Human life expectancy increased extraordinarily during the twentieth century worldwide,7 first because of child mortality reduction and then because of reduced mortality in middle and old age, probably related to medical advances (e.g. antibiotics, vaccinations, improved care of pregnant women, enhanced surgical techniques) and improved socioeconomic conditions during the recovery period after World War II (e.g. improved sanitation, greater food supply, improved work environment and decrease in excessive manual labour). Societal conditions remarkably affect life expectancy, as shown by the rapid increase in life expectancy in East Germany after the fall of the Berlin Wall.8 Of note, the increase in human life expectancy during the twentieth century took place not only in developed countries, but also in less developed regions, and the pace of the increase was greater in these nations: it is estimated that the over 60-year-old population in China will double in only 27 years.9 In 1900, 40% of newborns were expected to live beyond age 65 years in developed countries. In contrast, it has been estimated that if the pace of increase in life expectancy over the past century continues through the twenty-first century, most babies born since 2000 in developed countries with long life expectancies will reach 100 years.10 These dramatic demographic changes will undoubtedly impact societies to a major extent. However, life extension is of little value in the absence of quality of life during the gained years. The imminent rapid increase in numbers of ageing adults will pose major challenges to healthcare systems in the coming years and will have deep consequences for the sustainability of modern society. For instance, the oldest-old group (>85 years), which has been the most rapidly growing segment of the population, is also the most susceptible to disease and disability.11 Hence now more than ever, the search for ways to prolong health expectancy with effective prevention of disability has become a primary goal in medicine.

The secret to longevity has been related since mediaeval times to a healthy lifestyle and avoidance of excess. As far back as the thirteenth century, Friar Roger Bacon in England stated that in order to live a long life it was necessary to follow a controlled diet, proper rest, exercise, moderation in lifestyle, good hygiene and inhaling the breath of a young virgin.12 The modern equivalent is found in the results of the Norfolk-EPIC study, showing that four simple lifestyle habits (getting some exercise, eating five helpings of fruit and vegetables each day and drinking 1–14 glasses of alcohol per week) were associated with 14 years younger physiological parameters.13 Another aspect that has been confirmed to be associated with longevity in places such as Japan, Macau and Hong Kong is fatty fish intake, rich in eicosahexanoic and docosahexanoic acids.14

Evidence that human ageing can indeed be modified is the fact that disability has decreased in the older population in the USA15 and Europe.16 However, recent data suggest that disability rates did not change significantly between 2000 and 2005 among older non-institutionalized Americans.17 Furthermore, it has recently been suggested that there may be a possible slowing on the pace of life extension observed in the last century because of the poor lifestyle of young people today.18 The disabled population spends ten times more on care than non-disabled people,15 hence there are not only important humanitarian but also economic reasons to improve quality of life in old age.

There is currently much promise in research that provides information about the underlying biology of ageing and longevity, which has unveiled possible interventions to slow the ageing process. And a myriad of epidemiological studies have shown that interventions in lifestyle, along with early diagnosis of diseases, appropriate use of advanced medical care and new discoveries that result from basic research may indeed decrease the susceptibility to disease development, increasing longevity and healthspan.

This chapter explores the topic of antiageing therapies from different perspectives. First, it discusses the rationale behind the possible delay of death, disease and disability. Second, some of the advances in biogerontological research in animal models and possible translations into humans are explored. Third, it examines the results of epidemiological studies on lifestyle modification proven to be effective in the promotion of healthy ageing.

As far back as the ancients, humans have searched for immortality. Curiously, ancient Egyptians used olive leaves to extend life,19 while currently there is evidence that virgin olive oil, used as part of the Mediterranean dietary pattern, is associated with longer and healthier lives.20 Indian ayurvedic medicine has alluded for centuries to ‘rejuvenation’, developing specific lifestyle rules and herbs to prolong life. One of the most celebrated stories about antiageing is Ponce de León’s search for the ‘Fountain of Youth’ in Bimini, in the Bahamas. Instead, he discovered Florida, where now many American retirees spend their last years in facilities with various amenities and stimulating environments, a true heaven for many elders. The writer James Hilton created in 1933 a place called Shangri-La in his book ‘Lost Horizon’, which was a paradise where people would not age. Many persons went to search for the fantastic place in the Himalayan Mountains. Even Nobel Prize winners are tempted to believe in magic-bullet remedies for healthy longevity. This is the case of Élie Metchnikoff, who believed that Bulgarians lived extremely long lives due to the use of large amounts of yoghurt in their diets. One of the first books promoting longevity, entitled Life Extension, was published by Durk Pearson and Sandy Shaw in 1982. It provided detailed animal experiments and started a long list of self-improvement books that fill the shelves of bookstores worldwide.6

Ageing has always been seen as negative since it leads to death. However, now people who have witnessed the recent extraordinary increase in life expectancy want to learn more about what they can do to live longer and healthier lives and to remain vibrant and fit in their later years. As an answer to this widespread ambition, there is a proliferation of antiageing societies, advertisements, products and interventions. The term ‘antiageing medicine’ was created in 1992 after the foundation of the American Academy of Anti-Ageing Medicine (A4M). Antiageing medicine or interventions are defined by the A4M as ‘measures to slow, arrest and reverse phenomena associated with aging and to extend the human lifespan’. It provides a number of certifications in antiageing medicine for physicians, publishes the International Journal of Anti-Ageing Medicine and claims hundreds of thousands of members worldwide. Antiageing products have boomed in recent years perhaps due to the ageing of ‘baby boomers’, who started turning 65 years old around 2010, to the light regulation of antiageing products and easy availability for marketing on the Internet and to the enormous profits that this market can raise. Nevertheless, many of these interventions and products may cause harm, involve economic fraud and may move people away from proved beneficial therapies. Products that claim to reverse ageing mislead the public and impact on the reputation of those doing serious work.

Another example of antiageing initiatives is the Life Extension Foundation, based in Florida and founded by Saul Kent in 1980, which publishes the magazine Life Extension, with a readership thought to be ∼350 000, and sells dietary supplements by mail order. Two more physicians whose books have promoted antiageing philosophies are Andrew Weil and Deepak Chopra.

Aubrey de Grey, a Cambridge-educated scientist, editor/founder of the journal Rejuvenation Research and a regular guest on television programmes, has developed a theory called ‘Strategies for Engineered Negligible Senescence’ (SENS), which suggests seven types of ageing damage which are readily open to treatment and that will permit unlimited life extension in the near future: cancer mutations, mitochondrial mutations, intracellular junk, extracellular junk, cell loss, cell senescence and extracellular cross-links.21 The SENS proposal has been widely criticized by gerontologists, especially because it may make the research community dedicated to ageing studies appear exceptionally optimistic and unrealistic in its promises.22 Olshansky, Hayflick and Carnes have openly and extensively criticized this approach, stating that ‘no currently marketed intervention has yet been proved to slow, stop or reverse human ageing.… 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’.23

Numerous concerns about antiageing products have been raised in recent years. One of them entails human growth hormone (HGH), one of the oldest and still most popular antiageing treatments. HGH has been used widely since an article by Rudman et al.24 in the New England Journal of Medicine catapulted it to the forefront as a major breakthrough in ageing research in the eyes of the lay public. Several studies on animal models have supported a role for HGH in longevity.25–28 Nevertheless, a recent meta-analysis showed that the changes in body composition are small and the rate of adverse events is high, including cancer development, weight gain, high blood pressure and diabetes.29 In addition, studies in mice, flies and nematodes suggest a harmful role.30, 31 Mice genetically modified to produce more HGH live shorter lives than controls,32, 33 whereas mice producing less GH live longer; GH-deficient mice such as Snell mice (pit-1 gene mutation), Ames mice (PROP-1 gene mutation) and Laron mice (GM receptor knockout) live longer than controls. Patients with Laron syndrome (isolated IGF-1 syndrome) have lifespans into their eighties or nineties34 and receptor mutations in IGF-1, which lead to reduced activity, are more common in centenarians.35 An extreme example of scam is the HGH nasal preparation advertised and sold on the Internet.

Ageing is a progressive process, universal and irreversible, that takes place at different levels, affecting practically all living organisms, and is the greatest risk factor for death. Ageing and death have been viewed conventionally as programmed events, a kind of immutable biological clock for each individual. However, in several animal models genetic manipulation25, 26 and caloric restriction (CR) without malnutrition2 have repeatedly been shown to increase the lifespan vs. control littermates fed ad libitum, but there is little evidence that this can be translated to humans.5 On the other hand, numerous studies on dietary patterns20, 36, 37 have shown that balanced diets rich in foods of vegetable origin and fish, such as the Mediterranean diet, decrease overall mortality and mortality-associated with cardiovascular disease and cancer, and hence increase longevity. In addition, a high total energy expenditure in 70–80 year olds leads to increased longevity38 with climbing stairs being the major factor that resulted in an increased total energy expenditure. In fact, there is growing evidence that modifiable lifestyle factors may interact with the ageing process and may alter the susceptibility of an individual to develop age-associated diseases, which are the major causes of mortality.39 For instance, the best example of healthy ageing is given by exceptionally long-lived persons whose ability to survive appears to be the result of a complex combination of genetics, lifestyle, environmental and psychological factors and chance.40

As age advances, functional capacity reserve decreases and susceptibility to diseases and functional limitations/disability increases. Disability and functional dependence can be reversible to some extent; however, when the functional reserve becomes extremely depleted, the restoration of normal function is no longer possible but the prediction or identification of the ‘point of no return’ is not yet clear. The development of biotechnological devices, such as the ‘exoskeletons’ (lifesuits),41 nanotechnology42 or bionic implants (e.g. Advanced Bionics cochlear implants),43 suggests that technology will continue to push that point further away.

Since the main goal is not only to extend life but also (if not more so) to decrease disability, this is a key question. Indeed, this is the area of geriatrics that has been investigated most intensely, given epidemiological data for a factual decrease in disability in developed countries,15, 16 and the results from numerous studies showing that the onset of disease and disability may in fact 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. The recently published INVADE study (intervention project on cerebrovascular diseases and dementia in the district of Ebersberg, Bavaria) demonstrated that moderate to high physical activity is associated with a reduced incidence of cognitive impairment, an important cause of disability, in a large population of older adults.44 Likewise, the LIFE pilot study found that the rate of onset of mobility disability was lower among a group of older adults who engaged in a structured exercise programme for 1 year compared with a group of seniors who took part in a health education programme for the same time period.45 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.46

Several studies in a wide array of species (e.g. yeasts, worms, flies, mice) have shown that animals under CR without malnutrition have a longer lifespan than control littermates fed ad libitum.1 The first of these studies was published in 1935 by Clive McKay at Cornell University, showing that limiting the food intake of laboratory rats (dietary restriction) resulted in prolongation of their lifespan. Subsequent studies in mice and rats supported the idea that CR delays the ageing process.2 CR can increase the lifespan of mice by as much as 40% and even greater increases have been reported in non-mammalian models.3 Recently, striking results from a study in primates were published showing that 50% of ad libitum-fed animals survived compared with 80% of CR animals; in addition, CR delayed the onset of age-associated diseases (e.g. cardiovascular disease, diabetes, cancer).4 However, other studies in monkeys have shown that even if dietary restriction improves metabolic profiles (e.g. glucose, cholesterol)47 and may attenuate Alzheimer’s-like amyloid changes in their brains,48 these animals also show an increased propensity for bone loss and for the development of hip fractures. In addition, CR fails to extend life in older animals.33, 49 Furthermore, CR does not enhance longevity in all species.5 Species living in a fairly constant environment will have little opportunity to develop mechanisms to respond to food shortages; this may help to explain why tropical squirrel monkeys respond less to CR than the temperate Rhesus monkey. Also, medflies and some desert-living species (e.g. the spiny mouse) able to depress their metabolism while remaining active in response to food shortage fail to increase lifespan with CR.5 Several conditions in the laboratory environment may contribute to make the results very variable, even at the same laboratory when studying strains with uncontrolled genetic differences.50 A recent study found no increase in mean lifespan in wild-derived mice, which had a longer lifespan and lower food intake than the laboratory counterparts. Natural enemies, including pathogens, are greatly reduced in the laboratory and there is a superabundance of food and little opportunity for exercise, which make laboratory animals quite different from animals in the wild and more respondent to CR.50

In humans, some studies suggest that CR has a protective effect against atherosclerosis, beneficial effects on cardiac function and some benefits in reducing weight and adiposity,51 although 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 most people and a well-known risk factor for the development of atherosclerosis and type 2 diabetes, but the demonstration of a true delay of ageing in humans is not yet viable. Whether CR may also benefit lean people who already have a healthy lifestyle is questionable. Furthermore, CR may have important side effects, such as chronic lack of energy sensation, sexual dysfunction, infertility and mental stress for controlling hungry that may lead to depression and to anorexia.

An organization called the Caloric Restriction Society, founded in 1984 by Ray and Lisa Walford and Brian Delaney, have members who observe CR to varying degrees. Studies in this group, funded by the Nutritional Institutes of Health, have shown that the middle-aged among the members have lower blood pressure, glucose and cholesterol values52. However, multiple studies have shown that weight loss increases mortality, institutionalization and hip fractures in persons over 60 years of age.53 Hence CR may be harmful in elders who are at particular risk of malnutrition.54

There are currently several CR-type diets advertised to the public as a method of prolonging life. The CRON diet (Caloric Restriction with Optimal Nutrition), developed by the founders of the above-mentioned society, recommends a 20% CR based on individual basal metabolic rate. The Okinawa diet, a low-calorie, nutrient-rich diet, is founded on the original diet of people living on the Japanese island of Okinawa (Ryuku Islands), which has the highest concentration of centenarians in the world. The diet has fewer calories than a traditional Japanese diet and consists mainly of vegetables (especially sweet potatoes), a half serving of fish per day, legumes and soy. It is low in meat, eggs and dairy products. Other diets based on similar food combinations, such as the New Longevity Diet, have been developed. None of these diets have been proven to extend longevity and Roy Walford, a major proponent of dietary restriction, died at 79 years of age of amyotrophic lateral sclerosis (ALS). Of note, animal studies have suggested that CR is especially hazardous for animals with ALS.

Numerous mechanisms have been proposed to explain why CR may promote longevity. One of these mechanisms is autophagy or cellular self-digestion, involved in protein and organelle degradation. A common characteristic of ageing cells is the accumulation of damaged proteins and organelles that predispose the cells to a pathogenic phenotype with aggregate-prone mutant proteins. These deposits of altered components are particularly detrimental in non-dividing differentiated cells, such as neurons and cardiomyocytes, where the age-dependent functional decline usually manifests. It is proposed that the decreased autophagy with age may play a major role in functional deterioration. CR seems to improve autophagy induction, possibly owing to lower levels of insulin, an autophagy inhibitor.55 Another mechanism proposed to explain CR effects is hormesis, which states that CR represents a low-level stress that allows the animal to develop enhanced defences and to slow the ageing process.56 It has also been suggested that CR reduces oxidative damage, enhances insulin sensitivity and decreases tissue glycation.57

CR Mimetics

Current efforts aim to reproduce or mimic the beneficial effect of CR, without its side effects. Interest is particularly high with regard to CR mimetics as possible therapies for obesity. Autophagy induction has been tested through the use of antilipolytic drugs, which mimic the starvation state induced by CR.55 Another CR mimetic, which upregulates autophagy, is rapamycin (sirolimus) or its analogue everolimus.58 It has recently been demonstrated that treatment with this antibiotic delays ageing and extends lifespan in yeast,59 Caenorhabditis elegans60 and mice.61 The ‘silent information regulator’ (Sir) gene is upregulated by CR in yeast and in mammals and sirtuin-activating compounds (STACs) are under development. Resveratrol, an antioxidant component in red wine, is a STAC that has been shown to extend lifespan in yeast, flies and worms62, 63 and to modulate insulin secretion and action.64 Although it is possible that resveratrol is healthy, just as other antioxidants contained in vegetables and fruits, or may have a positive effect on the prevention of age-related diseases such as diabetes, there is at present no evidence that it can delay, even slightly, the human ageing process.

This is a field that has recently been linked to longevity. Epigenetics refers to changes in gene expression caused by mechanisms other than changes in the underlying DNA. These changes may remain through cell divisions for the remainder of the cell’s life and may also be transferred to the next generation. For example, nutrition might induce epigenetic changes that could be transmitted to the next generation, impacting on health. It has been shown that the ancestors’ food availability and nutrition during the slow growth period before the prepuberal peak is followed by different transgenerational responses, which are the main influence on longevity.65

Can the results of biogerontological research in experimental models be extended to humans? This is an unresolved question. There have been attempts to search for similarities in the IGF-1/insulin signalling (one of the main regulators implicated in the ageing process) in C. elegans and humans.66 A 6.4-fold increase in lifespan in C. elegans was first reported secondary to a single base mutation in daf-2, the equivalent of IGF-1 receptor in humans,67 but the relationship between insulin signalling and ageing seems to be more complicated in mammals: insulin-receptor knockout mice die in early neonatal life of diabetic ketoacidosis.68

Even though genetically modified animals such as dwarf mice have shown extreme lifespans25, 26 and rats bred to have high aerobic capacity had fewer cardiovascular risk factors than control rats,69 the identification of genetic determinants of human longevity is still inconclusive. Although many plausible candidate genes have been proposed, only one finding [apolipoprotein E (Apo-E)] has so far been replicated.66 The initial expectation that a few rate-limiting targets modulate ageing has been contrasted with the finding that over 100 gene manipulations may increase longevity in C. elegans.66 Another important downside in the search for longevity determinants is that mortality trends seem to be stochastic in nematodes70 and in humans,66 with enormous variations in lifespan.

It has been proposed that age-related defects in stem cells can limit proper tissue maintenance and contribute to a shortened lifespan.71 In competitive repopulation experiments, there was little difference in haematopoietic stem cell (HSC) activity 4 weeks after transplantation in young versus old HSCs. However, at 8 and 16 weeks post-transplantation, old HSCs showed a reduced contribution compared with young control HSCs.71

It has been suggested that stem cell ageing may determine the ageing process, but the connections at different levels are complex. At the genomic level, both internal and environmental factors may cause alterations in individual or groups of genes through epigenetic changes with direct damage to DNA. However, it is not clear whether age-related epigenetic changes render DNA more susceptible to damage or DNA damage underlies epigenetic changes.72

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 as compared with younger animals. In an animal model of induced myocardial infarction, cardiac structure and function were reversed dramatically in young animals treated with granulocyte colony-stimulating factor and stem cell factor, but old animals did not show any benefit.73