CLINICAL PHYSIOLOGY OF AGING
LEWIS A. LIPSITZ
Regulation of Oxygen and Metabolic Substrate Delivery to Vital Organs
Maintaining Structural Integrity
Mobility and Balance
Physiology is the integration of a complex network of control systems and feedback loops that enable an organism to perform a variety of functions necessary for survival. The control systems of the human body exist at molecular, subcellular, cellular, organ, and systemic levels of organization. Continuous interplay among the electrical, chemical, and mechanical components of these systems ensures that information is constantly exchanged, even as the organism rests. These dynamic processes give rise to a highly adaptive, resilient organism, which is primed and ready to respond to internal and external perturbations.
Recognition of the dynamic nature of regulatory processes challenges the traditional view of physiology, which was based on Walter B. Cannon’s concept of homeostasis. The principle of homeostasis states that all healthy cells, tissues, and organs maintain static or steady-state conditions in their internal environment. However, with the introduction of techniques that can acquire continuous data from physiologic processes, such as heart rate, blood pressure, nerve activity, or hormonal secretion, it became apparent that these systems are in constant flux, even under so-called steady-state conditions. Dr. Eugene Yates introduced the term homeodynamics to convey the fact that the high level of bodily control required to survive depends on a dynamic interplay of multiple regulatory mechanisms rather than constancy in the internal environment.
Although it is often difficult to separate the effects of aging from those of disease and lifestyle changes such as reduced physical activity, even aging without such confounding, secondary factors (primary aging) appears to have a profound impact on physiologic processes. Because of the progressive degeneration of various tissues and organs and the interruption of communication pathways between them, complex physiologic networks break down, become disconnected, and lose some of their capacity to adapt to stress.
There is considerable redundancy in many of these systems; for example, humans have far more muscle mass, neuronal circuitry, renal nephrons, and hormonal stores than are needed to survive. This physiologic reserve allows most persons to compensate effectively for age-related changes. Because the network structure of physiologic systems also enables alternate pathways to be used to achieve the same functions, physiologic changes that result from aging alone usually do not have much impact on everyday life. However, these changes may become manifest at times of increased demand, when the body is subjected to high levels of physiologic stress. For this reason, elderly persons are particularly vulnerable to falls, confusion, or incontinence when exposed to environmental, pharmacologic, or emotional stresses.
The traditional approach to the study of physiology is to divide the topic into separate organ-based systems, such as cardiovascular, respiratory, endocrine, immune, and neurologic systems. However, this approach ignores the integrated, cross-system nature of physiology. This chapter addresses the major functional roles of physiologic processes and how they are affected by normal aging.
REGULATION OF OXYGEN AND METABOLIC SUBSTRATE DELIVERY TO VITAL ORGANS
The vitality of all living tissues in the body depends on the delivery of optimal supplies of oxygen and glucose or other metabolic substrates to meet energy requirements during rest and exertion. This critical process relies on a complicated transport system, which picks up oxygen from the lungs and nutrients and metabolic substrates from the gastrointestinal tract or musculature, centrifugally delivers different amounts of these substances to different sites depending on the immediate need, and self-adjusts in response to transient perturbations. In reciprocal centripetal fashion, this system serves to deliver waste products to sites of excretion from the body, notably the kidney and liver. This circulatory system consists of the liquid and cellular components of the blood, vascular tree, cardiac pump, lungs, chemoreceptors, baroreceptors, and neuroendocrine communications between each of these structures. The driving force behind the delivery system is the arterial blood pressure.
AGE-RELATED CHANGES IN BLOOD PRESSURE REGULATION
Blood pressure is the product of heart rate, stroke volume, and systemic vascular resistance. Alterations in the response of any of these parameters may threaten adequate perfusion of vital organs. Normal human aging is associated with several changes that influence these three components of normal blood pressure regulation.
The baroreflex maintains a normal blood pressure by increasing heart rate (cardiovagal baroreflex) and vascular resistance (sympathetic vascular baroreflex) in response to transient reductions in blood pressure and by decreasing these parameters in response to elevations in blood pressure. Reduced sensitivity of the cardiovagal baroreflex is evident in the blunted cardioacceleratory response to stimuli (upright posture, nitroprusside infusions, phase II of the Valsalva maneuver, and lower-body negative pressure, for example) that lower blood pressure, and in a reduced bradycardic response to drugs such as phenylephrine or phase IV of the Valsalva that elevate blood pressure. Alteration of the sympathetic baroreflex is manifested as a blunted vasoconstrictor response to sympathetic outflow from the central nervous system. As a result of abnormal baroreflex function, elderly people have increased blood pressure variability, often with potentially dangerous blood pressure reductions during hypotensive stresses, such as upright posture or meal ingestion.
SYMPATHETIC NERVOUS SYSTEM AND END-ORGAN RESPONSE
Studies of sympathetic nervous system activity in healthy humans demonstrate an age-related increase in resting plasma norepinephrine levels and muscle sympathetic nerve activity, as well as the plasma norepinephrine response to upright posture and exercise. The elevation in plasma norepinephrine results primarily from an increased presynaptic norepinephrine secretion rate and secondarily from decreased clearance. Despite apparent elevations in sympathetic nervous system activity with aging, cardiac and vascular responsiveness is diminished. Infusions of b-adrenergic agonists result in smaller increases in heart rate, left ventricular ejection fraction, cardiac output, and vasodilation in older compared with younger men.
Age effects on the heart have been attributed to multiple molecular and biochemical changes in b-receptor coupling and postreceptor events. The number of b receptors on cardiac myocytes is unchanged with advancing age, but the affinity of b receptors for agonists is reduced. Postreceptor changes that occur with aging include a decrease in the activity of stimulatory G protein (Gs), the adenylate cyclase catalytic unit, and cAMP (cyclic adenosine monophosphate)-dependent phosphokinase-induced protein phosphorylation. As a result of these changes, G-protein–mediated signal transduction is impaired.
The decrease in cardiac contractile response to b-adrenergic stimulation has been studied in rat ventricular myocytes, where it appears to be related to decreased influx of calcium ions through sarcolemmal calcium channels and a reduction in the amplitude of the cytosolic calcium transit. These changes are similar to those seen in receptor desensitization owing to prolonged exposure of myocardial tissue to b-adrenergic agonists. Age-associated alterations in the b-adrenergic response may result from desensitization of the adenylate cyclase system in response to chronic elevations of plasma catecholamine levels.
The vascular response to sympathetic stimulation has received less attention, but it also appears to be altered by aging. The vasorelaxation response of arteries and veins to infusions of the b-adrenergic agonist isoproterenol is attenuated in elderly people (Fig. 16.1). a-Adrenergic vasoconstrictor responses to norepinephrine infusion also appear to be reduced in healthy elderly subjects (Fig. 16.2). The fact that this impairment is reversed by suppression of sympathetic nervous system activity with guanadrel suggests that it is also caused by receptor desensitization in response to heightened sympathetic nervous system activity. Thus, some of the physiologic changes associated with aging may be reversible.
FIGURE 16.1. Effects of isoproterenol infusion in preconstricted dorsal hand veins in the six populations studied. (From Pan HY-M, Hoffman BB, Pershe RA, Blaschke TF. Decline in beta adrenergic receptor-mediated vascular relaxation with aging in man. J Pharmacol Exp Ther 1986;239:802, with permission.)
FIGURE 16.2. Group mean data for the percent change in forearm blood flow from the baseline values in response to intra-arterial infusions of norepinephrine (NE) in young (—O—) and older (—
—) subjects. (From Hogikyan RV, Supiano MA. Arterial a-adrenergic responsiveness is decreased and SNS activity is increased in older humans. Am J Physiol 1994;266:E717, with permission.)
AUTONOMIC CONTROL OF HEART RATE
Alterations in sympathetic and parasympathetic influences on the heart may also influence the heart rate response to blood pressure changes. Previous studies demonstrating age-related reductions in overall heart rate variability in response to respiration, cough, and the Valsalva maneuver suggest that aging is associated with impaired vagal control of heart rate. Elderly patients with unexplained syncope have even greater impairments in heart rate responses to cough and deep breathing than elderly persons without syncope.
The age-related attenuation of autonomic, neurohumoral, and other influences on heart rate results in a reduction in heart rate variability and in a marked change in the dynamics of beat-to-beat heart rate fluctuations. As shown in Figure 16.3, the highly irregular, complex dynamics of heart rate variability characteristic of healthy young individuals are lost with healthy aging, resulting in a more regular and predictable heart rate time series. This loss of complexity in heart rate dynamics can be generalized to the fluctuating output of many different physiologic processes as they age. For example, measurements of continuous blood pressure, electroencephalographic waves, frequently sampled thyrotropin or luteinizing hormone levels, and center-of-pressure changes during quiet stance all show more regular, less complex behavior with aging. This apparent loss of dynamic range in physiologic functions may reflect fewer regulatory influences as a person ages, leading to an impaired capacity to adapt to stress.
FIGURE 16.3. Heart rate time series for (A) a 22-year-old woman and (B) a 73-year-old man. Approximate entropy is a measure of “nonlinear complexity.” Despite the nearly identical means and standard deviations of heart rate for the two time series, the complexity of the signal from the older subject is markedly reduced. (From Lipsitz LA, Goldberger AL. Loss of “complexity” and aging: potential applications of fractals and chaos theory to senescence. JAMA 1992;267:1806, with permission.)
CARDIAC VENTRICULAR FUNCTION
The maintenance of a normal blood pressure also depends on the ability to generate an adequate cardiac output. Cardiac output at rest and during exercise tends to decrease with normal aging because of a reduction in heart rate response to b-adrenergic stimulation and because of changes in systolic and diastolic myocardial performance, which influence stroke volume.
As a result of increased cross-linking of myocardial collagen and a prolonged ventricular relaxation time, the aged heart stiffens, and early diastolic ventricular filling becomes impaired (Fig. 16.4). The age-related impairment in early ventricular filling makes the heart depend on adequate preload to fill the ventricle and on atrial contraction during late diastole to maintain stroke volume. Orthostatic hypotension and syncope occur commonly in older persons as a result of volume contraction or venous pooling, which reduces cardiac preload, or as a result of the onset of atrial fibrillation when the atrial contribution to cardiac output is suddenly lost. These changes also render the elderly person more vulnerable to congestive heart failure attributable to diastolic dysfunction.
FIGURE 16.4. Cumulative percentage of the left ventricular end-diastolic volume filled during each third of diastole for young (dotted line) and old (dashed line) subjects. Notice the marked reduction in early diastolic filling and greater percentage of filling in late diastole in elderly subjects compared with young persons. (From Lipsitz LA, Jonsson PV, Marks BL, et al. Reduced supine cardiac volumes and diastolic filling rates in elderly patients with chronic medical conditions: implications for postural blood pressure homeostasis. JAGS 1990;38:103, with permission.)
With aging, myocardial contractile strength is preserved, but left ventricular ejection fraction in response to exertion decreases because of reduced b-adrenergic responsiveness and an increased afterload. Afterload, which represents opposition to left ventricular ejection, increases progressively with aging because of stiffening of the ascending aorta and narrowing of the peripheral vasculature. These changes result in an increase in systolic blood pressure with aging and a decrease in the maximum cardiac output during exercise.
The cardiac response to exercise is different in healthy young and old subjects (Fig. 16.5). Although the young increase cardiac output by increases in heart rate and decreases in end-systolic volume (greater contractility), the healthy elderly do so by increasing end-diastolic volume (cardiac dilatation). The elderly thus rely on the Frank–Starling relation to achieve an increase in stroke volume during exercise more than do younger persons. A similar mechanism can be demonstrated in young subjects during b-adrenergic blockade, suggesting that the age effect is caused by reduced b-adrenergic responsiveness.
FIGURE 16.5. Heart rate (top panel) and cardiac volumes (bottom panel) at end diastole and end systole at rest and during graded levels of exercise on a cycle ergometer in older and younger individuals. A blunted heart rate and cardiac dilatation at end diastole and end systole are characteristic features of the exercise response in older persons. (From Rodeheffer RJ, Gerstenblith G, Becker LC, et al. Exercise cardiac output is maintained with advancing age in healthy human subjects: cardiac dilatation and increased stroke volume compensate for a diminished heart rate. Circulation 1984;69:203, with permission.)
The age-related decrease in maximal cardiac output during exercise may also be related to a sedentary lifestyle and consequent cardiovascular deconditioning. A 6-month endurance exercise training program has been shown to enhance end-diastolic volume and contractility, thereby increasing ejection fraction, stroke volume, and cardiac output at peak exercise in elderly men. This illustrates the difficulty in teasing apart the changes occurring with aging that may be primary (and irreversible) from those that are secondary to age-associated changes in lifestyle.
INTRAVASCULAR VOLUME REGULATION
Adequate organ perfusion pressure depends on the maintenance of intravascular volume. Aging is associated with a progressive decline in plasma renin, angiotensin II, and aldosterone levels and with elevations in atrial natriuretic peptide, all of which promote salt and water wasting by the kidney. Healthy elderly people do not experience the same sense of thirst as younger persons when they become hyperosmolar during water deprivation. Dehydration and hypotension may develop rapidly during conditions such as a febrile illness, preparation for a medical procedure, or exposure to a warm climate when insensible fluid losses are increased or access to oral fluids is limited. The interaction between volume contraction and impaired diastolic function may threaten cardiac output and result in hypotension and organ ischemia.
REGULATION OF ORGAN BLOOD FLOW
The regulation of blood flow to various circulatory beds depends on complex interactions among the endothelium, local vasoactive peptides, neuroendocrine influences, and mechanical forces. In angiographically normal coronary arteries and forearm resistance vessels, the endothelium-dependent vasodilatory response to acetylcholine is reduced with aging.
Normal human aging is also associated with a reduction in cerebral blood flow, which is further compromised by the presence of risk factors for cerebrovascular disease. Although it is not clear whether the decline in cerebral blood flow results from reduced supply or demand, elderly persons, particularly those with cerebrovascular disease, probably have a resting cerebral blood flow that is closer to the threshold for cerebral ischemia. Consequently, relatively small, short-term reductions in blood pressure may produce cerebral ischemic symptoms.
The brain normally maintains a constant blood flow over a wide range of perfusion pressures through the process of autoregulation. During reductions in blood pressure, resistance vessels in the brain dilate to restore blood flow to normal. Although the effects of aging on cerebral autoregulation have received little attention, limited data suggest that the autoregulation of cerebral blood flow is preserved into old age. However, patients with symptomatic orthostatic hypotension appear to have a reduction in cerebral blood flow in response to decreased perfusion pressure.
CONTROL OF RESPIRATION
The delivery of necessary substrates for oxidative metabolism depends on maintaining an optimal tissue perfusion pressure and on the availability of oxygen from the lungs. Pulmonary and circulatory physiology are closely linked, enabling adjustments in heart rate, cardiac output, blood pressure, and organ flow to be made in response to changing demands for oxygen.
Aging is associated with a reduction in the partial pressure of oxygen in the blood, primarily caused by a mismatch of ventilation and perfusion in the dependent portions of the lungs. This results from a reduction in lung compliance, which causes airways to close prematurely at higher lung volumes (i.e., increased closing volume) within the range of vital capacity. The relative hypoxemia in advanced age was thought to be offset by a reduced tissue demand for oxygen (reduced maximal oxygen uptake). However, much of the reduction in maximum oxygen consumption (VO2max) is attributable to reduced muscle mass and is reversible with endurance exercise training.
Chemoreceptors located in brain stem respiratory centers adjust respiratory amplitude and frequency on a moment-to-moment basis to ensure adequate oxygen availability and carbon dioxide clearance in the blood. Longer-term changes in oxygen supply and demand are matched by finely tuned adjustments in the sensitivity (i.e., gain) of chemoreceptors. With advancing age, chemosensitivity to oxygen and carbon dioxide tension declines, resulting in relative hypoventilation in response to hypoxemia or hypercarbia. Therefore, older persons may be more vulnerable to vital organ ischemia during stresses such as surgery, acute pulmonary infections, or high altitude, when oxygen availability is reduced.
Another critical physiologic function is the production of sufficient energy to meet the metabolic demands of the body. This process requires the intake and processing of energy substrate (carbohydrate, fat, and protein) in the gastrointestinal tract; conversion of these substrates to simple sugars, fatty acids, or amino acids; production of glucose or ketoacids by the liver for oxidative metabolism; insulin-mediated uptake of glucose by metabolically active cells; and participation in the biochemical pathways leading to energy storage in high-energy phosphate bonds (i.e., adenosine triphosphate [ATP] production). Age-related changes in this complex system have not been fully elucidated, and research has focused primarily on the summary measures of resting metabolic rate and daily energy expenditure.
Resting metabolic rate is usually determined by indirect calorimetry, which measures the rate of oxygen consumption (VO2) during quiet, supine rest under fasting and thermoneutral conditions. The resting metabolic rate decreases with aging. Daily energy expenditure, which is measured by the doubly labeled water technique, includes the resting metabolic rate, the thermic response to feeding, and the energy expenditure of physical activity. Daily energy expenditure also declines with advancing age. However, the resting metabolic rate and daily energy expenditure are strongly influenced by physical fitness and activity, nutritional intake, and body composition, all of which may change over time. Many of the changes in energy metabolism observed in the elderly may reflect altered physical activity and loss of fat-free mass rather than biologic aging.
An exercise program that increases fat-free mass and energy intake can enhance energy expenditure in healthy elderly persons. Because the thermic effect of feeding is higher in physically trained than inactive older men, much of the age-associated reduction in energy expenditure is probably attributable to the adoption of a sedentary lifestyle, with its associated reduction in muscle mass.
Age-related changes in body composition may lead to a variety of disease states in the elderly. If energy intake remains constant despite reductions in physical activity, older individuals accumulate body fat. After a 3-week period of overfeeding, young men develop hypophagia and lose their excess body weight, but older men do not. This impairment in control of food intake and accumulation of body fat may lead to obesity, glucose intolerance, and hypertension.
The decline in glucose tolerance with advancing age has been well documented. It is manifested by modest elevations in fasting plasma glucose levels (approximately 1 mg per deciliter per decade) and marked elevations in 2-hour postprandial glucose levels (approximately 5 mg per liter per decade) during an oral glucose tolerance test. The glucose intolerance of aging is related to peripheral insulin resistance, caused by a postreceptor defect in target tissue insulin action. There is no age-related change in the number or affinity of insulin receptors or in maximal tissue responsiveness to insulin. However, healthy elderly subjects require larger quantities of insulin to achieve a level of glucose uptake similar to that of the young (Fig. 16.6).
FIGURE 16.6. Dose-response curves for insulin-mediated whole body glucose infusion rates in young (dashed line) and old (solid line) subjects. A (left): Glucose disposal is expressed as milligrams per kilogram of body weight. B (right): Glucose infusion rates are normalized for lean body mass. Elderly persons have reduced sensitivity to insulin but no change in maximal glucose disposal. (From Rowe JW, Minaker KL, Pallotta JA. Characterization of the insulin resistance of aging. Reproduced from J Clin Invest 1983;71:1581 by copyright permission of the American Society for Clinical Investigation.)
Studies of glucose-stimulated insulin secretion in healthy humans have shown impairments in insulin secretory capacity with advancing age. This is balanced by a reduction in insulin clearance, the net result of which is no change in circulating insulin levels. However, the presence of “normal” circulating insulin levels in the face of hyperglycemia suggests that insulin secretion is inappropriately low. Aging thus appears to be associated with insulin resistance and impaired insulin secretion.
Although insulin resistance was once thought to be a natural consequence of biologic aging independent of carbohydrate intake, body composition, or physical activity, studies have shown elevations in body mass index and mean arterial blood pressure to be significant predictors of reduced insulin sensitivity, regardless of age. Insulin resistance can be improved by exercise training. Glucose intolerance may also result from age-associated decreases in physical activity and fat-free mass. Because of the association between chronic hyperglycemia and the development of atherosclerotic cardiovascular disease, renal disease, neuropathy, and retinopathy, the glucose intolerance of advanced age has profound implications in the pathogenesis and prevention of disease in old age. This condition should not be considered a harmless, age-related process; it should be treated as a significant risk factor for disability, which may be preventable through physical exercise and proper nutrition.
The ability of the human body to defend itself from external pathogens and to prevent toxic effects of chemical exposures and metabolic by-products relies on the presence of integrated physiologic networks that cross multiple organ systems. Many of the components of these networks are altered by the aging process, making older persons more vulnerable to infectious disease, toxic drug effects, and malignancy (Table 16.1).
TABLE 16.1. PHYSIOLOGIC DEFENSES AND THEIR CHANGES WITH AGE
One of the invariant changes that occurs with advancing age is the progressive atrophy and dissolution of the thymus. As a result, thymic hormones are no longer detectable after 60 years of age, and the number of immature, undifferentiated T lymphocytes increases. The number of circulating B and T cells probably does not change with aging, but the number of T cells able to respond to an antigenic challenge or mitogenic stimulus is greatly reduced. Cells that can respond to a stimulus and enter the cell cycle appear to have a decreased ability to divide sequentially in culture.
The defect in T-lymphocyte response may reflect alterations in various lymphokines, particularly interleukin-2 (IL-2). The production of IL-2 by stimulated CD4 helper cells and the response to IL-2 by proliferating cells are reduced in the elderly, partly because of the loss of thymic hormones that augment IL-2 production by proliferating cells in culture. There appears to be a defect in the ability of lymphocytes to express IL-2 mRNA and in the IL-2 high-affinity receptor (Tac antigen). In addition to alterations in intercellular signaling, many cells lose their intrinsic ability to respond to various stimuli. Alterations in cytoskeletal structures, DNA repair mechanisms, membrane properties, enzyme activity, and protein synthesis all affect cellular responses.
B-cell production of antigen-specific antibodies is reduced with aging, in large part because of a reduction in helper T cells and increased activity of suppressor T cells. It appears as if a breakdown of communication pathways between cells rather than alterations in the intrinsic properties of the cellular components themselves is primarily responsible for immune senescence. Decreased T-cell control of B-cell function also may be responsible for the marked increase in monoclonal immunoglobulin levels seen in the elderly. Elevations of monoclonal immunoglobulins (M components) in the serum may be asymptomatic and benign, or they may be associated with malignancies such as multiple myeloma, Waldenström’s macroglobulinemia, primary amyloidosis, or heavy-chain disease. The fact that monoclonal gammopathies can be induced in young mice by ablation of the thymus gland and induction of inflammation by endotoxin lends support to the notion that dysregulation of immune function in the elderly is related in part to loss of thymic hormones.
Aging is also associated with an increase in autoantibodies such as anti-DNA or antithyroglobulin antibodies, although without an associated increase in autoimmune disease. This has been attributed partly to an increase in autoanti-idiotypic antibodies, which react with the antigen-binding portion of the immunoglobulin molecule and suppress the formation of other normal antibodies.
In addition to alterations in cellular components of the immune system, changes in soluble factors other than IL-2 also occur. The synthesis of inflammatory mediators such as tumor necrosis factor-a (TNF-a), IL-6, and interferon-a are increased with aging, although IL-1 has been reported to decrease.
Protection against infectious agents, foreign bodies, and chemical exposures depends on an intact immune system and on physical impediments to entry into the body. These defensive barriers include the skin, acid environment in the stomach, and respiratory mucociliary clearance mechanisms. Their changes with aging are summarized in Table 16.1.
Several organ systems participate in the metabolism and removal of potentially toxic chemicals and drugs from the body, particularly the liver and kidneys. These organs undergo changes with age that interfere with chemical defense functions. Most important of these are a reduction in hepatic blood flow that reduces first-pass elimination of drugs such as verapamil and propranolol, an impairment in hepatic oxidation and demethylation reactions that metabolize many of the long-acting benzodiazepines, and reduced renal blood flow and glomerular filtration rate, which reduce the clearance of drugs such as digoxin and the aminoglycosides (Chapter 469).
The kidneys participate in defense of the internal chemical environment of the body by maintaining intravascular volume as discussed previously and by excreting excess acid, sodium, potassium, and water. The ability to excrete an acid load is impaired with aging. This may result from a decrease in nephron mass and resultant reduction in the production of urinary ammonium and phosphorus. The ability to excrete an acute sodium load and, probably, a potassium load is reduced with aging, principally because of a decline in the glomerular filtration rate. Elderly persons require almost twice as long as young persons to excrete equivalent amounts of salt.
Normal aging is associated with an impairment in water excretion. After a water load, the elderly have less free water clearance and a higher minimum urine osmolality than middle-aged or young persons. This is largely attributable to an age-related decrease in the glomerular filtration rate, rather than inappropriate vasopressin secretion.
MAINTAINING STRUCTURAL INTEGRITY
Maintaining a skeletal framework sufficiently strong to withstand the stresses of physical activity is an essential physiologic function that depends on the complex interaction of multiple organ systems, hormones, local growth factors, cytokines, osteocytes, and biochemical pathways leading to calcium deposition in bone. The organs that participate in this function include the skin, kidneys, liver, small intestine, parathyroid and thyroid glands, and bone. They produce various hormonal signals that ultimately regulate calcium deposition and mobilization in bone. These hormones are estrogen or testosterone, vitamin D, parathyroid hormone, and calcitonin.
Maintaining skeletal integrity is a dynamic process, characterized by constant bone turnover or remodeling. Periods of bone resorption, mediated by osteoclasts, alternate with bone formation, mediated by osteoblasts. This cyclic process is normally closely coupled, resulting in no net change in bone mass. However, with aging and particularly after menopause in women, there is a relative increase in resorption over formation, resulting in osteoporosis. The acceleration of bone loss after menopause implicates estrogen deficiency as one of the key factors influencing age-related bone loss. However, bone loss also occurs in men, although at a slower rate than in women. Bone loss may be caused by testosterone deficiency in some elderly men or by calcium malabsorption, which is another major determinant of bone loss in both sexes.
Estrogen regulates the production of cytokines and growth factors that control bone remodeling. Stimulation of peripheral blood monocytes by estrogen decreases IL-1 and TNF-a production, inhibiting IL-6 production by osteoblasts and the effect of this cytokine on osteoclast formation and bone resorption. Estrogen decreases granulocyte-macrophage colony-stimulating factor (GM-CSF), which inhibits osteoclast differentiation. Estrogen also stimulates transforming growth factor-b (TGF-b) production by osteoblasts, which decreases osteoclast-mediated bone resorption. Estrogen deficiency results in an increase in IL-1, TNF-a, GM-CSF, and IL-6 and a decrease in TGF-b production, all of which promote osteoclast formation and bone resorption.