Ageing of Organs

Ageing of the Skin

The skin is the largest organ of the body and has many important functions. It functions as a mechanical barrier, regulates temperature, initiates immunological functions, communicates external stimuli to the body and protects against the effects of ultraviolet light. The skin is composed of three major layers: the outermost layer is the epidermis, followed by the dermis, which leads to the hypodermis. In the epidermis, a multitude of cells exist such as keratinocytes, melanocytes, Langerhans cells and Merkel cells. The basement membrane separates the epidermis from the dermis. The dermis is composed of connective tissue, consisting mainly of collagen fibres, and elastin. The fibroblasts are the major cell type. The hypodermis is composed of the adipocytes, and also the intravascular bundle. The typical signs of ageing include wrinkling and sagging of the skin. Extrinsic ageing is more prominent in the highly vascular retina unlike the lens, and it has six neural cell types organized in 10 layers. The photoreceptor cells (rods and cones), and the retinal pigment epithelium (RPE) are most affected with ageing.

Intrinsically aged skin is thin, pale, and finely wrinkled. Histological staining shows flattening of the dermo–epidermal junction. This form of ageing is felt to be secondary to superoxide free radical formation. Aged skin demonstrates a reduced keratinocyte proliferative capacity. The number of epidermal cell layers remains unaltered during ageing (Table 3.1). A decrease in melanocytes contributes to the paling of the skin.

Table 3.1 General effects of ageing on the cell types resident within the skin.

The dermo-epidermal junction flattens with age due to the retraction of the epidermal papillae (Table 3.2), which leads to a skin structural unit that is less resistant to shear forces than is younger skin. Skin thickness tends to decrease after the seventh decade.1 Within ageing skin, increased vasoconstrictor responses and decreases in both vasodilators and vasoprotective agents have been demonstrated, and atrophy and hypertrophy of the subcutaneous tissue are common in aged individuals.

Table 3.2 General effects of ageing on the function of individual components of the skin.

The repair of physical damage is an essential day-to-day function of skin. Alteration in wound healing may lead to chronic ulceration and non-healing. The dysfunction of dendritic cells leads to the formation of skin neoplasms. The decrease in the protective effect of the skin leads to further loss of protection from UV light. Sunlight is also felt to lead to the generation of oxygen radicals leading to ageing. It has been shown in vitro that keratinocytes and dermal fibroblasts from habitual sun-exposed sites have shorter life spans.

In summary, the skin is the major barrier for our body to protect us within the environment (Table 3.3). As the ageing process ensues, cellular functions are altered, leading to problems with wound healing, immunosurveillance, temperature regulation and general barrier functions.

Table 3.3 Summary of age-associated changes in skin function.

Skeletal Muscle Ageing

Skeletal muscle comprises 40–50% of the human body and is composed of muscle tissue, nerve tissue, blood vessels and connective tissue. Myoblasts are precursor cells, which fuse together forming bundles of muscle fibres. There are two types of individual muscle fibres: type I or slow twitch and type II or fast twitch. Type II has two components: type A are called fast-oxidative fibres, and type B are known as fast-glycolytic fibres. With ageing, there is a shift towards type I fibres.2 There are several types of muscle contractions: shortening contractions, isometric contractions and lengthening contractions. Skeletal muscles have developed adaptive responses to the generation of reactive oxygen species to protect themselves from oxidative damage.

These age-related changes in muscle mass are termed sarcopenia and lead to an age-related decrease in muscle strength and power. The basal metabolic rate of muscle decreases by 4% per year after the age of 50 years. The synthesis of myosin heavy chains declines with age, whereas the sarcoplasmic protein pool is unchanged.3, 4 The regenerative potential of skeletal muscle, and overall muscle mass, decline with age. There is an increased infiltration of fat into muscle with ageing. Some of the ageing changes are due to the decrease in physical activity that occurs with ageing.

During senescence, there is a loss of motor neurons and muscle fibres. The loss of motor neurons is of primary importance because it is likely to be the main reason for loss of muscle fibres. Electrophysiological studies have demonstrated a reduced number of motor units in old muscle.5 The size of the average motor unit increases with age. The loss of strength does not result from failure of the central nervous system to activate motor nerves; however, a reduced rate of firing of motor nerves during maximum voluntary contraction in older subjects may limit the maximum force production in some muscles.6 During a sustained contraction, central fatigue may be more common in older adults than in younger persons. Age-related fibre atrophy generally is restricted to type II fibres, at least in the muscles of the leg, and this selective atrophy is important functionally because type II fibres can generate more power than type I fibres. It is unclear whether there is impairment in the release of calcium affecting the rate of relaxation and contraction. Welle et al. have shown that older human muscle has reduced expression of several mRNA’s encoding proteins involved in mitochondrial electron transport and ATP synthesis.7 An accumulation of DNA deletions is seen in mitochondria of skeletal muscle with age.8

With ageing, changes occur with skeletal muscle, affecting size, strength, endurance and functionality in the elderly (Table 3.4).

Table 3.4 Summary of age-related changes in muscle.

The Ageing Eye

Multiple population-based studies have shown a significant increase in the prevalence of impaired vision with advancing age.9 As such, visual impairment is negatively associated with the independence and functional status of elderly people.10 In addition, impaired vision may negatively affect cognitive functions among the elderly.11 The eye suffers age-related disease and is affected by many systemic illnesses (see Chapter 85, Disorders of the eye). The eye consists of the retina, lens, cornea and a neurovasculature. The lens is a transparent, avascular tissue contained within a capsule. The lens cells divide, but are not shed, and as a result, the lens continues to grow throughout life. It has defence mechanisms from reducing compounds that can cause damage. Aggregation of proteins is thought to be responsible for the yellowing of the lens and also the increase in light scattering. Glutathione, a key protecting molecule in the lens, tends to decrease with ageing. Crystallins are proteins that provide the high refractive index of the lens. Alterations in structure and increased aggregation of these proteins are noted with ageing. Cataract formation increases with ageing and a multitude of enzymes have lowered activity in a cataract.

The retina is the light-responsive part of the eye and its density decreases with ageing. There is also loss of ganglion cells and RPE. Lipofuscin is a protein that is formed through many mechanisms and its accumulation can cause cell death in cell culture.12 Age-related macular degeneration (AMD) is the major cause of non-preventable blindness in Western countries and its prevalence increases with ageing. The molecular pathway leading to AMD has not yet been elucidated. There are also age-related changes to the sclera where it is thinner, yellower and less elastic. Light scattering appears to increase through the cornea with ageing. The vitreous body tends to liquefy with age and collagen fibres concentrate.

Table 3.5 summarizes the changes that occur with ageing affecting the functionality and cognitive capabilities of elders.

Table 3.5 Changes in vision with ageing.

The Ageing Cardiovascular System

Ageing is associated with complex and diversified changes in cardiovascular structure and function. Changes occur at the structural/functional levels and also the molecular/cellular level. The heart becomes slightly hypertrophic and hyperesponsive to sympathetic (but not parasympathetic) stimuli, so that the exercise-induced increases in heart rate and myocardial contractility are blunted in older hearts. The aorta and major elastic arteries become elongated and stiffer, with increased pulse wave velocity, evidence of endothelial dysfunction and biochemical patterns resembling atherosclerosis. These changes are thought to be caused by increased angiotensin II activity in the arterial wall,13 which leads to endothelial dysfunction, vascular smooth muscle proliferation and an increase in glycation and collagenization. Molecularly these changes are secondary to an increase in transforming growth factor beta-1 (TGF-β1), matrix metalloproteinase type II, calpain 1 and milk fat globule EGF-8. There is also an increase in reactive oxygen species reactivity, which leads to a decrease in endothelial nitric oxide bioavailability. The arterial baroreflex is altered in ageing, with the baroreceptor of the heart showing greater impairment than the baroreceptor control of peripheral vascular resistance. No conclusive evidence has been shown that alterations in afferent, central neural, efferent and effector organ portions of the reflex arch are altered with ageing. Reflexes arising from cardiopulmonary vagal afferents are blunted in aged individuals.

The changes that occur in the aged heart are outlined in Table 3.6. It is important to clarify that all these changes in cardiovascular function do not imply failure of the system and, in the absence of overt cardiovascular disease, do not result in symptoms.

Table 3.6 Effects of normal ageing on the cardiovascular system.

The Ageing Immune System

The function of the immune system declines with age (Table 3.7), which leads to an increased frequency of infections, increased prevalence of neoplasms and autoimmune disorders. Thymic involution is a hallmark of ageing, although there are thymic independent pathways for the development of the immune system. Response to vaccines is also decreased. The ability of haematopoietic stem cells to replicate decreases with ageing.14 There is a decrease in haematopoietic stem cells of the lymphopoietic heritage with progressive predominance of myeloid-biased clones, and this imbalance is responsible for the increase in myelodysplastic syndromes with ageing. All cells are not affected similarly by ageing so, for instance, memory CD4 T cells retain function whereas naive CD4 cells lose function.

Table 3.7 Changes in immune system function with age.

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