56: Assessing Antiaging Therapies for Older Adults

Most older Americans expect to live longer and more independently than previous generations, and many seek to be involved in their own health through diet, exercise, and participation in health care decision-making. The combination of the desire to be involved in health care, a recent surge in the ready access to information, the wish to promote health and avoid aging, and interest in new ways to approach problems have created tremendous interest in therapies designed to prevent or retard aging.

Knowledge about the biologic mechanisms involved in aging and the physiologic changes associated with aging provides a rational basis for the quest for antiaging therapies. An antiaging therapy could act by 1 or more of the following 3 mechanisms:

1. Modifying the biochemical and molecular events that cause aging.

2. Correcting physiologic changes that cause signs or symptoms associated with aging.

3. Lessening the susceptibility of an individual to diseases associated with aging.

Practices that act through the third mechanism (eg, colonoscopy, blood pressure reduction, cholesterol reduction, and other practices that aim to prevent age-associated diseases) are common in medical practice and are dealt with elsewhere in this book.

The pursuit of antiaging therapeutics is not without controversy and debate. There are several reasons for this. Most importantly, it has been difficult to come to an agreement on the definition of antiaging, with definitions running the gamut from a simple cosmetic procedure to reduce visible signs of aging to a quest for complete reversal of the body’s aging process. Because there are many ways to define antiaging therapeutics, patients and practitioners may have different expectations of therapeutic results. Discussions on definitions and expectations needs to take place before any therapeutic alliance can be successfully built. For our purposes, we exclude aesthetic procedures and focus mainly on treatments aimed at reversing or slowing pathologic aging.

With this in mind, it brings up the second area of controversy. When discussing aging, many cannot agree on what is “normal” aging and what is “pathologic” aging, nor on whether it is ethical to intervene in the aging process at all. Furthermore, extending life may not be a noble goal if the quality of that life is poor. It has been considered “a true failure” of antiaging medicine to significantly prolong a life that is full of functional disability.

Historically, there has been a lack of standardization of therapeutics, no established standard of care, little clinical research, and lack of training or certification of antiaging practitioners. To help with these issues the World Society of Interdisciplinary of Anti-Aging Medicine (WOSIAM) offers international education events and funds research projects to improve the scientific rigor of the antiaging field. In the United States, the American Academy of Anti-Aging Medicine (A4M) offers mini-fellowship and certification opportunities in the categories of regenerative medicine, aesthetics, integrative cancer treatment, and stem cell therapy. Despite these efforts, caution needs to be exercised when using or prescribing antiaging therapies, especially those that are marketed as supplements, which do not undergo rigorous efficacy or safety testing.

A final consideration in the antiaging debate is one of cost. The price of these therapies can be high and is often not covered by insurance. Older patients need to be warned against sacrificing better-proven pharmaceuticals or nonpharmacologic therapies for more expensive, but provocative, antiaging interventions.

Antioxidants: Vitamin A, Vitamin C, Vitamin E, Beta-Carotene

Aging has long been hypothesized to be partly caused by oxidative stress. Many cellular processes produce reactive oxygen or reactive nitrogen species, which via a free radical mechanism can chemically modify and hence damage proteins, DNA, and lipids. Aged animals show accumulation of oxidative damage, with markers of oxidative damage being elevated 2–3-fold between reproductive maturity and death. Experimental studies in animals have supported a role for oxidative damage in aging.

In humans, oxidative damage may contribute to atherosclerosis, cancer, Parkinson disease, and Alzheimer disease. The antioxidants most commonly used in people are vitamin A and its precursor beta-carotene, vitamin C, and vitamin E. When vitamins are used as antiaging therapies, they are often used in doses that are higher than the replacement doses that are appropriate for vitamin deficiencies. Early epidemiologic data suggested a reduction in mortality and prevention of diseases, such as cardiovascular and cerebrovascular disease, with dietary and nondietary vitamin intake. This caused great excitement among the public and researchers conducted multiple randomized controlled trials to further examine the effects of antioxidant supplementation.

Unfortunately, results of large population-based studies and randomized trials not only fail to show a benefit of antioxidant treatments for most conditions, but give evidence of harm with long-term supplementation with vitamins E, A, beta-carotene, and possibly α-lipoic acid (ALA). How should the largely negative results of randomized studies of the antioxidant vitamins be interpreted? Many theories exist, but the most recent evidence suggests that antioxidants reverse the beneficial effects of oxidation without blocking the harmful effects. Exercise is known to reduce blood pressure, improve insulin sensitivity and enhance nitric oxide availability at the endothelium. In trial subjects who took antioxidants prior to or after exercise, these beneficial effects were ameliorated. Even more alarming are the cumulative data of antioxidant and vitamin supplementation on mortality and longevity in large population studies. The most recent Cochrane review update found that long-term supplementation with vitamin E, beta-carotene, or vitamin A was associated with a significantly increased risk of mortality compared to controls. Vitamin C or selenium was not associated with increased mortality; however, the studies failed to show significant benefit of supplementation with these substances. In conclusion, the aggregated data of antioxidant supplementation indicates limited benefit with evidence of harm for all populations. Dietary intake of vitamins and antioxidants as part of an active lifestyle may, however, result in reduced signs and symptoms of aging.

Despite overwhelming evidence against the routine use of antioxidants for prevention or treatment of inflammatory conditions, vitamins A, E, and C have been shown to be beneficial in the treatment of 1 common geriatric condition: age-related macular degeneration. In patients with preexisting age-related macular degeneration, a combination of antioxidants decreased progression to advanced macular degeneration in the Age-Related Eye Disease Study. In contrast, 6 years of antioxidant supplementation had no effect on the incidence of age-related macular degeneration in smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial.

α-Lipoic Acid

ALA is considered to be a potent antioxidant because it can oxidize and regenerate other antioxidants, such as vitamin E and glutathione. It has been studied at dosages of 600 mg, 1200 mg, and 1800 mg a day, with the best-tolerated dose being 600 mg. Described side effects include headache, tingling or a “pins and needles” sensation, skin rash, or muscle cramps. In addition, ALA may lower blood glucose and alter thyroid hormone levels so these should be monitored in patients taking this supplement.

Several studies have demonstrated the effectiveness of ALA for the treatment of neuropathy, particularly in diabetics. Early evidence suggests that ALA may have a role in retarding the progression of neurodegenerative diseases, such as multiple sclerosis and Alzheimer dementia. However, the use of ALA for the latter reasons cannot be widely recommended until more rigorous studies can be performed.

Hormone Replacement (Table 56–1)

Growth hormone—

Growth hormone (GH) secretion (measured by serum insulin-like growth factor [IGF]-1, levels) reaches its maximum during the growth spurt accompanying puberty before beginning a steady decline with age in both men and women. Much of this decline is a result of a selective reduction in the nocturnal pulsatile secretion of GH. Some of the changes associated with aging are reminiscent of those seen in adult patients with frank GH deficiency, such as reduction in lean body mass, increase in body fat (especially abdominal obesity), decrease in muscular strength, and difficulty with cognitive functioning. As a result, there has been much interest in supplementing GH in older adults.

Most GH studies have titrated the doses to produce IGF levels in the low- to mid-normal range seen in young adults. Treatment with GH increases lean body mass, skin thickness, and vertebral bone mineral density and decreases fat mass, all more pronounced in older men than women. GH-induced increases in muscle mass were not accompanied by increases in physical strength, stamina, or functional status, however. Although widely touted by antiaging practitioners, GH for antiaging therapy is not an approved indication for use, and the effects of exogenous GH on cognition and memory have not been well studied. Side effects of GH include fluid retention, arthralgias, gynecomastia, glucose intolerance, headache, and carpal tunnel syndrome. More seriously is the possible increased risk of cancer related to the cell growth stimulant properties of IGF-1. Additionally, emerging evidence indicates that GH and IGF-1 signaling shorten, rather than prolong, life span. In summary, the limited benefits of GH, its high cost, and potential long-term risks weigh against the use of GH in older adults, and its use should be discouraged.

Testosterone—

In men, testosterone levels peak during late adolescence then decrease by roughly 0.5% to 1% per year. Hypogonadism is present in ≤10% of men age 50–69 years and in ≤30% of men 70 years of age and older. In parallel with the declines in testosterone levels, aging men experience decreases in muscle mass and strength, bone mass, sexual interest and potency, and cognitive function, and increases in fat mass. It is unknown, however, whether these changes can be attributed to declines in testosterone levels. Hypogonadism has also been associated with higher risk of type 2 diabetes mellitus, metabolic syndrome, cardiovascular disease, anemia, and osteoporosis.

Several studies have reported on the supplementation of testosterone in men with low testosterone levels via either injections or a scrotal patch (see Table 56–1). Most studies have shown increases in lean body mass and bone mineral density, and decreases in fat mass. Accompanying the increase in muscle mass has been an increase in either upper- or lower-extremity strength. However, only 1 experimental study has shown an increase in functioning with testosterone replacement. Sexual function has shown mixed results with supplementation, and men with lower initial testosterone levels tend to have the most significant improvements. Three studies suggested small improvements in cognitive function in middle-aged men receiving testosterone, but further data fail to show a benefit of testosterone replacement in improving cognitive impairment.

Concerns have been raised regarding potential effects of prostate disease, cardiovascular risk, and erythrocytosis. Testosterone supplementation does not worsen prostatic hypertrophy, and it is unknown whether it increases risk of prostate cancer. A meta-analysis failed to confirm the risk of adverse cardiovascular events with the use of testosterone for hypogonadism. In fact, testosterone therapy decreases angina, causes coronary artery dilation, and decreases ST depression during exercise stress testing. Administration of testosterone leads to no change or a slight decrease in total cholesterol and low-density lipoprotein cholesterol combined with no change or a slight decrease in high-density lipoprotein cholesterol. Erythrocytosis can be seen in up to 25% of patients receiving treatment. This can be easily managed by either decreasing the dose of testosterone given or using phlebotomy.

Hypogonadism can be detected by the Androgen Deficiency in Aging Males Questionnaire followed by direct measurement of a bioavailable testosterone. This questionnaire also identifies patients with depression, which should be treated before replacement therapy is considered.

Testosterone levels decline from age 20 years to menopause in females. Levels then stay constant through the menopausal transition and then increase after menopause. Estrogen therapy increases sex hormone-binding globulin and, therefore, decreases free testosterone levels. Testosterone replacement therapy in menopausal women improves libido and increases bone mineral density and muscle mass (see Table 56–1). Further studies are required to determine the role of testosterone in women as an anti-aging hormone.

Dehydroepiandrosterone—

Dehydroepiandrosterone (DHEA) and its sulfated derivative, DHEAS, are synthesized by the adrenal cortex and are the most abundant steroid hormones in young adults. After age 30 years, serum levels of DHEA decline approximately 2% per year. As a result, in 80-year-olds, DHEA levels are 10% to 20% of levels in young adults. Low levels of DHEA correlate with an increased risk of breast cancer in premenopausal women, an increase in cardiovascular disease and mortality in older men, a lower bone mineral density in perimenopausal women, a higher likelihood of depressed mood in older women, and a higher likelihood of cognitive decline in both sexes.

Several short-term studies in older persons have supplemented DHEA levels to those seen in young adults with 50–100 mg/day doses (see Table 56–1). In women, DHEA supplementation led to an improved sense of well-being, increased bone mineral density, and, in women older than age 70 years, increased sexual interest and satisfaction. In men, DHEA supplementation has led to improved well-being, increased strength, and decreased fat mass. In both sexes, DHEA supplementation improved skin thickness, hydration, sebum production, and pigmentation. Adverse effects on lipid profile and glycemic control were not seen.

In conclusion, short-term DHEA supplementation appears safe, but the effects have been modest. Routine supplementation is not recommended until long-term studies have demonstrated the safety and benefits of DHEA supplementation.

Bioidentical hormones—

After the many disappointing trials with synthetic hormone replacement, antiaging practitioners began to use individually compounded formulations called bioidentical hormones. Compounded bioidentical hormone therapy (CBHT) is the tailoring of plant-derived chemicals identical to the body’s natural hormone based on the needs of each individual patient. Typically, this is done by measuring the levels of hormones in a patient’s saliva and then compounding the hormones to replete the deficiencies observed. The use of CBHT became widespread after the frightening results of the Women’s Health Initiative studies of synthetic estrogen replacement. It is thought to be safer, more efficacious, and better tolerated than the standardized hormones. These formulations are non-FDA approved and therefore not tightly regulated as pharmaceuticals. Furthermore, there is no evidence that levels of hormone in saliva can be correlated to menopausal symptoms and this practice is not recommended for use as monitoring or titrating any hormonal treatments. Finally, wide variations in active ingredients with the paucity of data supporting the beneficial claims of CBHT should cause patients and practitioners to strongly reconsider the use of this form of treatment until more rigorous safety and efficacy data become available.

In conclusion, many antiaging therapies have been developed and used in older patients. Few have resulted in significant advantage and the few benefits are often outweighed by the potential harms. In the end, exercise and a regular diet with plenty of fish and fresh fruits and vegetables are the only proven antiaging measures.