chapter 58 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.
TABLE 58.1 Body changes with ageing
| System | Major changes |
|---|---|
| Musculosketal/Body composition | |
| Nervous | |
| Ocular | Degeneration of lens and retina |
| Ears | Decreased ossical function |
| Cardiovascular | |
| Immunity | Reduced cell-mediated immunity and increased auto-antibodies |
| Endocrine | Decrease in some hormones |
| Renal | Decreased number and function of glomeruli |
| Respiratory | |
| Digestive | Decreased digestive secretions and motility |
| Skin |
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
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