Ligia J. Dominguez, John E. Morley, Mario Barbagallo
Antiaging Medicine
Attempts to reverse the aging process stretch back to the time when Adam and Eve were expelled from the Garden of Eden. Since then, wise sages and charlatans have made numerous pronouncements on what the populace should do to extend their life span. In most cases, this has required that those who wish to benefit pay exorbitant sums of money to those who have developed the magical elixir of longevity. This has led to the concept that antiaging medicine is a scam.
On the other hand, we have seen a remarkable extension in longevity over the last century. In the United States, at the start of the twentieth century, half of the population was dead by 50 years of age, whereas by the dawn of the twenty-first century, half of women lived to older than 80 years. These dramatic changes were brought about by public health measures such as improved sanitation, greatly improved and available food supply, introduction of antibiotics, vaccinations, improved care of pregnant women and the birthing process, enhanced surgical techniques and, to a lesser extent, a variety of new medications introduced in the second half of the twentieth century. One needs also to give credit to the improved work environment and decrease in excessive manual labor.
The secret to longevity appears often to follow a healthy lifestyle and avoiding excesses. In the thirteenth century, Friar Roger Bacon in England wrote a best-selling antiaging book.1 His secrets to longevity were as follows:
George Valiant, a Harvard psychiatrist, studied inner city individuals and Harvard graduates from their mid-50s.2 His studies suggested that aging successfully occurred in those individuals who did the following:
The Norfolk-EPIC study found that persons who followed four simple lifestyle habits were physiologically 14 years younger than those who did none of them.3 The four magical ingredients that produced this greatly improved outcome were as follows:
A higher score of adherence to the modifiable lifestyle factors described in the Northfolk-EPIC study was significantly associated with a higher quality of life.4
Because long-lived populations tend to come from places such as Japan, Macau, and Hong Kong, where there is a high preponderance of fish in the diet, it is probably reasonable to suggest that fatty fish intake, rich in eicosahexanoic and docosahexaenoic acids, should be included in a diet of a person who wishes to live for a long time.5
Brief History of Antiaging Medicine
In ancient Egypt, the olive leaf was used to improve beauty and extend life.6 This is paralleled in the twenty-first century by the recognition that the Mediterranean diet is associated with longer and healthier lives. Ayurvedic medicine in India developed specific diets, lifestyle practices, and herbs that would extend life.
The search for the Fountain of Youth was first made famous by Ponce de Leon, the Governor of Puerto Rico, who went searching for Bimini, where it was believed that there was a fountain of youth. Instead, he discovered Florida, a modern day haven for retirees in the United States. In 1933, in the novel Lost Horizon, James Hilton created a paradise where no one got older, called Shangri-La. So riveting was this concept for the public that a number of expeditions set out to try and find this paradise in the Himalayan Mountains. Nobel Prize winner (for physiology or medicine) Elie Metchnikoff mistakenly believed that Bulgarians lived extremely long lives, and this was due to yogurt. This created an antiaging cult based on eating yogurt.
The modern quasiscientific approach to antiaging medicine was expressed in the book Life Extension by Durk Pearson and Sandy Shaw, published in 1982.7 In an 858-page volume, they provided detailed accounts of animal experiments that increased longevity, claiming that their book was “for anyone, regardless of age, who seeks greater youthfulness-starting right now.” This book opened the door to multiple others where snippets of animal science were fed to the public, suggesting that these findings should be used by humans who wished to live a long life.
The American Academy of Anti-Aging Medicine (A4M) was founded in 1992 by Dr. Ronald Klatz and Dr. Robert Goldman. Its avowed purpose is to advance “technology to detect, prevent and treat aging related disease and promote research into methods to retard and optimize the human aging process.” It provides a number of certifications for physicians in antiaging medicine. It claims to have more than 26,000 members from more than 120 countries (www.worldhealth.net). It produces the International Journal of Anti-Aging Medicine.
The Life Extension Foundation, founded by Saul Kent in 1980, is based in Florida and produces the monthly magazine, Life Extension. Its readership is thought to be around 350,000. It also sells dietary supplements by mail order. Two more mainstream physicians whose books have promoted antiaging philosophies are Andrew Weil and Deepak Chopra.
Aubrey De Grey, a Cambridge-educated scientist, has developed a theory called “Strategies for Engineered Negligible Senescence (SENS).” He has been extraordinarily successful at promoting his theories to the lay public. He suggested that there are seven types of aging damage, which are readily open to treatment:
The De Grey SENS proposal has been widely criticized by gerontologists: “Each one of the specific proposals that comprise the SENS agenda is, at our present stage of ignorance, exceptionally optimistic,” and it “will take decades of hard work, if [these proposals] ever prove to be useful.”8 His approach is a classic example of the quasiscientific methods that have been used to create antiaging literature.
The most extensive criticism of the modern antiaging medicine came in 2002 from Olshansky and colleagues.9 The article stated that:
…no currently marketed intervention has yet been proved to slow, stop or reverse human aging…. The entrepreneurs, physicians and other health care practitioners who make these claims are taking advantage of consumers who cannot easily distinguish between the hype and reality of interventions designed to influence the aging process and age-related diseases.
Caloric Restriction
In 1934, Mary Crowell and Clive McKay at Cornell University published a series of experiments showing that limiting the food intake of laboratory rats (dietary restriction) resulted in prolongation of their lives.10 Subsequently, studies in some species have shown that caloric restriction (CR) results in a prolongation of lives. Some studies have suggested that caloric restriction needs to be started in younger animals, and it fails to prolong life in older animals.11
Studies in monkeys have suggested that dietary restriction improves the metabolic profile (glucose, cholesterol) in these animals12 and may attenuate Alzheimer-like amyloid changes in their brains.13 However, these animals also showed a loss of bone and an increased propensity to develop hip fractures. Two studies addressing the effect of CR on nonhuman primates have reported contrasting results. The University of Wisconsin-Madison (UWM) study showed prolonged life span under CR,14 but a National Institute of Aging (NIA) study did not.15 A possible explanation may lie in the diet composition—the high sugar concentration in the ad lib diet of the control group in the UWM study14 may have led to a shortened life span compared to the group under CR. Conversely, the ad lib healthier diet in the NIA study15 led to longer life span in the control group without conferring additional benefit for those under CR.
Numerous theories exist about why CR may enhance longevity. The hormesis theory suggests that CR represents a low level of stress, which allows the animal to develop enhanced defenses that slow the aging process. It has also been suggested that CR reduces oxidative damage, enhances insulin sensitivity, and decreases tissue glycation. CR reduces the release of growth factors such as growth hormone, insulin, and insulin-like growth factor 1 (IGF-1), which have been associated to accelerated aging and increased mortality in diverse organisms.16 The silent information regulator (Sir) gene is upregulated by CR in yeast and in mammals. However, the role of Sir genes in longevity is controversial. For example, the polyphenol resveratrol found in grapes and in red wine has been shown to prolong the life span of mice fed a high-fat diet, flies, and worms, mimicking CR by a suggested interaction with sirtuins.17 However, recent data have indicated that the degree of life span extension in worms and flies on resveratrol supplementation may be shorter than previously reported.18
The Caloric Restriction Society was founded in 1984 by Roy and Lisa Walford and Brian Delaney. Members of this society practice CR to varying degrees. Studies of members of this society have suggested that they have lower blood pressure, glucose, and cholesterol values.19 The National Institutes of Health has funded a number of short-term studies to determine the utility of CR in middle-aged persons. The enthusiasm for CR in older persons has been tempered by multiple studies in persons older than 60 years showing that weight loss is associated with increased institutionalization, increased mortality, and increased hip fracture.20 In younger populations, prolonged CR may decrease fertility and libido, lead to wound-healing problems, amenorrhea, osteoporosis, and decreased potential to combat infections and be harmful in lean humans.16
At present, there are a number of CR diets that are advertised to the public as a method for life prolongation. The CRON diet (caloric restriction with optimal nutrition) was developed by Walford and Delaney. It was based on the research conducted in the Biosphere. In general, this diet recommends a 20% CR based on determining one’s basal metabolic rate. The Okinawa diet is a low-calorie, nutrient-rich diet based on the original diet of people living on the Japanese island of Okinawa (Ryukyu Islands). Its popularity is based on the large number of centenarians who used to live in the Ogimi Village on Okinawa. The diet is calorie-restricted compared with the Japanese diet. It predominantly consists of vegetables (especially sweet potatoes), a half-serving of fish per day, legumes, and soy. It is low in meat, eggs, and dairy products. The New Longevity Diet of Henry Mallek represents a popularization of other longevity diets. It needs to be recognized that none of these diets has been proven to extend longevity. It is interesting to note that Roy Walford, a major proponent of dietary restriction, died at 79 years of age of amyotrophic lateral sclerosis (ALS). Animal studies have suggested that CR is especially bad for animals with ALS.
Exercise
Exercise in moderation appears to be a cornerstone of longevity. Mice with an excess of phosphoenolpyruvate carboxykinase (PEPCK-C) in their skeletal muscle are more active than their controls and can run for 5 km at a speed of 20 m/min compared with 0.2 km for control mice.21 These mice live longer than controls, and females remain reproductively active until 35 months of age.
Observational studies in humans have strongly suggested that those who are physically active live longer. In a study of 70- to 80-year-olds, those with a higher total energy expenditure lived longer than those with less energy expenditure.22 A major factor in enhancing energy expenditure was stair climbing. Interestingly, long-lived Okinawan people usually combine an above-average amount of daily exercise with a below-average food intake.23
Fries found that older runners compared with sedentary older adults tended to become disabled 13 years later.24 The LIFE pilot study has shown that a structured physical activity program significantly improves functional performance.25 Walking speed is associated with decreased disability. Physical activity is associated with decreased dysphoria. Persons aged 50 years of age who exercise regularly are less liable to develop Alzheimer disease as they age.26 Regular physical activity reduces the rate of deterioration in persons with dementia.27 CR and exercise seem to stimulate diverse molecular pathways, but both induce autophagy28 (from the Greek auto-, “self,” and phagein, “to eat”), a catabolic process that degrades defective cellular components for recycling.
The Hormonal Fountain of Youth
Since the publication of Wilson’s Feminine Forever in the 1950s, touting the role of estrogen to maintain youth, there has been increasing interest in the antiaging effects of hormones.5 Previously, toward the end of the nineteenth century, Brown-Séquard had suggested that a testicular extract produces remarkable antiaging effects. It is unlikely that this extract had any testosterone, demonstrating the powerful effect of the placebo. This led to a large number of wealthy men in Europe and the United States receiving monkey testicular implants, which were claimed to rejuvenate them. Brinkley, in the United States, pioneered a series of goat gland extracts, which were equally ineffective but made him a rich man. Subsequently, almost every hormone has been touted to produce antiaging effects. In general, it can be said that the more enthusiasm that the lay public has expressed in these hormones, the less likely they are to be effective.
Vitamin D (25[OH] vitamin D) levels decline with aging.29 Low levels of vitamin D have been associated with increased mortality.30 In persons with 25(OH) vitamin D levels below 30 ng/mL, replacement has been demonstrated to enhance function, decrease falls, and decrease hip fracture.31 Vitamin D replacement of more than 625 IU/day in a meta-analysis led to decreased mortality.32 It is now generally accepted that older adults should get regular skin exposure (15 to 30 min/day) without sun block or should take 800 to 1000 IU of vitamin D/day. All persons older than 70 years should have their 25(OH) vitamin D levels measured at least annually (preferably in winter) because they may need higher doses of vitamin D to raise their level above 30 ng/mL.
Studies on men with low testosterone levels have shown conflicting results concerning whether low testosterone is associated with an increased mortality rate (Table 27-1).33–37 Overall, testosterone should be considered a quality of life drug and not a life extension drug. The major effects of testosterone are to enhance libido and sexual function.38 Testosterone also increases muscle and bone mass and muscle strength in hypogonadal males.39 No studies have evaluated its effect on hip fracture. Testosterone also increases visuospatial cognition.40 Studies have suggested that testosterone may be cardioprotective.41 Despite multiple potential positive effects of testosterone, recommendations for its use in older men, from the International Society for the Study of the Aging Male, are that it should only be given to men who have symptoms and are biochemically hypogonadal.42 Either the Aging Male Survey or the St. Louis University Androgen Deficiency in the Aging Male (ADAM) questionnaire43,44 can be used to screen for symptoms (Table 27-2).
TABLE 27-1
Does Low Testosterone Predict Death?
| Author, Year | Population | Predicts Death? |
| Morley et al, 199633 | Healthy men in New Mexico,14-yr follow-up | No |
| Shores et al, 200634 | Veteran population, 8-yr follow-up | Yes |
| Araujo et al, 200735 | Massachusetts Male Aging Study | No |
| Khaw et al, 200737 | Europe | Yes |
| Laughlin et al, 200836 | Rancho Bernardo, CA, 11.8-yr follow-up | Yes |
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