fat distribution, the attenuation of weight gain tended to reflect less of an increase in fat mass18,23-25 and, more specifically, less accumulation of fat in the abdominal region.18,19,22,23,25,26 It remains uncertain as to whether estrogens and/or progestins mediate the effects on body composition that have been observed. However, based on results from trials that included estrogenonly and estrogen-plus-progestin treatment arms,19,20,22 the responses appear to be estrogen-mediated.

Figure 4

Figure 4. Resting metabolic rate (lavendar bars) and serum estradiol (E2) levels (pg/mL) (red bars) in premenopausal women during the mid-luteal and early follicular phases of the menstrual cycle, and in response to 6 days of gonadotropin-releasing hormone antagonist (GnRHANT) therapy.

Adapted from Day et al.28

The likelihood that menopausal withdrawal of estrogen promotes fat gain is bolstered by observations that the suppression of estrogen in young women has such effects. Women on gonadotropin-releasing hormone agonist (GnRHANT) therapy for 4–6 months gain 1–2 kg of fat, with a disproportionate gain in central body regions; they also lose lean mass.27,28 The mechanisms by which estrogens regulate energy balance and body weight remain largely unknown, but there is some evidence that estrogens influence resting metabolic rate. In a recent study from the authors’ laboratory, 29 premenopausal women underwent assessments of resting metabolic rate in the mid-luteal (highestradiol) and early-follicular (low-estradiol) phases of the menstrual cycle, and after 6 days of GnRHANT treatment (further suppression of estradiol). As shown in Figure 4, the resting metabolic rate was highest when serum estradiol levels were elevated, and lowest when estradiol was suppressed; the decrease in resting metabolic rate across these conditions was about 70 kcal/d. If such a reduction in resting metabolic rate were not compensated for by a decrease in food intake or an increase in exercise, it would be predicted to result in a fat gain of about 1.5 kg in 6 months, an amount similar to the fat gain after 4-6 months of sex hormone suppression with GnRHANT therapy.

Should menopause-related fat gain be considered a target for therapy? It is well known that increased adiposity, particularly in the abdominal region, is a potent risk factor for cardiovascular disease and type 2 diabetes mellitus. However, the Women’s Health Inititative (WHI) trials have demonstrated that the benefits of oral estrogen therapy on body weight and adiposity do not necessarily translate into reduced disease risk. Because cardiovascular disease and type 2 diabetes mellitus have many common risk factors and often coexist, the findings from the WHI trials and the Heart and Estrogen/ progestin Replacement Study (HERS)—that HT reduces the risk of type 2 diabetes mellitus17,21 but not cardiovascular disease—are perplexing. Such paradoxes serve as a reminder that there is much to learn about the physiologic consequences of the menopausal transition and the development of safe and effective therapeutic strategies to ameliorate those consequences.

Recent prospective cohort study found that later age at menopause was associated with an age-adjusted decrease in total mortality risk.
Menopause, Survival, and Longevity

Another area of interest is whether menopause influences survival or longevity. A recent prospective cohort study followed (for 17 years) 12,134 Dutch women who were not on HT and found that later age at menopause was associated with an age-adjusted decrease in total mortality risk.30 For every 1-year delay in the onset of menopause, there was a 2% decrease in mortality risk that persisted after adjustment for potential confounders such as body mass, smoking and hypertension. Although the authors interpreted this as an increase in “life span” among women with later onset of cessation of ovarian function, it is not possible to determine whether this represents an increase in average life span, maximal life span, or both. Until valid biomarkers of primary aging are discovered, it will not be possible to make such distinctions in studies of humans. However, there is evidence that the manipulation of ovarian function influences life expectancy in mice.31 Transplantation of young (2-month-old) ovaries into older mice (11 months old) that had been ovariectomized at 3 weeks of age significantly increased average, but not maximal, life span when compared with either shamtransplanted or intact control mice. Additional studies in mice and other species are needed to corroborate these findings, and to determine the mechanisms underlying potential benefits of a delayed onset of menopause on survival and/ or longevity.

There is optimism that anti-aging medicine for humans will one day be evidence-based.
Conclusions

There is no doubt that anti-aging strategies, most notably caloric restriction, have proven to be effective in extending average and maximal life span in many species of animals. Because of the uniformity of the findings across species, it might be logical to assume that such strategies would also be effective in humans. But it would be just that—an unproven assumption—because the key piece of evidence for an anti-aging effect, the extension of maximal life span, is lacking for humans.

Despite the fact that anti-aging claims are hype, it is important to understand that some of the products and strategies being promoted for their potential anti-aging effects may, indeed, have benefits on health promotion and disease prevention. For example, the Web site of the American Academy of Anti-aging Medicine (www.worldhealth.net) suggests that you have experienced anti-aging medicine if you participate in regular exercise. Although exercise has not been proven to increase maximal life span, it is undeniably a sound practice for promoting good health.

The field of anti-aging science is advancing rapidly and there is optimism that anti-aging medicine for humans will one day be evidencebased. The results of HERS and the WHI trials reinforce the need for rigorous scientific investigation prior to broad adaptation of possible anti-aging strategies. HT had been touted as an “anti-aging” therapy based solely on observational data, but randomized controlled trials32,33 found that the benefits of HT did not outweigh the risks when given to older women for chronic disease prevention. Future research endeavors should not abandon inquiry into the potential anti-aging properties of HT or ovarian replacement (transplantation) therapies. Research efforts should focus on understanding the physiologic mechanisms behind menopause and its consequences. Such investigations are essential for the development of safe and effective strategies to minimize the negative consequences of menopause and, perhaps, prolong not only quality, but also the quantity, of women’s lives.

Wendy M. Kohrt, PhD, is Professor of Medicine in the Division of Geriatric Medicine; and Wendolyn S. Gozansky, MD, MPH, is Assistant Professor in the Division of Geriatrics, University of Colorado at Denver and Health Sciences Center, Denver, CO.

Dr. Kohrt and Dr. Gozansky report no potential conflicts related to the content of this article.

Submitted: January 24, 2006. Accepted March 2, 2006.

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