Medical Physiology, 3rd Edition

Aging of the Human Physiological Systems

The age-related changes just described at the cellular and molecular levels can also manifest themselves as deterioration of physiological systems. Although here we discuss typical age-related changes in physiological systems, the extent of change among individuals may range from barely perceptible to very marked. Indeed, a subset of individuals shows minimal physiological deterioration—these people have undergone “successful” aging. Many individuals show marked deterioration with age in all physiological systems (Box 62-1), whereas other individuals exhibit little or no deterioration in one or more systems. Although the nature of the aging process is similar in the two sexes—except, of course, for the reproductive system—important quantitative differences exist. Because of the great reserve capacity or redundancy of some physiological systems, the effect of aging on a physiological process is often not apparent until either the individual faces an unusual challenge or function has fallen below some critical level.

Box 62-1

Frailty

Frailty is a geriatric syndrome prevalent at advanced ages. It has been estimated that 7% of people over age 65 years and 20% of those over age 80 years are frail. According to the Fried frailty criteria, frailty exists when at least three of the following characteristics are present*:

• Unintentional weight loss (4 kg in the past year)

• Self-reported exhaustion

• Weakness (reduced grip strength)

• Slow walking speed

• Low physical activity

Individuals defined as frail using these criteria are at increased risk of falls, worsening disability, hospitalization, and death. Frailty is distinct from age-associated diseases and is not a synonym for disability—the inability to perform one or more of the so-called activities of daily living. In a cohort identified as frail, ~27% of the individuals had neither comorbidity nor disability. However, comorbidity and disability are risk factors for becoming frail, and disability is an adverse outcome of frailty.

Although it had long been believed that long-term involuntary weight loss is due to reduced food intake, newer insights indicate that this is not the case. For example, attempting to increase the patient's food intake is usually not effective. Moreover, rats of advanced ages undergo a prolonged terminal weight loss, even though many of the rats exhibited an increase and not a decrease in food intake during the weight loss (a phenomenon not related to a particular pathological process). The likelihood and extent of frailty rises with increasing steepness as the number of abnormal physiological processes increases.


*The following list is taken from Fried LP, Tangen CM, Walston J, et al: Frailty in older adults. Evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56:M146–M157, 2001.

Aging people lose height and lean body mass but gain and redistribute fat

Women reach peak height by age 16 to 17 years and men by 18 to 19 years. After reaching these peaks, height starts to decline, primarily due to compression of the cartilaginous disks between the vertebrae and loss of vertebral bone. This decline begins at ~20 years of age in women and at 25 years in men. By the age of 70 years, height has fallen 2.5% to 5% from the peak level.

In most Americans, body mass increases until middle age in both sexes and begins to decrease after age 70. Fat-free mass is defined as body mass minus adipose-tissue fat mass, and lean body mass is defined as fat-free mass minus both bone mass and non–adipose-tissue fat mass. Both fat-free mass and lean body mass progressively decrease over most of adult life in both sexes. Although a sedentary lifestyle may contribute to this loss, lifelong athletes also show a progressive age-associated loss in fat-free mass and lean body mass.

Adipose-tissue fat mass increases with adult age, with the extent differing markedly among individuals. Although a sedentary lifestyle may be a factor, even physically fit individuals who do not exhibit an age-associated increase in body mass show a small but progressive increase in adipose-tissue fat mass (in parallel with the aforementioned decrease in fat-free body mass). In addition, the distribution of body fat changes with increasing age, with an accumulation of fat around abdominal viscera and in abdominal subcutaneous tissue. At the same time, a decrease in fat occurs in the extremities and the face; facial fat loss can give rise to a gaunt look. Visceral adipose tissue is an important source of cytokines (often referred to as adipokines) that promote inflammation, which in turn may play a role in the occurrence and progression of senescence.

Aging thins the skin and causes the musculoskeletal system to become weak, brittle, and stiff

Skin

As is clearly evident from cosmetic advertisements, most of us use the skin as an indicator of aging. Intrinsic aging (see p. 1237) is manifest in skin areas protected from the sun, such as the buttocks. The additional damage caused by long-term exposure to the sun's ultraviolet radiation is called photoaging.

In intrinsic aging, the thickness of the epidermis (see pp. 383–384) decreases slightly, with no change in the outermost epidermal layer, the stratum corneum. The rate of generation of keratinocytes, which end their lives as the stratum corneum, slows with age, which increases the dwell time of stratum-corneum components. The decreasing number of melanocytes reduces photoprotection, and the decreasing number of Langerhans cells reduces immune surveillance.

Intrinsic aging of the dermis affects mainly the extracellular matrix. The amount of elastin and collagen decreases, and their structures change. Glycosaminoglycan composition also changes. imageN62-15 As a result, the dermis thins by ~20% and becomes stiffer, less malleable, and thus more vulnerable to injury.

N62-15

Effect of Aging on Glycosaminoglycan Composition

Contributed by Edward Masoro

As indicated in the text, glycosaminoglycan composition changes with aging. However, the story is complex. The levels of hyaluronic acid and the proteoglycan versican—which contains chondroitin sulfate (CS) and dermatan sulfate (DS)—are decreased. On the other hand, the level of the proteoglycan decorin—which also contains CS and DS—is increased.

Photoaging increases the extent of most intrinsic age changes in both the epidermis and dermis, and it has additional effects. For example, photoaging causes coarse wrinkles, which occur minimally or not at all because of intrinsic aging.

Aging also reduces the number and function of sweat glands as well as the production of sebum by sebaceous glands. The number of active melanocytes in hair follicles decreases, resulting in graying of hair. Nail growth also slows with increasing age.

Skeletal Muscle

A steady loss in skeletal muscle mass—sarcopenia—occurs with aging, particularly beyond 50 years, and it primarily reflects a loss of number and, to a lesser extent, size of muscle fibers. The sarcopenia is due in part to inactivity, but also to a progressive loss of the motor neurons innervating type II motor units (see pp. 228–229 and 1205–1206), which are recruited less frequently. With loss of their motor nerve, affected muscle fibers either atrophy and die or become innervated by a sprout that emerges from a healthy axon nearby. This process of reinnervation ultimately results in larger motor units and thus a decrement in fine motor control. The reduction in muscle strength and power is often a major cause of disability in the elderly. However, strength training in elderly persons can increase the size of the fibers and can thereby increase muscle mass.

Bone

Remodeling of bone (see pp. 1057–1058) occurs throughout adult life; it involves the coordinated activity of osteoclasts, which resorb bone, and osteoblasts, which form bone. During early adulthood, bone resorption and formation are in balance. However, starting late in the third decade of life, resorption exceeds formation, which leads to a slow progressive loss in bone mass. This loss is likely due to the action on osteoblasts of ROS, decreased insulin-like growth factor 1 (IGF-1), and increased parathyroid hormone. In women, bone loss accelerates for 5 to 10 years following menopause because of decreased levels of estrogen and increased levels of follicle-stimulating hormone (FSH). After this postmenopausal period, the rate of bone loss with increasing age in women returns to that of men. In addition to the factors noted for bone loss in 20- and 30-year-olds, low levels of estrogen and testosterone are also involved at advanced ages. Bone loss can progress to osteoporosis (see Box 52-3), defined by the World Health Organization as a bone mineral density ≥2.5 SD below the mean values for young adults. Osteoporosis, a major problem in geriatric medicine, carries a heightened risk of bone fractures.

Synovial Joints

The synovial joint permits free movement of the bones linked by the joint. With increasing adult age, joint flexibility falls, due mainly to the aging of articular cartilage. This cartilage thins and exhibits altered mechanical features, including decreased tensile stiffness, fatigue resistance, and strength. These changes are partly due to decreases in water content. Aging impairs the function of chondrocytes, increases the cross-linking of collagen, and causes a loss of proteoglycans. The age-related changes in joint cartilage undoubtedly play a major role in the development of osteoarthritis.

The healthy elderly experience deficits in sensory transduction and speed of central processing

It is a common misconception that advancing age causes marked deterioration in the nervous system. However, in the absence of neurodegenerative disorders such as Alzheimer disease and Parkinson disease, impairment of the nervous system with age is much less severe than often believed.

Sensory Functions

Most sensory systems exhibit some deterioration with age. Sensitivity to touch decreases, as do the abilities to sense vibration and to distinguish two spatially distinct points of contact. Proprioception, including the vestibular system of the inner ear, also deteriorates somewhat. As discussed on page 1194, the loss of thermoregulatory ability, a serious problem for many elderly, occurs in part because of an impaired ability to sense heat and cold.

Hearing loss, particularly of high-frequency sound, is an almost invariable consequence of advancing age. This impairment is usually caused by loss of hair cells of the organ of Corti (see pp. 377–378), but it can also stem from loss of nerve cells of the auditory nerve or from a reduced blood supply to the cochlea. A deficit in central processing can make it difficult for some elderly to distinguish spoken words from background noise.

Vision also deteriorates with increasing age. A progressive loss in the power of accommodation—presbyopia—occurs during adult life (see p. 362). Almost all elderly have a reduced number of retinal cones, lessened ability to alter pupil size in response to light intensity, and decreased ability of retinal rods to adapt to low intensity light (see pp. 368–369). In addition, age-associated diseases—cataracts, glaucoma, and macular degeneration—can markedly decrease vision in many of the elderly.

The ability to detect and discriminate among sweet, sour, salty, and bitter taste qualities (see p. 356) deteriorates somewhat at advanced ages, along with a marked reduction in olfaction (see pp. 354–356). Because “taste” involves both gustation and olfaction, many elderly live in a world of “pastel” food flavors.

Motor Functions

A major effect of aging is the slowing of reaction time: the time elapsed between the occurrence of a stimulus and the motor response to it. This delay is observable in simple responses and becomes more pronounced as the complexity of the response increases (e.g., the need to make a choice among responses). Thus, a hallmark of nervous system aging is the slowing of central processing. One result is that the elderly tend to execute movements more slowly than the young.

The ability to maintain posture and balance deteriorates with increasing age. Slowing of central processing is a factor, but decreased muscle strength and deterioration of vision and proprioception also play important roles. Not surprisingly, the elderly have a high incidence of falls. Even when capable of walking at normal speeds, the healthy elderly tend to walk more slowly than the young and take shorter and more frequent steps. This walking pattern is less taxing for a person with knee and ankle joints that are less flexible, aids in maintaining balance, and enables a deteriorating sensory system to monitor hazards more effectively.

Cognitive Functions

Although lay people generally believe that cognitive functions (e.g., intelligence, memory, learning) decline with advancing age, the cognitive decline is not marked in the absence of dementia. The decline that does occur in the healthy elderly may reflect the slowing of central processing. The capacity to use knowledge is not decreased in the healthy aged, but the ability to solve novel problems does decline. Certain types of memory deteriorate with advancing age, such as remembering where the car keys were left, but other types are not lost, such as retrieving conceptual information. Older people are capable of learning, but they do so less quickly than younger people.

Aging causes decreased arterial compliance and increased ventilation-perfusion mismatching

Atherosclerosis can cause marked deterioration of cardiovascular function in the elderly, and chronic obstructive pulmonary disease (see p. 619) can do the same for pulmonary function. However, in the absence of such diseases, age-associated changes in these physiological systems are modest.

Cardiovascular Function

As discussed on pages 458–459, aging decreases the distensibility of arteries. The decreased compliance elevates systolic pressure, slightly decreases diastolic pressure, and thus widens pulse pressure. Afterload (see p. 526), the resistance to ejection of blood from the left ventricle, increases with advancing age, primarily because of reduced arterial compliance. The increased afterload causes thickening of the left ventricular wall, which involves an increase in size but not number of myocytes.

Preload, the end-diastolic volume of blood in the left ventricle (see p. 526), does not change with age in subjects at rest. Although early diastolic filling falls, a compensatory increase in left atrial contraction enhances late-diastolic filling.

Many elderly experience postural hypotension (see p. 576) because of age-associated blunting of the arterial baroreceptor reflex.

Pulmonary Function

The strength and endurance of the respiratory muscles decrease with age, primarily because of atrophy of type IIa muscle fibers. Lung volumes—both static volumes and forced expiratory volumes (e.g., FEV1; see p. 602) gradually decrease with age. In addition, small airways have an increased tendency to collapse (atelectasis) because of degeneration of the collagen and elastin support structure. The result is impaired ventilation of dependent lung regions, ventilation-perfusion mismatch, and reduced resting arterial image. In spite of these functional deteriorations, healthy elderly people do not experience a failure of either ventilation or gas exchange. However, when challenged by homeostatic disturbances—such as those occurring during ill health—old people may have compromised pulmonary function.

Exercise

Maximal O2 uptake (image; see pp. 1213–1214) declines progressively with aging in physically trained individuals and even more so in untrained individuals of the same chronological age. Decreasing muscle mass as well as reduced cardiovascular and pulmonary function probably all contribute to the decline in image, and the relative importance of each factor varies among individuals.

The cardiovascular system responds to exercise differently in the elderly than in the young. For a given increase in cardiac output, heart rate rises less and stroke volume rises more in the elderly. Because the aging heart is less responsive to adrenergic stimulation, the increase in stroke volume is due primarily to the Frank-Starling mechanism (see pp. 524–526). Thus, during exercise, the left ventricular end-diastolic and end-systolic volumes increase, and maximal left ventricular ejection fraction falls.

The elderly exhibit a decrease in the pulmonary diffusing capacity (DL)—due in part to decreased alveolar capillary volume—and an increase in the ventilation-perfusion mismatch. These alterations in pulmonary function have been implicated in the decrease in image.

The ability of the body to respond to physical conditioning decreases with aging. Nevertheless, skeletal muscle and the cardiovascular system remain responsive to exercise into the 10th decade of life.

Glomerular filtration rate falls with age in many but not all people

On average, renal blood flow decreases progressively with increasing age. Basal levels of renin and angiotensin II are lower in older adults. Cross-sectional studies show that glomerular filtration rate (GFR) starts to decline at 30 years of age and thereafter falls linearly with age. However, analysis of longitudinal data from the Baltimore Longitudinal Study of Aging reveals that one third of the participants exhibited the GFR decline predicted from cross-sectional analysis, one third had a steeper decline, and one third had no decline at all. Thus, an age-associated decline in GFR is not inevitable.

Cross-sectional studies indicate that renal-tubule transport functions decrease with age. The kidneys do not respond as effectively to changes in sodium load, do not dilute or concentrate urine as effectively, and also have a somewhat impaired ability to excrete potassium, phosphate, and acid.

Many elderly men and women experience bladder symptoms such as urgency, nocturia, and frequency. The capacity and compliance of the urinary bladder decrease with advancing age, and the number of uninhibited or inappropriate detrusor contractions increases. These changes make it more difficult to postpone voiding, a symptom known as urgency. A decrease in detrusor activity can contribute to a decreased rate of bladder emptying as well as an increase in residual bladder volume after voiding—poor emptying performance, which contributes to urinary frequency.imageN62-16 Sensory dysfunction also can underlie the above pathologic conditions.

N62-16

Effect of Aging on Bladder Function

Contributed by Edward Masoro

A decrease in the rate of urine flow with age occurs in both sexes. In men, benign prostatic hypertrophy (BPH) is the major factor causing an increase in residual bladder volume after voiding. However, a small increase with age often occurs in women as well.

Aging has only minor effects on gastrointestinal function

Although gastrointestinal (GI) problems are the second most common reason for hospital admission of elderly patients, the GI system functions in the healthy elderly about as well as in the young. Although a loss of ability to secrete gastric acid was previously thought to be a part of aging, it is now clear that this loss is limited to those infected with Helicobacter pylori (see Box 42-3). The loss of skeletal muscle at both ends of the GI tract can lead to minor age-related decreases in function (i.e., chewing, swallowing, fecal continence). imageN62-17 Minor decreases occur in secretion by exocrine glands. Liver mass and hepatic blood flow, as well as the clearance of certain drugs, decrease significantly. Moreover, the elderly experience a delay in hepatic regeneration following damage.

N62-17

Effect of Aging on the GI Tract

Contributed by Edward Masoro

Aging is associated with a loss in the mass of the skeletal muscles at both ends of the GI tract. At the oral end, muscles involved in mastication and the oropharyngeal phase of swallowing tend to decrease in mass. However, the loss usually is not sufficient to cause morbidity.

The frequency of fecal incontinence increases with age. The problem is underreported because it is often hidden, even from physicians. Weakness of the external anal sphincter is often an important contributory factor.

Aging causes modest declines in most endocrine functions

Total energy expenditure decreases with age, primarily due to decreases in physical activity. An age-associated decrease in the resting metabolic rate (RMR; see p. 1170) reflects a decrease in fat-free mass (see p. 1243); that is, the RMR per kilogram of fat-free mass does not decrease.

Insulin

The impaired glucose tolerance (see Fig. 51-3) that usually occurs with aging is due primarily to increased insulin resistance, which in turn results mainly from increased adiposity and decreased physical activity. However, aging per se does play a small role. In addition, the elderly exhibit an age-associated decrease in insulin secretion that does not appear to be due to the lifestyle factors underlying insulin resistance.

Growth Hormone and IGF-1

Aging diminishes the concentrations of growth hormone (GH) generated by the pulsatile action of somatotrophs. A consequence is greatly reduced plasma IGF-1 concentrations (see p. 997). However, it is not clear what roles, if any, these alterations play in age-associated physiological deterioration.

Adrenal Steroids

The basal, circadian, and stimulated secretion of cortisol exhibits little age-related change. Aldosterone secretion is also well preserved. In contrast, the plasma concentration of the adrenal cortical hormone dehydroepiandrosterone (see p. 1097) decreases markedly with increasing age.

Thyroid Hormones

Thyroid function appears to be unaffected by age into the ninth decade of life. However, in centenarians plasma levels of thyroid-stimulating hormone (TSH) may decrease due to decreased secretion, and free triiodothyronine levels may fall due to impaired 5′/3′-deiodinase (see p. 1010).

Parathyroid Hormone

Plasma parathyroid hormone levels increase with advancing age due to an increase in the rate of secretion by the parathyroid glands.

Gonadal Hormones

Reproductive ability in women abruptly ceases at ~50 years of age with the occurrence of the menopause (see pp. 1127–1128). Men do not undergo an abrupt change in reproductive function during middle age. However, a progressive decrease in male reproductive and related functions does occur, often referred to as the andropause (see Box 54-1).