Ageing
INTRODUCTION AND OVERVIEW
The global population trends of ageing reported by the US government show that the world population nearly quadrupled during the twentieth century, and is projected to grow by roughly 50% before stabilising during the late twenty-first century.1 This transition is expected to leave the population much larger and, on average, older than it was previously, with significant health and socioeconomic implications.
Before the demographic transition of populations began,2,3 fertility and mortality were both high throughout the world. Children often died in infancy, and people who reached adulthood tended to have many children and die relatively young. Famines and epidemics could rapidly and suddenly kill many people, causing large fluctuations in rates of mortality. As a consequence, most people were young, and very few lived to old age.2
The pattern of population mortality change has a number of recognised stages (listed below) and links with the epidemiological transition that began in Europe in the 1700s (Fig 58.1).3
At present, people born in one of the developed countries can expect to live well into their mid-seventies, or longer if current mortality rates prevail, and even longer if those rates continue to fall. Life expectancy at birth in these countries is therefore projected to rise continuously well into the future. This trend is exemplified in the growth of the world’s population (Fig 58.2).
FIGURE 58.2 World population growth throughout history
(adapted from Population Reference Bureau5 and United Nations 19986)
Significant gains have occurred through reductions in death rates among the middle-aged and elderly, especially from artery disease (heart disease and stroke), over the past few decades. In Australia, males aged 30 in 2001 could expect to live to 78 years and females to 82.8 years.7 This is about 12 years longer than the respective life expectancies during 1901–1910. Males aged 65 years in 2001 could expect to live to 81.6 years and females to 85.2 years, about 6 years longer than for those in 1901–1910.1–3,7 Similar trends can be observed with the populations from other developed countries, such as the United States.1
Ninety per cent of all healthcare dollars are spent on extraordinary care in the last 2–3 years of life.2,3 The leading causes of death have undergone a profound shift, primarily due to improvements in sanitation and infection control since the turn of the twentieth century. The most common causes of death are now cardiovascular disease (heart disease and stroke) and cancer, and these diseases consume approximately 50% of the healthcare budget.7 In the United States, the reported leading causes of death include heart disease, malignant neoplasms, cerebrovascular diseases (stroke), chronic lower respiratory diseases, accidents (unintentional injuries), diabetes mellitus and Alzheimer’s disease.8 Nearly 80% of people aged 65 years or older in the United States have at least one chronic condition, such as heart disease, diabetes, arthritis or depression, and half have at least two chronic conditions.2,8 These trends are also applicable to other developed countries.1,9 In the United States, chronic diseases account for 16.2% of the nation’s gross domestic product, and this is among the highest of all industrialised countries.9
In order to make an impact on healthcare, there must be a focus on preventing degenerative diseases of ageing that are lifestyle-related.9 There needs to be an emphasis on preventing, delaying or reversing the diseases associated with ageing. In the past 10 years, fewer Australians have died from heart attacks, strokes and cancer. The life expectancy of Australians continues to increase; however, there are a number of areas where we can do better. For example, Australians are getting fatter and exercising less, which has serious implications for the health of our population and potentially could reduce life expectancy in the future.7 Recently, an international Chronic Disease Action Group was established that will encourage, support and monitor accomplishments on the implementation of evidence-based efforts to promote global, regional and national actions to prevent and control the development of chronic diseases.10
LIFE EXPECTANCY
Japan has the highest life expectancy of any nation. Approximately one-third of those aged over 110 years worldwide are living in the Okinawa region of Japan.11–13 It is clear that the Japanese rural lifestyle and diet are important in determining their longevity.
When the Japanese move to the United States, their life expectancy is reduced to that of the local population by the second generation. Japanese who migrate to the United States develop breast cancer at the same rate as locals after one generation, but with bowel cancer a similar rate occurs by the second generation.14
Considerable attention has also been focused on populations from three other geographical areas in the world: Abkhazia, in Georgia; Hunza, in Northern Pakistan; and Vilcabamba, in Ecuador. Life expectancy in these regions is considered to be much higher than average.13–19 In these areas, several observations have been made indicating that these people live in an area that is reasonably isolated and has little pollution. Some of the features of long-lived populations such as those documented from Okinawa are that families are closely knit, couples report having happier relationships, the elderly are respected within their communities, in general their diets would be considered healthy, and their level of physical activity is high. It is of great significance that not only do these groups live to an above-average life expectancy, but they are also healthy most of the time when they are elderly.15–17
PHYSIOLOGICAL CHANGES WITH AGEING
The ageing process is characterised by a number of factors that can reduce human mean life expectancy, and these changes are summarised in Table 58.1.
| System | Major changes |
|---|---|
| Musculosketal/Body composition |
Level of evidence: I = strong, II = moderate.
MOLECULAR BIOLOGY OF LONGEVITY
CELL DIVISION, CHROMOSOMES AND TELOMERES
The ends of chromosomes are called telomeres (Fig 58.3). In most animal cells the enzyme responsible for replication of the ends of the chromosomes is telomeradse.20–22
If the telomeres of the chromosomal DNA are lost, cell cycle or cellular functions are lost, resulting in reduction of cell proliferation and re-differentiation. DNA nucleotides are added to the tip of the strand by the reverse transcriptase enzyme called telomerase. Telomerase hence adds DNA sequence repeats (i.e. TTAGGG in all vertebrates) to the 3′ end of DNA strands in the telomere regions. These regions are found at the ends of eukaryotic chromosomes, stabilising the structure and function of the entire chromosome. Normal human somatic cells undergo a finite number of cell divisions before they reach a non-dividing or senescence state. Each time a cell divides, the telomeres shorten due to the end of replication. As a consequence, this is reflected by the ever-shortening telomeres during organismal ageing, which is documented to occur in most animals.20–22 The absence of telomere shortening has led to the hypothesis of telomere length and cell longevity.24,25
It is possible to influence the length of telomeres of human cells in vitro by adding telomerase. This has subsequently been reported to decrease the rate of cellular ageing.25 Cancer cells do not seem to lose their telomerase activity and hence do not undergo cell death, indicating that cancer and longevity may have common properties.
A gene called longevity assurance or LAG-1 gene has been discovered in yeast cells.24 The LAG-1 gene can influence the number of yeast cell divisions and the cell’s longevity. The function of this gene is unknown, but it is believed to result in the synthesis of a protein found in the cell membrane. Attempts to clone a similar human gene are under way to ascertain whether it may influence longevity of the human cell.
In 1987, Denham Harman proposed that oxygen free radicals cause much of the damage associated with ageing.26 Oxygen free-radicals are molecules with an unpaired highly reactive electron produced normally as the body converts food and oxygen into energy. In an attempt to stabilise the free-radical, oxygen molecules take up an electron from another molecule, which then becomes unstable and starts a chain reaction. Some of these free-radicals are harmful to proteins, DNA, cell membranes and other cell structures such as mitochondria. In the normal cell most oxidative damage can be prevented by enzymes such as superoxide dismutase (SOD), catalase, glutathione, peroxidase and antioxidants such as vitamins C, E and beta-carotene, but the damage to the cells is felt to be cumulative. SOD levels and other antioxidants have been correlated with lifespan in at least 20 species.
MITOCHONDRIA AND FREE-RADICALS
That mitochondria have a pivotal role in the effective provision of energy to eukaryotic cells is an undisputed scientific fact. Cellular mechanisms regulating energy utilisation must function properly to sustain life. With increased ageing, there is a decrease in mitochondrial energy output.27 Hence, in aerobic animals, mitochondrial health for effective energy provision is central to life.
The free-radical theory of ageing, as formulated by Denham Harman,26 is supported by observations that the lifespan of most organisms is roughly proportional to their metabolic rate and thus due to the rate at which the organism generates mitochondria-derived reactive oxygen species (ROS). This view, however, may require modification within the confines of ageing. Cellular-generated ROS contributing to the overall production of ROS are apparently traced back to the mitochondria.27 ROS have been viewed as mostly deleterious to health and hence ageing. Reports that show that in a wide spectrum of animal species, dietary antioxidants or caloric restriction as well as chemical antioxidants or increased expression of antioxidant proteins can lower mitochondrial ROS production, which translates into an extension of the lifespan of these species, serve to support the free-radical theory of ageing.28–31 However, it is known that ROS are generated in multiple cellular compartments and by multiple enzyme systems within the cell and have cellular signalling functions that are critical for the normal physiological function of the cell.32–34
ROS produced by mitochondria have been demonstrated to have important and specific roles in cellular signalling.34 The notion that the mitochondria are the sole most abundant site of ROS formation is currently subject to much discussion and debate.33–38
The disruption of mitochondrial functions has been implicated in more than 40 known diseases, including atherosclerosis, ischaemic heart disease, cancer, diabetes and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis.39–41 Together these data indicate that mitochondrial health is an important factor for health and ageing. Current and future research would aim to further improve and preserve mitochondrial function. Although further research is warranted, recent reports show that supplementation with coenzyme Q10 shows promise in maintaining the health of mitochondria.42,43
ENDOCRINOLOGY OF AGEING
It is possible that the physical changes associated with ageing are physiological, but there is some evidence to suggest that a decline in hormonal activity plays an important role. As a result, studies have looked at the role of hormonal replacement strategies, so as to increase blood hormone levels. Unfortunately, the use of hormone replacement therapy (HRT) was not an overall success. There may be specific reasons for this failure, and hence more studies are necessary in order to establish whether hormone replacement can be both of benefit and safe.
PHYSICAL FRAILTY WITH AGEING
Physiological functions gradually decline with ageing. Such decline in functions includes diminished capacity for cellular protein synthesis, a decline in immune function, an increase in fat mass, a loss of muscle mass and strength and a decrease in bone density. People die from old age and it is mostly from cardiovascular disease, cancer or dementia. The characteristics of ageing include generalised weakness, impaired mobility and balance and poor endurance.44,45
Associated with physical frailty are falls (contributing to 40% of admissions to nursing homes), fractures that impair daily activities of everyday living and loss of independence.46
Experts on ageing define the characteristic aspect of ageing as a loss of muscle strength.33,37 A decline in muscle strength results from a sedentary lifestyle and decreased physical activity, as well as ageing of muscle fibres and their innervation, osteoarthritis and chronic debilitating diseases.47
A study utilising 100 frail nursing home residents with an average age of 87 years investigated supervised resistance exercise training, and found a doubling of muscle strength and a significant increase in their walking and climbing power. The investigation demonstrated that these muscle changes of ageing are not irreversible and that they can be reduced and possibly prevented. Prevention of frailty can be achieved by exercise, which is difficult to institute in an ageing population and, hence, there are very high numbers of dropouts from these programs.48 Muscle resistance exercises can also improve insulin sensitivity.49 A cultural change where exercise becomes a routine part of life may make a difference.
Changes in the endocrine system may be responsible for part of the ageing process that affects the body composition, including loss of muscle size and strength, loss of bone and increase in fat mass.50
PHYSICAL ACTIVITY AND AGEING
One of the common traits of the elderly is sarcopenia, which gives them the appearance of frailty due to loss of skeletal muscle mass. In a study with a representative North American population sample, it was reported that sarcopenia increased from 24% in those aged less than 70 years of age to over 50% in those aged over 80 years of age.51 The age-related sarcopenia that results in loss of skeletal muscle mass has been associated with a decrease in muscle fibre area, especially type II fibre.52 There are numerous consequences related to this reduction in muscle mass, including a decline in muscle strength and function, and impaired functional capacity. Sarcopenia also results in a reduction in the body’s major protein pool. Adequate dietary protein to replace obligatory nitrogen loss and to support protein turnover is essential for maintaining muscle mass, and therefore nutritional options are equally important in order to reduce and significantly slow the progression of loss of skeletal muscle mass. It is usually recommended that protein requirements in older people should be maintained above 1 g/kg/day. An inactive lifestyle may contribute to the loss of skeletal mass in elderly people. Physical activity can significantly assist in reversing this deficit and may improve the regeneration potential of muscle fibres.52
HORMONES AND AGEING
PANCREAS AND THYROID FUNCTION
The reduction of pancreas and thyroid function is clinically the most important change in endocrine activity with ageing. Approximately 40% of those aged 65–74 years and 50% of those aged over 80 years old have diabetes mellitus and nearly half are undiagnosed.53,54 Apart from insulin secretion by the beta cells, there is also insulin resistance related to stress, poor diet, lack of exercise, increased abdominal fat mass and decreased lean body mass.55–57
Age-related thyroid dysfunction is also common in the elderly.58,59 Lowered thyroxine (T4) and increased thyroid thyrotropin-stimulating hormone (TSH) occur in approximately 5–11% of elderly hospitalised men and women.60–62 Dysfunction is mainly the result of autoimmunity and is not a consequence of ageing.63–65 Ageing is accompanied by a decrease in TSH release and a decline in conversion of T4 to the more active triiodothyronine (T3).65 A study has found that T3 and T4 lead to improvements in cognition, depression, fatigue and general wellbeing.66
MENOPAUSE
The evidence that both the brain and the ovary are key pacemakers in menopause is compelling.67,68 Menopause does not result only from exhaustion of ovarian follicles.
Whereas menopause occurs quite abruptly, the changes in the hypothalamic–pituitary–gonadal axis in males are slower and more subtle (andropause, see below). There is a gradual decline of testosterone with ageing.69,70 This andropause is characterised by a decrease in testicular Leydig cell numbers and a decrease in gonadotropin secretion.69,70
In most women, the period of decline in oestrogens is accompanied by vasomotor reactions, depressed mood and changes in skin and body composition (increase in body fat and decrease in muscle mass). Menopause is associated with the increased incidence of cardiovascular disease, loss of bone mass and cognitive impairment.71,72 With increasing life expectancy, the time a woman spends after menopause is more than a third of her life.
A large prospective study on HRT, the Women’s Health Initiative, found that HRT helped in reducing hip fracture and bowel cancer but had negative effects in increasing heart deaths, thrombosis (embolic disease) and breast cancer. This study proved that the form of HRT being used was an overall failure.73 The results of this study were confirmed by the Million Women Study.74
The significant adverse effects that have been documented with the long-term use of HRT have elicited caution in relation to the long-term use of other forms of HRTs, such as natural oestrogens (e.g. oestradiol valerate extracted from soya beans), synthetic oestrogens (e.g. ethinyloestradiol), tibolone (a synthetic hormone that has some oestrogen-like and some progesterone-like activity), skin patches and oestrogen gels, oestrogen implants, vaginal oestrogen, phyto-oestrogens, progesterone treatments (e.g. tablets: dydrogesterone, levonorgestrel/norgestrel, medroxyprogesterone; patches) and testosterone replacement.72–74
ANDROPAUSE
There is a gradual decline in testosterone levels with ageing. Variability exists among the aged. Of those men aged over 65 years, two-thirds have testosterone levels below the normal values of men aged between 30 and 35 years.75 Impotence increases in men aged 60–70 years, to over 50%.76–78 There is an association between decline in free testosterone levels and increase in impotence.79 Overall, testosterone replacement therapy is not effective for the treatment of impotence in elderly males. Other factors such as artery disease, diabetes, excessive alcohol consumption, smoking and quality of the relationship seem to be more important.80,81
Although it has been shown that testosterone has anabolic effects,82–85 it is not clear whether the decline in muscle mass and muscle strength with ageing is related to the decrease in free testosterone levels. In mid-adult hypogonodal men who have muscle weakness, anaemia, decreased bone mass and mood disturbances, there is a rapid normalisation with testosterone replacement therapy.83,84 Pharmacological doses of testosterone therapy combined with exercise or weight training have been shown to increase muscle mass and strength in eugonadal adult men.84 An early study demonstrated that testosterone supplementation for 6 months in older men with a low normal testosterone concentration did not affect functional status or cognition but increased lean body mass and had mixed metabolic effects.85
There are limited long-term data on testosterone replacement therapy but in general there is a positive effect on muscle mass and strength as well as on cognition and sense of wellbeing.86,87 An adverse effect on lipid profiles has been reported with testosterone treatment.87 There are inadequate studies on testosterone replacement therapy in the elderly to ascertain who benefits and whether prostate disease and artery disease negate these benefits. Androgenic compounds with variable biological actions in different organs (antiandrogenic in the prostate) are currently being investigated.88 Moreover, a recent review concluded that on current evidence the studies in elderly men with lower than normal testosterone that have reported improvement in features of the metabolic syndrome, bone mineral density, mood and sexual functioning have provided no definitive proof. The beneficial effects of restoring testosterone levels to normal in elderly men, with regard to clinical parameters, requires further rigorous research.88
ADRENOPAUSE
With age there is a gradual decline in dehydroepiandrosterone (DHEA), resulting in adrenopause.89,90 Adrenal secretion of DHEA gradually decreases over time, whereas adrenocorticotropin (ACTH) secretion, which is physiologically linked to plasma cortisol levels, remains largely unchanged. The decrease in DHEA is due to a decrease in production from the adrenal cortex and is not due to a hypothalamic pacemaker.
Males over 90 years of age with the lowest DHEA levels have the lowest levels of activities of daily living.90 DHEA levels at age 30 are approximately five times higher than at age 85.90
In animal studies with very low levels of DHEA, its administration prevents obesity, diabetes mellitus, cancer and heart disease, while enhancing immune function.91–94 Supportive data in humans are few and highly controversial. Higher DHEA levels are associated with some reduced risk of cardiovascular deaths in males.91
DHEA has been shown to be beneficial in two randomised placebo-controlled studies.95,96 Twenty adults aged between 40 and 70 years were given 50 mg of DHEA daily over a 3-month period, with an increase in DHEA levels similar to those in young adults, resulting in increased androgen and insulin-like growth factor (IGF-1) concentrations. There was also a significant increase in physical and psychological wellbeing without an effect on libido in both sexes.96
Another study using 100 mg of DHEA for 6 months showed an increase in lean body mass in both sexes, but muscle strength was increased in men only.97
Recent short-term and long-term studies investigating the administration of an oral low dose (25 mg/day) of DHEA have demonstrated that DHEA increased serum DHEA, DHEAS, androstenedione and oestradiol levels of participants in the older group to the same level as that of younger participants.98 Further, it has been shown that DHEA was capable of modifying circulating levels of androgens and progestins in both early- and late-postmenopausal women by modulating the age-related changes in adrenal function.99
SOMATOPAUSE
The growth hormone (GH) / insulin-like growth factor I (IGF-1) is the third endocrine system that gradually declines with ageing.100,101 There is a progressive fall in circulating IGF-1 levels in both sexes with ageing.102 The triggering pacemaker appears to be localised in the hypothalamus and is linked with a decrease in GH.103 It is not known whether changes in gonadal function (menopause and andropause) are interrelated with adrenopause and somatopause, which occur in both sexes.
Changes such as muscle size and function, fat and bone mass, progression of atherosclerosis and changes in cognitive function have not been related to the changes in GH/IGF-1 endocrine activity. Some effects of normal ageing resemble features of isolated hormonal deficiency (i.e. hypogonadism and GH deficiency), which in mid-adult patients are reversed by replacement therapy with the appropriate hormone.104 Ageing is not simply the result of various hormone deficiencies.
The biological consequences of somatopause are poorly understood.105 A number of catabolic processes that are central in the biology of ageing can be reversed with GH administration. The IGF-1 levels in elderly individuals can be increased to those seen in the young after 3–6 months of GH administration.106 GH also significantly increased muscle mass, skin thickness and bone mineral, and reduced fat mass.107 Muscle strength and maximal oxygen consumption were not improved with GH therapy.108 GH therapy did not give any additional benefit to that of resistance exercise training in relation to muscle mass and muscle strength.109 An association between maximum aerobic capacity and circulating IGF-1 levels has been demonstrated.108,109
In summary, GH replacement therapy in GH-deficient adults has been shown to increase:
In addition, lipid profile was improved and fat mass decreased.106–109
If GH is given to those over 65 years old with hip fracture, there is an earlier return to independent living.110
Several other similar studies have investigated the role of GH in the treatment of acute catabolic states in the frail elderly. Hypothalamic peptide growth hormone releasing hormone (GHRH), when given subcutaneously over 2 weeks to healthy 70-year-old men, increased GH and IGF-1 levels to those of 35-year-olds.111 Long-term oral non-peptide analogues of GH-releasing peptides have even more powerful GH-releasing effects, restoring IGF-1 secretion in the elderly to those of young adults.112 Long-term administration in the elderly increased lean body mass but not muscle strength.113 These non-peptide analogues may be important in the prevention of frailty and reversing acute catabolism. Studies of the long-term use of these analogues are not available. There is concern about tumour growth, as IGF-1 receptors are present in most human solid cancers. The concerns related to GH have recently been reviewed.114
LIFESTYLE
Willet emphasised that genetic and environmental factors, including diet and lifestyle, both contribute to cardiovascular diseases, cancers and other major causes of mortality and that numerous lines of evidence indicate that environmental factors are the most important in disease prevention (Fig 58.4).115 Hence, environmental factors may certainly have the strongest influence on life expectancy and hence lifespan (Fig 58.2).115,116 It should be noted that life expectancy is a statistical projection of the length of time a human being is expected to live, based upon probabilities and assumptions of genetic predispositions, living conditions, medical discoveries and advances, natural disasters and other environmental factors, compared with lifespan defined as the characteristic observed age of death for its very oldest individuals.117 Intertwined with nutritional practices and lifestyle is life stressor modification.116
Stressors and negative stress-related reactions have been documented and recognised as having multiple ill-health-related sequelae, and exposure to chronic social stress has been associated with many systemic and mental disorders.118 These have significant deleterious outcomes that significantly reduce life expectancy.
Different research groups support the notion that health consequences are more likely to occur when unpredictable stressors of a social nature chronically induce physiological and behavioural adjustments that may create wear and tear on underlying physiological functions. When stressors challenge an organism’s integrity, a set of physiological reactions is elicited to counteract the possible threat and adjust the physiological setting of the organism to the new situation. This has become known as the stress response.119
Stressors and lifestyle choices can be a significant trigger for disease through immunomodulation of the immune system enhancing disease susceptibility, which can then affect life expectancy.119 Immune function modulation influenced and expressed by stressful life experiences has a significant correlate with Willett’s115 environmental trigger view of disease initiation.
Some recent research is now suggesting that psychological factors such as chronic stress and pessimism120 may have a direct effect on telomere length and telomerase activity, thus giving plausible mechanisms to explain the relationship between mental health and ageing. There is now also research to suggest that psychological strategies such as mindfulness techniques may help to slow the ageing process through their effects on stress, cognition and, consequently, telomerase activity.121
NUTRITION
Triggers for adverse and inappropriate nutritional practices in childhood have been shown to have psychosocial correlates in adult life, with an increase in risk for disease.122
Recently it was reported, and further confirmed, that a greater adherence to a traditional Mediterranean diet was associated with a significant reduction in total all-cause mortality.123 Meyer and colleagues have demonstrated that associating a CR diet with adherence to a Mediterranean-type diet that consisted of whole grains, beans, fish, fruit, olive oil and many different kinds of vegetables was beneficial for heart health.124 Hence, when optimal nutritional choices are coupled with CR, an increase in life expectancy is made possible. Such nutritional practices can serve to further extend the human lifespan.
CALORIC RESTRICTION
Optimising nutrition relates food intake to the benefits of prudent CR. That is, CR refers to a dietary regimen low in calories without under-nutrition that would lead to increased disease risk due to nutritional deficits. Following the pioneering work of McCay and colleagues over 70 years ago, CR was then first noted to significantly extend the lifespan of rodents.125 Since that time, the increase in longevity has been demonstrated to result from the limitation of total calories derived from carbohydrates, fats or proteins to 25–60% below that of control animals fed ad libitum.29,126,127 The extension in lifespan can approach 50% in rodents.125,128 Moreover, CR has been shown to extend the lifespan in a broad range of organisms including yeast, rotifers, spiders, worms, fish, mice and rats.126 Emerging data show that its effect may also apply to non-human primates.129 CR has also been reported to delay a wide spectrum of diseases in different experimental animals such as kidney disease,129 a variety of neoplasias,130–132 autoimmune disease133,134 and diabetes,135 and it reduces age-associated neuronal loss in most mouse models of neurodegenerative disorders such as Parkinson’s disease136 and Alzheimer’s disease.137,138 The CR regimen also prevents age-associated decline in psychomotor and spatial memory tasks139 and loss of dendritic spines necessary for learning,140 and improves the brain’s plasticity and ability to self-repair.137
Numerous biomarkers of CR have been identified in rodents, such as temperature, and DHEAS, insulin and glucose levels.141 Roth and colleagues have recently observed that body temperature and insulin and DHEAS levels were also altered in primates that had been subjected to CR, hence validating the usefulness of these biomarkers in longer-lived species.141 More importantly, they have also shown that these parameters were altered in longer-lived men. Together these findings support the role of these factors as biomarkers of longevity in humans.
Recently, a trial on the effect of a 6-month CR diet on metabolic biomarkers such as energy expenditure, and oxidative stress in humans was completed.142 The report showed that prolonged CR significantly reduced two biomarkers of longevity, namely, fasting insulin level and body temperature. This is the first human study to show that CR, in addition to significantly reducing well known biomarkers of ageing, also caused a metabolic adaptation in CR individuals and a reduction in DNA fragmentation that reflected less DNA damage.142
Plant factors such as resveratrol have been shown to increase longevity in several organisms by regulating genes.143 In mammals, there is growing evidence that resveratrol can prevent or delay the onset of cancer, heart disease, ischaemic and chemically induced injuries, diabetes, pathological inflammation and viral infection. These effects are observed despite extremely low bioavailability and rapid clearance of resveratrol from the circulation.143 Resveratrol has been suggested to be associated with the prevention of age-related diseases such as cancer because of its regulation of transcription factors that control tumour cell survival.144,145
NON-DRUG INTERVENTIONS IN CHRONIC DISEASES
The role of non-drug interventions in chronic diseases is summarised in Tables 58.2 and 58.3.
TABLE 58.2 Chronic diseases (by system) and non-drug interventions and supplements
| System/disorder | Non-drug interventions and supplements* and strength of evidence |
|---|---|
| Musculoskeletal/Body composition | |
Level of evidence: I = strong, II = moderate, III = weak.
* Progression halted by lifestyle changes including diet, stress reduction, exercise, relaxation techniques and adequate sunlight exposure.
TABLE 58.3 Chronic diseases and non-drug interventions and supplements
| Disorder | Non-drug interventions and supplements* and strength of evidence |
|---|---|
| Metabolic syndrome | |
| Chronic inflammation: can involve most body systems | |
| Cancer | |
| Behavioural | |
| Pain | Pain relief with acupunctureI, antiinflammatory herbs (see above) |
| Urinary problems | Saw palmettoII, other herbs: stinging nettle (Urtica dioica)II, pygiumII |
| Sleep apnoea |
Level of evidence: I = strong, II = moderate, III = weak.
* Progression halted by lifestyle changes including diet, stress reduction, exercise, relaxation techniques and adequate sunlight exposure.
HEALTHY AGEING
Throughout most of recorded human history, it has been recognised that poor socioeconomic and nutritional status are strongly associated with decreased life expectancy, a trend that is also very much evident today.146
The Alameda County Study highlights the importance of an overall plan for health maintenance and disease prevention that can lead to enhanced survival. The Human Population Laboratory, known as the Alameda County Study, quantified health risk practices and lifestyle issues such as exercise, diet, sleep, smoking and alcohol consumption, and defined their relationship to mortality.147 The first cohort participated in a health survey in 1965 and this has been followed with subsequent surveys to the present day. Health behaviours including seven health habits were considered and were reported to be strongly associated with most (current) or subsequent morbidity and mortality. This study emerged from efforts in the 1950s to measure health—physical, mental and social wellbeing—in accordance with the WHO definition of health, and asked questions about common health-related habits.
Lifestyle and future health issues were investigated and it was reported that there was a disparity of good health practices in 1965 between those with good health and those with poor health practices. Those with an intermediate level of health practices experienced about two-thirds the relative disability risk of those with poor health practices.148
Subsequent studies from the Alameda County Study showed that greater personal control over one’s biopsychosocial health after retirement was beneficial to health, providing a greater survival advantage.149,150
Restoration of telomerase activity, isolation and deciphering the activity of longevity genes, protection against environmentally induced free-radicals (e.g. excessive UV radiation) and supplementation with beneficial hormones, nutrients and herbs may increase longevity. We need to learn more about why people from certain countries have a greater life expectancy. Individuals who live to be 100 years of age or more also require further study to show how they may be different from others with an average life expectancy. Increasing knowledge should help us to postpone or prevent the advent of chronic and disabling diseases, as well as resetting the internal biological clocks that control longevity.
Duke University Center for the Study of Aging and Human Development. http://www.geri.duke.edu/resource/resource.html.
National Academy of an Aging Society. http://www.agingsociety.org/agingsociety/index.html.
National Institute on Aging (NIH). http://www.grc.nia.nih.gov/branches/blsa/blsanew.htm.
Resource Centre on Aging, University of California, Berkeley. http://socrates.berkeley.edu/~aging/Web.html.
Rosenthal Centre, Information Resources for Research on Aging. http://www.rosenthal.hs.columbia.edu/Aging_resources.html.
Sheffield Institute for Studies on Ageing. http://www.sheffield.ac.uk/sisa/.
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