Anti-aging medicine: pitfalls and hopes

Abstract

Since the beginnings of time humans have searched for a fountain of youth. This has led to many extravagant claims which have been highly profitable for their proponents. This area has become known as anti-aging medicine and has deservedly been frowned upon by the medical establishment. On the other hand, in the last decades dramatic advances in our understanding of the aging process have come from studies in worms, flies and mice. This article reviews some of these advances and places the extravagant claims of anti-aging medicine in perspective. We conclude that a balanced diet of moderate proportions and exercise remain today the only proven fountain of youth.

Keywords:

• Anti-aging
• aging
• lifestyle
• stem cells
• physical exercise
• hormones

‘Cowards die many times before their deaths, the valiant never taste of death but once. Of all the wonders that I have heard, it seems to me most strange that men should fear, seeing that death, a necessary end, will come when it will come’.

William Shakespeare (1564-1616)

“Julius Caesar” Act 2, Scene 2

Introduction

Anti-aging medicine is a subject, and especially a term, surrounded with controversy and also with profound societal implications. The history of anti-aging therapies and research is full of confidence tricks, pseudoscience and charlatanry, which has repeatedly given a bad name to the whole field. Claims for miraculous cures and dreams for extremely long lifespan have been present since ancient times and are still prevalent today [1],[2]. On the other hand, several investigators in the fields of gerontology and geriatrics are making genuine attempts to develop strategies for the prevention and treatment of age-related diseases, functional decline and disability.

Aging of the world populations represents one of the most remarkable success stories of medicine and of humankind; but it is also a source of various challenges. Human life expectancy around the world has increased steadily for nearly 200 years and it is expected to continue to do so. During the last century the increase was of about 2 years every decade; driven in the first decades by improvements in sanitation, housing and education, with a steady decline in early and mid-life mortality mostly due to infections. The continuing increase in life expectancy in the latter half of the past century was almost entirely attributable to a decline in late-life mortality, related to medical advances such as the treatment of hypertension and improved socioeconomic conditions [3]. The remarkable effect of societal conditions has been shown by the rapid increase in lifespan when East Germany was reunited after the fall of the Berlin Wall [4] and the increased deaths in older males during the transition of Hong Kong back to China.

Longevity, however, is of little value in the absence of quality of life. The imminent rapid increase in numbers of aging adults will significantly impact society and the health systems in the coming years. It reveals the limits of the management of an aging population with multiple co-morbidities for which the health systems are not prepared. Hence, the search for ways to prolong health expectancy with effective prevention of disability is a primary goal in medicine. The imperative is to allow older adults to maintain their independence and health for as long as possible and to prevent the harm of chronic diseases and disabilities or the development of frailty. Even if disability trend has slowed down in older populations according to data from the US [5] and Europe [6], the number of disabled people remains remarkably high: about 7 million of disabled persons in the US in 1999 [5]. The cost of care for the disabled population is about 10-fold that of non-disabled people [5], hence, there are not only important humanitarian, but also economic reasons to improve quality of life during aging.

Regarding longevity and disability, there are three relevant questions:

1. Can death be delayed? In several animal models, genetic manipulation [7],[8] and caloric restriction (CR) [9] have shown to increase the lifespan respect to their control littermates fed ad libitum, but there is little evidence that this can be translated to humans [10]. However, several studies on dietary patterns [11],[12] have shown that prudent diets, such as the Mediterranean diet, decrease total mortality and mortality-associated with cardiovascular disease and cancer, hence, to increase longevity. On the other hand, high total energy expenditure in 70- to 80-year olds leads to increased longevity [13], with climbing stairs being the major factor that resulted in increased total energy expenditure.

2. Can the course of disability and functional dependence be reversed? Although disability and functional dependence can be reversible to some extent, the functional reserve may become so depleted that no further restoration of a normal function is possible but the ‘point of no return’ has not yet been identified. The development of ‘exoskeletons’ (lifesuits) suggests that technology will continue to push that point further away [14].

3. Can disability and functional dependence be delayed? This is probably the area of geriatrics that has been investigated most intensely. Several studies have shown that the onset of disease and disability may be delayed by adopting a healthy lifestyle, by managing chronic conditions such as diabetes and hypertension, and by detection and treatment of cancer at an early stage. Recent studies on physical exercise at midlife delaying the onset of dementia in late life and similar effects for mental exercise further support this concept. The prolongation of the ‘active life expectancy’ of the population suggests that disease and disability may indeed be delayed. Compression of morbidity and of disability rather than prolongation of survival may be one of the main goals of disease management in the older patient [15].

What is anti-aging medicine?

As far back as the ancients, humans have searched for immortality and have employed words that connote longevity. The term ‘rejuvenate’, meaning to restore youth, has been used as a verb for at least 200 years. Conversely, the term ‘anti-aging medicine’ is relative new. Perhaps some of the controversy surrounding this term has to do with its negative connotation. Aging has been ever seen as negative because it leads to death, but currently people are always more interested in learning what they can do to live longer as well as to remain healthy during their later life. Furthermore, in a society that tends to propose endless limits on the way of living, people are looking in their later years to remain vibrant and fit. As an answer to this widespread desire, there is a proliferation of anti-aging societies, advertisings, products and interventions. The proliferation of anti-aging products has increased in the past years may be due to the aging of baby boomers, to the light regulation of anti-aging products, e.g. dietary supplements, to the easy availability of internet sites for marketing, and to the vast profit that this market can raise. There are, though, several concerns that may come with anti-aging interventions including physical harm, economic fraud and diversion from beneficial regiments. Indeed, products that claim to cure or reverse aging mislead the public and impact on the reputation of those doing serious work.

For example, one of the oldest and still most popular anti-aging treatments involves human growth hormone (HGH) that has been used as an anti-aging treatment because the article by Rudman et al. [16] in the New England Journal of Medicine catapulted it to the forefront as a major breakthrough in aging research in the eyes of the lay public. Several reports of research on animal models supported a role for HGH in longevity [7],[8],[17],[18]. However, a recent meta-analysis showed that the changes in body composition are small and the rate of adverse events is high, the most serious probably being cancer. Other side-effects might include weight gain, high blood pressure and diabetes [19]. Furthermore, studies in mice, flies and nematodes suggest a harmful role [20],[21]. Mice genetically modified to produce more HGH live less than controls [22],[23] whereas mice producing less GH live longer. Growth hormone deficient mice such as Snell mice (pit-1 gene mutation), Ames mice (PROP-1 gene mutation) and the Laron mice (GM receptor knockout) live longer than their controls. Patients with Laron syndrome, i.e. isolated IGF-1 syndrome, have lifespans into their eighties or nineties [24], and receptor mutations in IGF-1 which lead to reduced activity are more common in centenarians [25]. An extreme example of fraud is the HGH nasal preparation advertised and sold in the internet.

Evidence from studies in experimental animals and lack of translation of these results to humans

Since the first study by McCay in 1935 several studies in animals have demonstrated the beneficial effects of CR and its potential to delay the rate of aging. In particular, studies in mice and rats support the idea that CR delays the aging process [9]. Life-extension in mice by CR can be higher than 40% and even greater increases have been reported in non-mammalian models [26]. However, CR fails to extend life in older animals [23],[27], and studies in primates are not conclusive [28]. Furthermore, CR does not enhance longevity in all species [10]. Species living in fairly constant environments will have little opportunity to evolve the means to respond well to food shortages, which may be one reason why tropical squirrel monkeys respond less favorable to CR than the temperate Rhesus monkey. Inconsistent results have also been reported for medflies and some desert living species such as the spiny mouse that are able to depress their metabolism whilst remaining active in response to food shortage [10]. There are also several conditions in the laboratory environment that may affect lifespan [29]. This may contribute to make results from different laboratories and even from different strains at the same laboratory very variable. The most pervasive problem being the presence of uncontrolled genetic differences between strains under study. CR can produce substantial increase in mean and maximal span in laboratory-adapted rodents, but a recent study found no increase in mean lifespan in wild-derived mice, which had longer lifespan and lower food intake. Also, the impact of natural enemies, including pathogens, is greatly reduced in the laboratory, and there is a superabundance of food and little opportunity for exercise which make them quite different from animals in wild conditions and more respondent to CR [29].

In humans, there are no conclusive studies but some studies suggest that CR might be beneficial, at least in some groups of people. In a review paper [30], there are several reports with protective effect against atherosclerosis, beneficial effects on cardiac function and some benefits in reducing weight and adiposity, though the benefits were similar to those obtained by exercising. The observation that reducing calories is beneficial to overweight patients is not surprising. A high-calorie diet is unhealthy for the vast majority of people, increasing the probability of developing age-related diseases like atherosclerosis and type 2 diabetes. Hence, CR, in part by reducing body fat which tends to accumulate with aging, may help to diminish the chance of developing age-related diseases and increases average lifespan but the demonstration of a truly delay of aging in humans is not viable. It is uncertain whether CR may benefit lean people who already have a healthy lifestyle. Moreover, there are important side effects, such as sexual dysfunction, infertility, chronic lack of energy sensation and mental stress for controlling hungry that may lead to depression and to anorexia. In older persons multiple studies have shown that weight loss increases mortality, institutionalisation and hip fractures [31].

Even if the mechanisms that mediate CR are unknown at present and it is not confirmed that CR delays human aging, several scientists and companies are trying to develop products that mimic the effects of CR without the side-effects. This is a growing area of research in view of CR mimetics as a possible treatment for obesity and the metabolic syndrome. Some of the most well-known molecules being tested as CR mimetics are sirtuin-activating compounds that include plant polyphenols such as resveratrol, contained in significant amounts in red wine. Resveratrol has antioxidant properties and it also appears to be a cancer chemopreventive agent. Interestingly, resveratrol has been shown to extend lifespan in animal models, by the activation of sirtuins, which are genes involved in silencing other genes. These CR mimetic effects of resveratrol were first described in yeasts with the activation of sir2 [32], and later on in flies and worms [33]. Although it is possible that resveratrol is healthy, just as other antioxidants contained in vegetables and fruits, or may have positive effect on the prevention of certain age-related diseases such as diabetes, there is at present no evidence they can delay, even if slightly, the human aging process.

The unresolved question is, can the results of biogerontological research in experimental models such as yeasts, nematode worms, houseflies, mice and rats be extended to humans? There have been attempts to search for similarities in the IGF-1/ insulin signalling in Caenorhabditis elegans and humans [34], because this signalling has been proposed as one of the main regulators implicated in the process of aging. The first indication of a possible role for IGF-1/insulin signalling on aging was the report of a 6.4-fold increase in maximum lifespan in Caenorhabditis elegans secondary to a mutation (a single base change) in daf-2, which has been proposed as the equivalent of IGF-1 receptor in humans [35]. However, the relationship between insulin signalling and aging seems to be more complicated in mammals than in lower metazoans, as exemplified by metabolic disarray and shortened lifespan after dramatic reductions in insulin signalling in mammals: insulin-receptor knockout mice die in early neonatal life of diabetic ketoacidosis [36].

Even if genetically modified animals have been shown to reach extreme lifespan such as dwarf mice [7],[8] and rats bred to have high aerobic capacity had fewer cardiovascular risk factors compared with control rats [37], the determination of these genetic components that may play a role in human longevity is in its infancy. Although there are many biologically plausible candidates for genes that influence human lifespan, only one finding [APO-E] has so far been replicated [34]. On the other hand, the initial expectation in experimental animals that a few rate-limiting targets modulate aging has been contrasted with the finding that over 100 genes manipulations may increase longevity in Caenorhabditis elegans [34].

Another important drawback in the research of longevity determinants is that mortality trends seem to be a stochastic phenomenon. For example, the broad range of lifespan in nematodes is indicative of the randomness of the aging process [38]. Also in humans, in a Swedish female 1900 birth cohort, a large variation in lifespan has been reported [34].

May stem cells aging explain the aging process?

It has been proposed that age-related defects in stem cells can limit proper tissue maintenance and hence contribute to a shortened lifespan [39]. In competitive repopulation experiments, there was little difference in hematopoietic stem cells (HSCs) activity 4 weeks after transplantation in young vs. old HSCs. However, at 8 and 16 weeks post-transplantation, 21 months old HSCs showed a reduced contribution compared with 2 months old control HSCs. Expression analysis of more than 14,000 genes identified 1500 that were age-induced and 1600 that were age-repressed. Genes associated with stress response, inflammation and protein aggregation were among those up-regulated, which confirms a role for these mechanisms in the aging process. Conversely, genes involved in the preservation of genomic integrity and chromatin remodelling were down regulated. Inappropriate expression of genes normally regulated by epigenetic mechanisms was also observed. It has been proposed that loss of epigenetic regulation at the chromatin level may drive functional attenuation of cells [39].

The possibility that stem cells aging may determine the aging process has been suggested, but the interactions at different levels are complex. At the genomic level, both internal and environmental factors may cause alterations in individual genes, groups of genes through epigenetic changes, and in turn may cause direct damage to DNA. However, the juxtaposition of these interactions raises a conundrum similar to that of ‘chicken or egg’: do age-related epigenetic changes render DNA more susceptible to damage, or does DNA damage underlie epigenetic changes? Likewise, at the cellular and tissue level, functional changes in stem cells and other cells influence each other and are, in turn, influenced by systemic changes [40].

The emergence of possible therapies with stem cells in order to regenerate tissues, for example the heart, has created a fair amount of hope. However, the response to stem cell therapies has been shown to be different in aged animals respect to young counterparts. A study in an animal model of induced-myocardial infarction showed that cardiac structure and function was reversed dramatically in young animals treated with granulocyte colony-stimulating factor and stem cell factor after myocardial infarction but old treated animals did not show any benefit [41]. Sarcopenia, loss of muscle with aging, is a major predictor of disability [42]. Stem cells with a muscle specific IGF reversed the muscle loss seen in aging mice [43]. A recent review of the possible role of stem cell aging in the determination of human aging concluded that more precise mechanistic understanding of stem cell aging and therapies will be requested before it can be translated into human anti-aging therapies. Therefore, a recommendation of adhesion to a healthy lifestyle including smoking cessation, a balance diet and regular exercise is still the most prudent, clinically validated advice [44].

The hormonal fountain of youth

We have already alluded to the growth hormone fiasco with many rich persons paying exorbitant amounts of money to attain their quest for everlasting youth. Dehydroepiandrosterone (DHEA) is similarly touted by the anti-aging pundits, but despite positive animal studies [45] well-controlled human studies have failed to show any convincing beneficial effects [46],[47]. DHEA replacement in a randomised controlled trial increased bone mineral density in elderly subjects. However, the effect was relatively small compared with established therapies for osteoporosis [48]. In the same trial, 2 years of DHEA supplementation did not change body composition, muscle strength, physical endurance, insulin sensitivity or quality of life. DHEA replacement may improve some metabolic variables and measures of psychological well-being in subjects with adrenal insufficiency, but these benefits are not consistently sustained in long-term therapy [49].

Of the hormones the best available positive data is for vitamin D. Vitamin D replacement, in a meta-analysis, was shown to decrease mortality [50]. In addition, in persons with low vitamin D, replacement improved function, decreased falls and prevented hip fracture [51].

Because Brown Sequard produced his testicular extract and ‘Pud’ Galvin the Pittsburg Steeler pitcher demolished the Boston Red Sox, testosterone has had a checkered history as an anti-aging hormone. Like growth hormone, testosterone levels decline with aging (men and women). Although some but not all studies, have shown that low testosterone is associated with increased mortality in males, this finding is confounded by the fact that illness decreases testosterone levels [52-57]. Meta-analyses in older men have shown that testosterone improves sexual function and muscle mass and strength [58],[59]. Bone mineral density in hypogonadal men increases under testosterone substitution [60]. Nevertheless, fracture data are not yet available and thus the long-term benefit of testosterone requires further investigation. In women, testosterone enhances sexual function in oophorectomised women [61]. This has led to the development of selective androgen receptor molecules, which appear to improve power in older males and females [62]. The role of testosterone in older persons is established for the treatment of sexual dysfunction (both low libido and in some cases erectile problems) [63]. A recent consensus statement from diverse international scientific societies has provided valuable guidelines for the diagnosis of age-associated testosterone deficiency syndrome, for the treatment with testosterone supplementation, and for the identification of possible adverse effects and contraindications of such treatment [64]. A careful selection of candidates, an appropriate dosing of hormonal supplementation, and a diligent clinical follow-up are crucial instruments to a correct use of hormonal replacement therapy.

Even if short-term estrogen/progesterone replacement therapy (HRT) to treat severe menopause-related symptoms and to reduce osteoporosis fracture risk in selected postmenopausal women is well established, its long-term use for disease prevention in postmenopausal women has generated extensive debate. Two large randomised trials in the US [65],[66], and two in the UK [67],[68] showed no effect on protection against the development of cardiovascular disease and suggested that this therapy may increase the risk. Recent reanalysis of these trials results support positive cardiovascular outcomes provided that hormone therapy is initiated within 10 years since menopause. The favorable benefit-risk ratio for HRT decreases with aging and with time since menopause [69]. Furthermore, HRT seems to increase the incidence of dementia when initiated in women age 65 and older [69]. Current guidelines recommend HRT use close to menopause, when indicated, for the shortest time possible and at the lowest dose.

Anabolic steroids are emerging as possible candidates for adjuvant therapy during rehabilitation. Thus, it is possible that anabolic steroids will play a role in improving healthspan. However, their potential deleterious effects on the prostate [70], and the fact that the longest-lived Chinese emperor's castrate lived to 94 years of age, suggest it is not going to be a longevity agent.

Although frequently dishomogeneous, most of data available in anti-aging intervention trials are referring just to hormonal replacement therapies. Nevertheless, despite promising results in numerous studies over the past decade, available data do not justify the broad use of hormones as anti-aging treatments. At present, it should be concluded that the search for an hormonal fountain of youth has been as disappointing as Ponce DeLeon's search for a fountain of youth. Though it should be noted that, at last, Ponce DeLeon discovered Florida, a haven for retired older Americans.

Sustainable progress

Although almost daily we are seeing amazing breakthroughs in the basic science understanding of aging, we are not yet ready to move these findings to human beings. Technology may make our life better but the price paid sometimes is high and a world that depends completely on technology may be a world of slaves. It is essential that well-controlled human trials are carried out so that we do not end up shortening rather than prolonging lifespan. Healthspan is as important as lifespan.

Longevity medicine–preventive gerontology

Longevity medicine or preventive gerontology should apply to all means that would extend healthy life, including health promotion, disease prevention, balanced diet, regular exercise, smoking cessation, as well as advanced medical care and new discoveries that result from basic research. These strategies search for the reduction of morbidity, improvement of quality of life and active aging maintenance, based on the comprehensive assessment, validated in geriatric medicine by multiple studies.

As a confirmation of the positive effects of a healthy lifestyle on longevity, a recent prospective study conducted in 2357 men suggest that modifiable biological and lifestyle factors, assessed at a mean age of 72 years, are associated with exceptional longevity of 90 or more years and with high functional status in late life [71]. The EPIC-Norfolk study showed that not smoking, getting some exercise, eating five helpings of fruit and vegetables each day, and drinking 1 to 14 glasses of alcohol per week provided an estimated 14-year improvement in chronological age [72]. This would suggest that encouraging favorable lifestyle behaviors, including smoking abstinence, weight management, blood pressure control and exercise, may not only enhance life expectancy but may also reduce morbidity and functional decline in elderly years.

Regarding physical exercise, Fries has shown that disability was delayed by about 13 years in a group of older runners respect to sedentary older subjects [73]. In the LIFE-Pilot study, the short physical performance battery, which includes walking, balance, and chair stands tests, as well as the 400-m walking speed, was significantly improved by a structured physical activity intervention, suggesting that this type of intervention may offer benefit on more distal health outcomes, such as mobility disability [74]. High total energy expenditure in 70- to 80-year olds leads to increased longevity [13]. Climbing stairs was the major factor that resulted in increased total energy expenditure.

Numerous studies have shown that different components of a balanced diet may contribute to decrease the incidence of cardiovascular disease, diabetes mellitus and some types of cancer. Furthermore, the effects of the combination of different components of a balanced diet may potentiate the effect of single elements as shown by the effects of a ‘polymeal’ on cardiovascular events frequency. Analyses of data from the Framingham heart study and the Framingham offspring study showed that the combination of different food (wine, fish, dark chocolate, fruits, vegetables, garlic and almonds) with known evidence of cardioprotection would reduce cardiovascular events by 76%[75]. Several studies have shown positive effects on total mortality, cardiovascular mortality and cancer-related mortality of a dietary pattern similar to that followed by traditional populations living in the Mediterranean basin, based on bread, grains, olive oil, legumes, fruits, fresh vegetables, nuts and fish [6],[11],[12],[76-85]. A study conducted in 74607 subjects without coronary artery disease, stroke or cancer at enrollment recruited from 10 European countries concluded that every 2 unit increment in a score constructed with the aforementioned elements of the Mediterranean diet conferred a reduction of 8% in overall mortality [11]. In patients with coronary heart disease at baseline, the reduction in overall mortality was even higher, with a 27% reduction in mortality [12]. A recent meta-analysis of 12 large studies including a total of over 1.5 million subjects confirmed a significant reduction in all-cause mortality with increases in Mediterranean diet score adherence [86]. It also included recent studies demonstrating a reduction in the risk of developing Parkinson's and Alzheimer's disease.

As proposed by Rattan [87], it seems that in order to achieve healthy old age and longevity three main components should be considered. First, the genetic component that may be responsible for maximum a quarter of the possibility of a long life. Second, the environment which has been extensively studied and recognised as an important determinant of the lifespan of an individual. However, the third component that should be considered is chance, or the probability of stochastic effects leading to accumulated damage in complex interacting systems, which is not controllable.

In Gulliver's Travels by Jonathan Swift, written when the average life expectancy was 40, Gulliver, shipwrecked yet again, hears of a race of immortal humans named the Struldbruggs. Initially, he is overjoyed at the thought of freedom from death, but his joy soon turns to ashes when he learns that while they never die, they continue aging. ‘At 90 they lose their teeth and hair, they have at that age no distinction of taste, but eat and drink whatever they can get, without relish or appetite … In talking they forgot the common appellation of things, and the names of persons, even … their nearest friends and relations’. As they age, ‘they had not only all the follies and infirmities of other old men, but many more which arose from the dreadful prospects of never dying’[88].

Like Tantalus, modern gerontologists, are constantly teased by exciting animal findings suggesting clues to human longevity. However, as pointed out by Friar Roger Bacon in thirteenth century England, the secrets of a healthy long life are controlled diet, proper rest, exercise, moderation in lifestyle and good hygiene [2]. Unfortunately, like the good friar we are rarely satisfied with simple solutions that may require some physical labor, but a balanced diet of moderate proportions and exercise remain today the only proven fountain of youth.

Declaration of interest: The authors report no conflict of interest. The authors alone are responsible for the content and writing of the article.