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Older People: Physiological Changes
Physiological Changes N Solomons, Aging and Metabolism (CeSSIAM), Guatemala City, Guatemala r 2013 Elsevier Ltd. All rights reserved. This article is reproduced from the previous edition, volume 3, pp 431–437, r 2005, Elsevier Ltd.
The Aging of the Population and its People The maximal human life span is approximately 120 years. Approaching this degree of longevity, however, was not a prominent feature in the evolutionary phases of our species, Homo sapiens. The imperative was to survive the various mortal hazards long enough to reproduce and provide initial care for the offspring. The twenty-first century has ushered in an unprecedented longevity. The life expectancy of infants born today in Western Europe or Japan is more than 75 years. The most rapidly increasing population segment in the world today is the centenarian. By the year 2020, there will be more than 1 billion people older than 60 years of age, constituting 13.3% of the global population, and three-quarters of them will be living in developing countries. Many people are living a long time, but not all of them are healthy and functional throughout their lifespan. Chronic disability and the cost of health services and custodial care are a growing burden on the economies of developed and developing countries alike. To understand the pathological aspects of advancing age, the normative pattern of changes in physiological function in older persons is an essential benchmark.
The Nature of Senescence Aging has been described as ‘‘a series of time-related processes that ultimately bring life to a close,’’ that is, a process of physiological ‘wearing out.’ Physiology is the basis of human functionality as well as of our susceptibility to disease. The late gerontologist, Nathan Shock, established the principle of a progressive decline in physiological reserves as a consequence of ‘normal’ aging, recognizing that the rate of decline differed markedly among the body’s organ systems. In fact, one cannot really separate the concept of the physiology of older persons from the physiology of the aging process itself. Similarly, the high prevalence of chronic diseases in older persons challenges our ability to discriminate ‘normative’ senescence from pathophysiological changes. The origin of physiological changes in older persons begins within the domain of cellular senescence. The extension to tissue and organ levels originates in what we interpret to be the physiological changes of human aging. Major advances in our cellular and molecular understanding of basic aging processes have been made in recent years.
Cellular Senescence In most tissues, with the notable exception of neural tissue, healthy cells are replicating cells, which are capable of mobilizing at least 20 enzymes and proteins that must be
400
preassembled to initiate deoxyribonucleic acid (DNA) synthesis for cell division. An irreversible state of growth arrest known as replicative senescence is the fundamental basis of cellular aging. Such senescent cells remain viable and metabolically active, but their genomic function and protein expression are distinct from that of normal, proliferating cells. Iron accumulates in senescent cells, possibly contributing to the greater oxidative stress and cellular dysfunction seen in senescent cells. Senescent cells also express proinflammatory enzymes, an internal process that could possibly contribute to the aging process; intercellular adhesion molecules, which are part of the inflammatory response, are overexpressed in association with senescent cells and aging tissue.
Telomeres and Telomerase Telomeres are small units composed of the tandem DNA repeats and associated proteins, which cap the end of linear chromosomes and are responsible for maintaining chromosome length. They provide stability to the chromosome and protect against DNA loss associated with cellular replication. The mechanism of replicative arrest of senescent cells has been related to changes in the function of telomerase, a nuclear enzyme that synthesizes and maintains the telomeres. Shortening and uncapping of these structures, related to the number of past cell divisions, renders the DNA strand incapable of replication.
Apoptosis Another factor involved in aging at the cellular level is the orderly ‘retirement’ of cells. For every cell that divides in, another would somehow have to make space for the extra cell in order to maintain numerical stability in the organ. This is achieved by a process of programmed cell death, known as ‘apoptosis.’ Cell senescence disrupts these apoptotic processes. Necrosis, by contrast, is cell death due to injury or noxious stimuli. Diseases of aging may favor the necrotic process.
Mitochondrial Senescence and Oxidative Stress The intracellular mitochondria, organelles involved in energy metabolism, are central to the process of cell senescence. They are also involved in regulating thermogenesis, calcium buffering, and integrating apoptosis. With aging, mitochondria become less efficient, partly due to mutations in the cell nucleus, derepressing the expression of proteins that compete with mitochondrial function. This disrupts energy metabolism for the cell and makes the mitochondria more porous, releasing reactive oxygen species into the rest of the cell. The mitochondrial production of reactive oxygen species is
Encyclopedia of Human Nutrition, Volume 3
http://dx.doi.org/10.1016/B978-0-12-375083-9.00219-1
Older People: Physiological Changes
inversely proportional to longevity in animals. The oxidative activity also damages the mitochondria themselves. Mitochondria have their own DNA strands, and these accumulate mutations with age. In tissues dependent on progenitor (stem) cells, mitochondrial DNA mutations can disrupt replication. Free radicals and reactive oxidative species can produce mutations in nuclear material and oxidize proteins and lipids throughout the cells. Aging involves an accumulation of oxidative damage at the cellular level, if not an increase in its intensity as well. The thiol-containing antioxidant mechanisms, typified by glutathione but represented by a number of sulfur-containing species, represent an important buffer against intracellular free radicals, but decline with age due to downregulation of their synthetic enzymes. Confirming the cellular trend to oxidative stress in aging cells, clinical biomarkers of oxidation, and antioxidant mechanisms reveal that systemic oxidative stress increases with aging characterized by lower concentrations of vitamins E and C and carotenes as well as lower activities of Cu–Zn–superoxide dismutase, catalase, and glutathione peroxidase.
Physiological Changes Occurring in Tissues and Organ Systems with Human Aging Physiology has classically been organized around organ systems. According to this convention, the important features of the age-associated changes are enumerated and synthesized, with implications for human nutrition.
Integumentary Tissues The integumentary tissues (skin, hair, and nails) cover and protect the body. Two of the more classical and reproducible manifestations of aging can be seen in this system. The depigmentation of hair to gray or white is an almost universal aging effect given its sufficient survival. Wrinkling of the skin, due to alteration in connective tissue composition, is another consequence of aging; it should be assessed by the changes in skin texture only in the nonsun-exposed regions of the body. Beyond the cosmetic consequences of the aging integumentary tissues, wound healing is a health-relevant consideration. Healing of wounds is slower with increasing age, but the resulting scars have the same tensile strength. Reduced recruitment of vessels of the microvascular is a function of aging. The skin is an endocrine organ. Vitamin D is produced from the conversion of 7-hydroxy-cholesterol to cholecalciferol in the dermis of the skin. The efficiency of vitamin D decreases with age, such that older persons need a longer exposure to solar radiation to produce a given quantity of the vitamin.
Pulmonary and Respiratory System Compliance of the chest wall changes with age, which gets stiffer and less compliant. The muscular force of the diaphragm is reduced with advancing years. The combination of these two factors reduces the maximal amount of air that can
401
be moved into and out of the lungs. This diminution in the socalled forced vital capacity of the lungs occurs as one gets older. There is less compliance, less recoil, and greater dead space. The original lung capacity, however, is sufficient to allow for sufficient gas exchange throughout life in the absence of underlying pulmonary disease. Nonetheless, the longitudinal Framingham Heart Study found an association between decrease in lung capacity and all-cause mortality. The hygiene of the respiratory airways is somewhat compromised by a decreasing function of the microcilia of the bronchial epithelial cells. Because this mechanism is used to clear microbial pathogens, it has a direct influence on host defenses. Finally, because the basis of the respiratory system is an exchange of gases (oxygen, carbon dioxide, trace gases) with the bloodstream, any cardiovascular changes involving the side chambers of the heart will influence the overall gas exchange efficiency for the body.
Cardiovascular and Circulatory System For this system, it is necessary to separate the aging effects on the cardiac muscle and its apparatus from the aging of the vessels of the circulatory system, which transports blood to and from the heart. A characteristic of aging is a diminished resting cardiac output, which can have the combined bases of lower force of the cardiac muscle and a lesser oxygen demand for metabolism with diminished active cell mass. Aging of the myocardium reduces its capacity for cellular repair and replacement. With aging, elevations of noradrenaline (norepinephrine) associated with downregulation of b-1 receptors mimic the process of the failing heart. The compliance of the arteries emanating from the heart decreases with age. Stiffening of these vessels produces a progressive rise in the systolic blood pressure. It is the circulation through smaller blood vessels and the generation of new vessels (neovascularization) that is a major concern with advancing years. The process of angiogenesis, through which new blood vessels are formed, is impaired during aging. The integrity of endothelial cells lining the vessels, the cascade of coagulation factors, and growth factors and neurochemical mediators, and their respective receptors are all altered by aging in the neovascularization processes.
Oral Cavity and Alimentary Tract The digestive tract is subject to functional changes with aging. Beginning in the oral cavity, loosening and loss of teeth is a frequent companion of aging. Saliva secretion decreases leading to relative degrees of xerostomia or dry mouth. Reduced parietal cell function develops in older persons, but prior Helicobacter pylori infections are now thought to be a major cause of hypochlorhydria in later life. An important nutritional consequence of reduced gastric acid secretion is a lesser biological availability of iron. Because iron stores are generally replete in both men and women in later life, this has little practical nutritional impact. The reduced secretion of gastric intrinsic factor, however, contributes to vitamin B12 deficiency, which is an important nutritional problem of older persons.
402
Older People: Physiological Changes
The capacity of the liver for biliary secretion and the pancreas for digestive enzyme and bicarbonate secretion begins adult life with a 490% excess of the necessary minimum. Secretory function declines with increasing age, but rarely falls below the minimal reserve capacity. The metabolic and detoxifying capacity of the human liver also has a reserve capacity and is not usually compromised by normal aging. Intestinal motility is reduced with aging as a result of functional changes in the visceral nerves. With decreased transit, the residence time of the chyme on the absorptive surfaces is longer, compensating for any senescence in the mucosal uptake itself. The reduction in motility produces the most noticeable and notorious of the manifestations of intestinal health in older persons, namely reduced frequency of defecations.
Gonads and Reproductive System It has been aptly stated by Harman that: ‘‘It is clear that aging results in alterations of endocrine physiology, which in turn appear to contribute to development of the senescent phenotype.’’ Aging is associated with a decrease in pituitary hormone secretions. This decline explains, in part, the reduction in gonadal hormone production with aging. Primary aging of the testes and ovaries themselves accounts for the remainder of the changes. As the ovaries have a finite number of eggs, ovulation can only continue through the number of cycles that correspond to the original store of ova. Menopause ensues with the characteristic cessation of estrogenic hormone secretion. In both sexes, gonadal androgenic hormone production declines with consequent effects on libido.
Endocrine Systems and Metabolism Musculoskeletal System Bone mineral content declines with age; this aging process is known as ‘osteopenia.’ (It should be distinguished from the related pathological process in which bone architecture is altered, producing ‘osteoporosis.’) From the peak in the third and fourth decades, a 30% average decline in bone mineral density occurs through the ninth decade. In women, there is well-characterized acceleration of the rate of bone mineral loss immediately following the menopause. Decreasing levels of anabolic hormones may be associated with musculoskeletal atrophy and decrease in function that is observed in older women. This change in skeletal mineralization with aging is not associated with any apparent change in vitamin D nutriture as reflected in circulating levels of the vitamin. The joints of the body undergo changes with the senescence of replacement of the cartilaginous substance, complicated by the pathological effects of cumulative use over the life span. Recently, increasing attention has been given to the loss of muscle strength and substance with increasing age. Sarcopenia loss of lean body mass skeletal muscle mass replacement by fat mass decreased creatinine-to-height ratio in normative aging in healthy subjects diminished grip strength is a function of age. Reduction in muscle mass (sarcopenia obesity) is an important determinant of physical function and metabolic rate.
As stated above, the pituitary gland is the hub of endocrine regulation. Important among the decline stimulation within the axis is that growth hormone (GH) secretion declines with increasing age, a condition termed ‘somatopause.’ The changes in the GH/insulin-like growth factor axis with aging produce changes in function, metabolism, and body composition analogous to the pathological GH deficiency seen in younger adults. Another change with age is the efficiency with which physical activity stimulates the secretion of GH. The availability of hormones is not the only variable in endocrine signaling. Cellular and intracellular receptor function is complementary. An attractive explanation for the disordering of hormonal axes is oxidative damage to cell membranes, compromising the function of receptors. Basal and resting metabolism and diet-induced thermogenesis are all reduced with increasing age. Changes in body composition, and the replacement of lean tissue with fat and the increasing visceral distribution of fat, as well as decreasing physical activity, influence these metabolic changes of aging. Basal metabolic rate declines in aging more than can be attributed to body composition changes and intracellular mitochondrial senescence may explain part of this discrepancy. For practical purposes, the standard oxygen consumption value equivalent to one metabolic equivalent, that is, 3.5 ml min 1 kg 1, is not appropriate for elderly people.
Renal and Urogenital System
Hematopoietic and Immune System
Renal creatinine and inulin clearance decreases with aging have been demonstrated for decades. These functional changes in filtration are associated with changes in the glomerular structure in the kidney. Circulatory senescence decreases blood flow to the kidneys, which further reduces the efficiency of renal clearance. The reserve capacity of these organs is such, however, that age-associated glomerular decline per se does not compromise the net excretion of nitrogenous waste. Urine flow at the outlet is another aging consideration. The male urogenital system undergoes a characteristic aging change in the hypertrophy of the prostate gland, associated with decreased secretion of prostatic fluid. The anatomical consequence is a constriction in the passage through which urine flows from the bladder.
The formation of new red and white blood cells and platelets is one of the most proliferation-dependent physiological processes of the body. The various classes of circulating white cells are the underpinning of the host defense system, together with tissue macrophages, hepatic proteins, and the alimentary tract’s mucosa.
Hematological Aging The blood-forming organ is the bone marrow. Aging is associated with fatty infiltration of the marrow spaces in the long bones, but enough marrow remains to support the turnover of erythrocytes and red blood cell lines. The circulating red blood cell mass neither changes normally with advancing age nor does the normative peripheral white cell count or platelet
Older People: Physiological Changes
number. As noted, iron stores tend to be abundant in later life; nutritional problems influencing red blood cell production are based on alterations in gastric function (vitamin B12 malabsorption), which result in a macrocytic (megaloblastic) anemia.
Immunological Aging Circulating phagocytic white blood cells counts do not reduce with aging but aging does influence the innate host defense system. Mucosal barrier functions are influenced by aging of the gut in its interaction with microflora. Although not reduced in number, aged macrophages and neutrophils have blunted intracellular signaling by specific receptors, decreased metabolic functions, and impaired bacterial killing. Production of superoxide anion, chemotaxis, and orderly apoptosis of neutrophils is also disrupted by the disordered signaling. The tumor cell-destroying capacity of natural killer cells in the elderly is diminished. More profound changes occur in the adaptive immune functions, which rely on the memory (T-cell) lymphocytic cell line. Life-long antigen exposure induces increases in the number of memory T-cells, but with enhanced reactivity against self-antigens, priming the individual for autoimmune disease. In healthy adults, immunoglobulin A concentration increases by 0.2 g l 1 per decade throughout life. The T-lymphocytes, however, respond more poorly to ongoing antigen assault in later life. Thymic involution associated with neural and hormonal changes of aging is an impediment to T-cell maturation in older persons. The basis of intrinsic function deficits of memory cells, however, has been ascribed to defective signaling and includes hyporesponsiveness to mitogen-stimulated proliferation and decrease in genetic suppression, allowing increased stimulation of inflammatory cytokines; the balance between pro- and anti-inflammatory cytokines shifts with aging, favoring the inflammatory pole, especially with the greater expression of interleukin 6. This has a negative systemic effect on bone metabolism, as well as dysregulating overall immune function. Aging of mitochondria in the immune cell lines produces increased intracellular reactive oxygen species burdens. Finally, there is diminished programmed death (apoptosis) of immune cells and dysregulation of apoptosis-dependent functions.
Central and Peripheral Nervous System The integration of all senses and origins of all systemic coordination is a function of the brain and central nervous system. This is the one system in which proliferation of the primary cells (neurons) is not an issue after early childhood, although the supportive, nerve-tending (glial) cells continue to depend on replication and apoptosis for normal function.
Central Nervous System The neurons of the brain continue to divide only through to the second year of life. Thereafter, the goal is to preserve the number and health of the cerebral nerve cell mass. Myelination of axons of nerve cells must be maintained throughout life. This is the function of the supporting cells
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(oligodendrocytes), which for more than 40 years continue to differentiate into myelin-producing cells. Free radicals pose a threat to these axon-tending cells, whose metabolic demands for producing the brain’s cholesterol and maintaining its array of myelin sheaths render them particularly vulnerable to stress. Positron emission tomography imaging of the aging brain has revealed and mapped the plethora of changes in blood flow and neurotransmitter metabolism that occurs with advancing years.
Special Senses The special senses related directly to the cranial nerves (vision, hearing, taste, and smell) experience age-related change. With respect to vision, the most typical of all biological aging changes is presbyopia, or the loss of accommodation function for the ocular lens with loss of capacity of the associated musculature. The consequence is loss of near-vision, which leads to the need for reading glasses or bifocal spectacles. A more important aging change related to the lens is the opacification that leads to cataract formation. The eye is designed to translate light energy into visual images, but the energy of light, particularly the ultraviolet b-rays of solar energy, damages ocular tissue. Thus, there is as a strong environmental component to the disarranging of the laminar stacking of the fibrillar proteins of the lens, which imparts its clear, transparent basis; consumption of diets high in antioxidant vitamins has been associated with the delay in cataract formation. Age-related hearing loss is a feature of biological aging. It affects the cochlear neural structures and leads to loss of acuity, especially for higher pitched tones. It is speculated that apoptosis of the most vital neural cells drives this hearing loss, based on mutations in the mitochondria due to life-long free-radical stress. Taste and smell acuity decline with aging, both in sensitivity and in accuracy of recognition. Because these combined senses account for the recognition of flavors, their diminution with age could affect appetite and reduce the enjoyment of meals.
Cognitive Function The intellectual, reasoning, and memory functions of the cerebral cortex decline with increasing age. This has been a universal observation in general elderly populations. The debate is whether this is a consequence of neurodegenerative diseases (pathological change) or a biological correlate of aging (senescence). Continued intellectual stimulation has been posited as an approach to retard cognitive decline, and a role for B-complex vitamins and antioxidants has been advanced.
Peripheral Nervous System Vibratory perception in the peripheral extremities is the classical index of peripheral nervous decline with aging. Less well appreciated is the effect of aging on pain perception, in which there can be a numbing of sensation or, less commonly, an accentuation of perception. Pain perception from the visceral organs is often dulled, which can have adverse implications for the early detection of organic diseases. All of the peripheral nerve dysfunction can result from the compensatory sprouting
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Older People: Physiological Changes
of axonal limbs to compensate for the loss of motor neurons. This is well directed at first, but with further aging, the synaptic connections are poorly directed and motor function suffers as a consequence.
Drug Metabolism The metabolism of drugs and pharmacological agents is not the purview of any single organ system. Older persons tend to be prescribed increasing numbers of medications with advancing age. Important changes in drug metabolism occur with aging. Metabolism and disposition of drugs change with age. This involves age-associated decrease in the function of some, but not all, cytochrome P-450 enzymes. Among the pharmacokinetic and pharmacodynamic changes that occur with advancing age are reductions in renal and hepatic clearance and an increased effective half-life of lipid-soluble drugs. The older population shows increased sensitivity to some psychotropic drugs and anticoagulants, with the frail elderly being more susceptible than healthy elders.
Synthesis and Conclusion The number of older people is increasing in all regions and all societies of the world. Advancing age produces senescent changes in cellular function that are reflected in a declining capacity of all physiological systems. The increased prevalence of disease in older population aging is a major risk factor for disease but does not necessarily lead to age-related diseases. All physiological systems are intrinsically interrelated in maintaining the health and function of the organism. Aging is associated with a loss of complexity in the dynamics of many physiological systems. It has been speculated that the basis for the syndrome of frailty in older persons may result from a reduced ability to adapt to internal and external stresses of
daily life due to the loss of dynamic coordination among the interrelated physiological systems. The alterations in physiological functions with aging have important implications for absorbing, retaining, and utilizing nutrients. The extent to which dietary patterns and nutrient intakes are accelerating or retarding the rates of functional decline is a matter of ongoing investigation in gerontological nutrition and physiology.
See also: Aging. Brain and Nervous System: Biology, Metabolism, and Nutritional Requirements. Cytokines: Nutritional Aspects. Older People: Nutritional Management of; Nutritional Requirements. Osteoporosis: Nutritional Factors. Vitamin K
Further Reading Ahluwalia N (2004) Aging, nutrition and immune function. Journal of Nutrition, Health and Aging 8: 2–6. Balin AK (ed.) (1994) Practical Handbook of Human Biologic Age Determination. Boca Raton: CRC Press. Harman SM (2004) What do hormones have to do with aging? What does aging have to do with hormones? Annals of the New York Academy of Science 1019: 299–308. Hayflick L (2003) Living forever and dying in the attempt. Experimental Gerontology 38: 1231–1241. Hutchinson ML and Munro HN (1986) Nutrition and Aging: Bristol-Meyer Nutrition Symposia, vol. 5, Academic Press. Leveille SG (2004) Musculoskeletal aging. Current Opinion in Rheumatology 16: 114–118. Lipsitz LA (2004) Physiological complexity, aging, and the path to frailty. Science of Aging Knowledge Environment 16: 16. Mishra SK and Misra V (2003) Muscle sarcopenia: An overview. Acta Myol 22: 43–47. Park HL, O’Connell JE, and Thomson RG (2003) A systematic review of cognitive decline in the general elderly population. Internation Journal of Geriatric Psychiatry 18: 1121–1134. Timiras PS (1994) Physiological Basis of Aging and Geriatrics, 2nd edn. Baton Raton: CRC Press.
The Aging of the Population and its People The maximal human life span is approximately 120 years. Approaching this degree of longevity, however, was not a prominent feature in the evolutionary phases of our species, Homo sapiens. The imperative was to survive the various mortal hazards long enough to reproduce and provide initial care for the offspring. The twenty-first century has ushered in an unprecedented longevity. The life expectancy of infants born today in Western Europe or Japan is more than 75 years. The most rapidly increasing population segment in the world today is the centenarian. By the year 2020, there will be more than 1 billion people older than 60 years of age, constituting 13.3% of the global population, and three-quarters of them will be living in developing countries. Many people are living a long time, but not all of them are healthy and functional throughout their lifespan. Chronic disability and the cost of health services and custodial care are a growing burden on the economies of developed and developing countries alike. To understand the pathological aspects of advancing age, the normative pattern of changes in physiological function in older persons is an essential benchmark.
The Nature of Senescence Aging has been described as ‘‘a series of time-related processes that ultimately bring life to a close,’’ that is, a process of physiological ‘wearing out.’ Physiology is the basis of human functionality as well as of our susceptibility to disease. The late gerontologist, Nathan Shock, established the principle of a progressive decline in physiological reserves as a consequence of ‘normal’ aging, recognizing that the rate of decline differed markedly among the body’s organ systems. In fact, one cannot really separate the concept of the physiology of older persons from the physiology of the aging process itself. Similarly, the high prevalence of chronic diseases in older persons challenges our ability to discriminate ‘normative’ senescence from pathophysiological changes. The origin of physiological changes in older persons begins within the domain of cellular senescence. The extension to tissue and organ levels originates in what we interpret to be the physiological changes of human aging. Major advances in our cellular and molecular understanding of basic aging processes have been made in recent years.
Cellular Senescence In most tissues, with the notable exception of neural tissue, healthy cells are replicating cells, which are capable of mobilizing at least 20 enzymes and proteins that must be
400
preassembled to initiate deoxyribonucleic acid (DNA) synthesis for cell division. An irreversible state of growth arrest known as replicative senescence is the fundamental basis of cellular aging. Such senescent cells remain viable and metabolically active, but their genomic function and protein expression are distinct from that of normal, proliferating cells. Iron accumulates in senescent cells, possibly contributing to the greater oxidative stress and cellular dysfunction seen in senescent cells. Senescent cells also express proinflammatory enzymes, an internal process that could possibly contribute to the aging process; intercellular adhesion molecules, which are part of the inflammatory response, are overexpressed in association with senescent cells and aging tissue.
Telomeres and Telomerase Telomeres are small units composed of the tandem DNA repeats and associated proteins, which cap the end of linear chromosomes and are responsible for maintaining chromosome length. They provide stability to the chromosome and protect against DNA loss associated with cellular replication. The mechanism of replicative arrest of senescent cells has been related to changes in the function of telomerase, a nuclear enzyme that synthesizes and maintains the telomeres. Shortening and uncapping of these structures, related to the number of past cell divisions, renders the DNA strand incapable of replication.
Apoptosis Another factor involved in aging at the cellular level is the orderly ‘retirement’ of cells. For every cell that divides in, another would somehow have to make space for the extra cell in order to maintain numerical stability in the organ. This is achieved by a process of programmed cell death, known as ‘apoptosis.’ Cell senescence disrupts these apoptotic processes. Necrosis, by contrast, is cell death due to injury or noxious stimuli. Diseases of aging may favor the necrotic process.
Mitochondrial Senescence and Oxidative Stress The intracellular mitochondria, organelles involved in energy metabolism, are central to the process of cell senescence. They are also involved in regulating thermogenesis, calcium buffering, and integrating apoptosis. With aging, mitochondria become less efficient, partly due to mutations in the cell nucleus, derepressing the expression of proteins that compete with mitochondrial function. This disrupts energy metabolism for the cell and makes the mitochondria more porous, releasing reactive oxygen species into the rest of the cell. The mitochondrial production of reactive oxygen species is
Encyclopedia of Human Nutrition, Volume 3
http://dx.doi.org/10.1016/B978-0-12-375083-9.00219-1
Older People: Physiological Changes
inversely proportional to longevity in animals. The oxidative activity also damages the mitochondria themselves. Mitochondria have their own DNA strands, and these accumulate mutations with age. In tissues dependent on progenitor (stem) cells, mitochondrial DNA mutations can disrupt replication. Free radicals and reactive oxidative species can produce mutations in nuclear material and oxidize proteins and lipids throughout the cells. Aging involves an accumulation of oxidative damage at the cellular level, if not an increase in its intensity as well. The thiol-containing antioxidant mechanisms, typified by glutathione but represented by a number of sulfur-containing species, represent an important buffer against intracellular free radicals, but decline with age due to downregulation of their synthetic enzymes. Confirming the cellular trend to oxidative stress in aging cells, clinical biomarkers of oxidation, and antioxidant mechanisms reveal that systemic oxidative stress increases with aging characterized by lower concentrations of vitamins E and C and carotenes as well as lower activities of Cu–Zn–superoxide dismutase, catalase, and glutathione peroxidase.
Physiological Changes Occurring in Tissues and Organ Systems with Human Aging Physiology has classically been organized around organ systems. According to this convention, the important features of the age-associated changes are enumerated and synthesized, with implications for human nutrition.
Integumentary Tissues The integumentary tissues (skin, hair, and nails) cover and protect the body. Two of the more classical and reproducible manifestations of aging can be seen in this system. The depigmentation of hair to gray or white is an almost universal aging effect given its sufficient survival. Wrinkling of the skin, due to alteration in connective tissue composition, is another consequence of aging; it should be assessed by the changes in skin texture only in the nonsun-exposed regions of the body. Beyond the cosmetic consequences of the aging integumentary tissues, wound healing is a health-relevant consideration. Healing of wounds is slower with increasing age, but the resulting scars have the same tensile strength. Reduced recruitment of vessels of the microvascular is a function of aging. The skin is an endocrine organ. Vitamin D is produced from the conversion of 7-hydroxy-cholesterol to cholecalciferol in the dermis of the skin. The efficiency of vitamin D decreases with age, such that older persons need a longer exposure to solar radiation to produce a given quantity of the vitamin.
Pulmonary and Respiratory System Compliance of the chest wall changes with age, which gets stiffer and less compliant. The muscular force of the diaphragm is reduced with advancing years. The combination of these two factors reduces the maximal amount of air that can
401
be moved into and out of the lungs. This diminution in the socalled forced vital capacity of the lungs occurs as one gets older. There is less compliance, less recoil, and greater dead space. The original lung capacity, however, is sufficient to allow for sufficient gas exchange throughout life in the absence of underlying pulmonary disease. Nonetheless, the longitudinal Framingham Heart Study found an association between decrease in lung capacity and all-cause mortality. The hygiene of the respiratory airways is somewhat compromised by a decreasing function of the microcilia of the bronchial epithelial cells. Because this mechanism is used to clear microbial pathogens, it has a direct influence on host defenses. Finally, because the basis of the respiratory system is an exchange of gases (oxygen, carbon dioxide, trace gases) with the bloodstream, any cardiovascular changes involving the side chambers of the heart will influence the overall gas exchange efficiency for the body.
Cardiovascular and Circulatory System For this system, it is necessary to separate the aging effects on the cardiac muscle and its apparatus from the aging of the vessels of the circulatory system, which transports blood to and from the heart. A characteristic of aging is a diminished resting cardiac output, which can have the combined bases of lower force of the cardiac muscle and a lesser oxygen demand for metabolism with diminished active cell mass. Aging of the myocardium reduces its capacity for cellular repair and replacement. With aging, elevations of noradrenaline (norepinephrine) associated with downregulation of b-1 receptors mimic the process of the failing heart. The compliance of the arteries emanating from the heart decreases with age. Stiffening of these vessels produces a progressive rise in the systolic blood pressure. It is the circulation through smaller blood vessels and the generation of new vessels (neovascularization) that is a major concern with advancing years. The process of angiogenesis, through which new blood vessels are formed, is impaired during aging. The integrity of endothelial cells lining the vessels, the cascade of coagulation factors, and growth factors and neurochemical mediators, and their respective receptors are all altered by aging in the neovascularization processes.
Oral Cavity and Alimentary Tract The digestive tract is subject to functional changes with aging. Beginning in the oral cavity, loosening and loss of teeth is a frequent companion of aging. Saliva secretion decreases leading to relative degrees of xerostomia or dry mouth. Reduced parietal cell function develops in older persons, but prior Helicobacter pylori infections are now thought to be a major cause of hypochlorhydria in later life. An important nutritional consequence of reduced gastric acid secretion is a lesser biological availability of iron. Because iron stores are generally replete in both men and women in later life, this has little practical nutritional impact. The reduced secretion of gastric intrinsic factor, however, contributes to vitamin B12 deficiency, which is an important nutritional problem of older persons.
402
Older People: Physiological Changes
The capacity of the liver for biliary secretion and the pancreas for digestive enzyme and bicarbonate secretion begins adult life with a 490% excess of the necessary minimum. Secretory function declines with increasing age, but rarely falls below the minimal reserve capacity. The metabolic and detoxifying capacity of the human liver also has a reserve capacity and is not usually compromised by normal aging. Intestinal motility is reduced with aging as a result of functional changes in the visceral nerves. With decreased transit, the residence time of the chyme on the absorptive surfaces is longer, compensating for any senescence in the mucosal uptake itself. The reduction in motility produces the most noticeable and notorious of the manifestations of intestinal health in older persons, namely reduced frequency of defecations.
Gonads and Reproductive System It has been aptly stated by Harman that: ‘‘It is clear that aging results in alterations of endocrine physiology, which in turn appear to contribute to development of the senescent phenotype.’’ Aging is associated with a decrease in pituitary hormone secretions. This decline explains, in part, the reduction in gonadal hormone production with aging. Primary aging of the testes and ovaries themselves accounts for the remainder of the changes. As the ovaries have a finite number of eggs, ovulation can only continue through the number of cycles that correspond to the original store of ova. Menopause ensues with the characteristic cessation of estrogenic hormone secretion. In both sexes, gonadal androgenic hormone production declines with consequent effects on libido.
Endocrine Systems and Metabolism Musculoskeletal System Bone mineral content declines with age; this aging process is known as ‘osteopenia.’ (It should be distinguished from the related pathological process in which bone architecture is altered, producing ‘osteoporosis.’) From the peak in the third and fourth decades, a 30% average decline in bone mineral density occurs through the ninth decade. In women, there is well-characterized acceleration of the rate of bone mineral loss immediately following the menopause. Decreasing levels of anabolic hormones may be associated with musculoskeletal atrophy and decrease in function that is observed in older women. This change in skeletal mineralization with aging is not associated with any apparent change in vitamin D nutriture as reflected in circulating levels of the vitamin. The joints of the body undergo changes with the senescence of replacement of the cartilaginous substance, complicated by the pathological effects of cumulative use over the life span. Recently, increasing attention has been given to the loss of muscle strength and substance with increasing age. Sarcopenia loss of lean body mass skeletal muscle mass replacement by fat mass decreased creatinine-to-height ratio in normative aging in healthy subjects diminished grip strength is a function of age. Reduction in muscle mass (sarcopenia obesity) is an important determinant of physical function and metabolic rate.
As stated above, the pituitary gland is the hub of endocrine regulation. Important among the decline stimulation within the axis is that growth hormone (GH) secretion declines with increasing age, a condition termed ‘somatopause.’ The changes in the GH/insulin-like growth factor axis with aging produce changes in function, metabolism, and body composition analogous to the pathological GH deficiency seen in younger adults. Another change with age is the efficiency with which physical activity stimulates the secretion of GH. The availability of hormones is not the only variable in endocrine signaling. Cellular and intracellular receptor function is complementary. An attractive explanation for the disordering of hormonal axes is oxidative damage to cell membranes, compromising the function of receptors. Basal and resting metabolism and diet-induced thermogenesis are all reduced with increasing age. Changes in body composition, and the replacement of lean tissue with fat and the increasing visceral distribution of fat, as well as decreasing physical activity, influence these metabolic changes of aging. Basal metabolic rate declines in aging more than can be attributed to body composition changes and intracellular mitochondrial senescence may explain part of this discrepancy. For practical purposes, the standard oxygen consumption value equivalent to one metabolic equivalent, that is, 3.5 ml min 1 kg 1, is not appropriate for elderly people.
Renal and Urogenital System
Hematopoietic and Immune System
Renal creatinine and inulin clearance decreases with aging have been demonstrated for decades. These functional changes in filtration are associated with changes in the glomerular structure in the kidney. Circulatory senescence decreases blood flow to the kidneys, which further reduces the efficiency of renal clearance. The reserve capacity of these organs is such, however, that age-associated glomerular decline per se does not compromise the net excretion of nitrogenous waste. Urine flow at the outlet is another aging consideration. The male urogenital system undergoes a characteristic aging change in the hypertrophy of the prostate gland, associated with decreased secretion of prostatic fluid. The anatomical consequence is a constriction in the passage through which urine flows from the bladder.
The formation of new red and white blood cells and platelets is one of the most proliferation-dependent physiological processes of the body. The various classes of circulating white cells are the underpinning of the host defense system, together with tissue macrophages, hepatic proteins, and the alimentary tract’s mucosa.
Hematological Aging The blood-forming organ is the bone marrow. Aging is associated with fatty infiltration of the marrow spaces in the long bones, but enough marrow remains to support the turnover of erythrocytes and red blood cell lines. The circulating red blood cell mass neither changes normally with advancing age nor does the normative peripheral white cell count or platelet
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number. As noted, iron stores tend to be abundant in later life; nutritional problems influencing red blood cell production are based on alterations in gastric function (vitamin B12 malabsorption), which result in a macrocytic (megaloblastic) anemia.
Immunological Aging Circulating phagocytic white blood cells counts do not reduce with aging but aging does influence the innate host defense system. Mucosal barrier functions are influenced by aging of the gut in its interaction with microflora. Although not reduced in number, aged macrophages and neutrophils have blunted intracellular signaling by specific receptors, decreased metabolic functions, and impaired bacterial killing. Production of superoxide anion, chemotaxis, and orderly apoptosis of neutrophils is also disrupted by the disordered signaling. The tumor cell-destroying capacity of natural killer cells in the elderly is diminished. More profound changes occur in the adaptive immune functions, which rely on the memory (T-cell) lymphocytic cell line. Life-long antigen exposure induces increases in the number of memory T-cells, but with enhanced reactivity against self-antigens, priming the individual for autoimmune disease. In healthy adults, immunoglobulin A concentration increases by 0.2 g l 1 per decade throughout life. The T-lymphocytes, however, respond more poorly to ongoing antigen assault in later life. Thymic involution associated with neural and hormonal changes of aging is an impediment to T-cell maturation in older persons. The basis of intrinsic function deficits of memory cells, however, has been ascribed to defective signaling and includes hyporesponsiveness to mitogen-stimulated proliferation and decrease in genetic suppression, allowing increased stimulation of inflammatory cytokines; the balance between pro- and anti-inflammatory cytokines shifts with aging, favoring the inflammatory pole, especially with the greater expression of interleukin 6. This has a negative systemic effect on bone metabolism, as well as dysregulating overall immune function. Aging of mitochondria in the immune cell lines produces increased intracellular reactive oxygen species burdens. Finally, there is diminished programmed death (apoptosis) of immune cells and dysregulation of apoptosis-dependent functions.
Central and Peripheral Nervous System The integration of all senses and origins of all systemic coordination is a function of the brain and central nervous system. This is the one system in which proliferation of the primary cells (neurons) is not an issue after early childhood, although the supportive, nerve-tending (glial) cells continue to depend on replication and apoptosis for normal function.
Central Nervous System The neurons of the brain continue to divide only through to the second year of life. Thereafter, the goal is to preserve the number and health of the cerebral nerve cell mass. Myelination of axons of nerve cells must be maintained throughout life. This is the function of the supporting cells
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(oligodendrocytes), which for more than 40 years continue to differentiate into myelin-producing cells. Free radicals pose a threat to these axon-tending cells, whose metabolic demands for producing the brain’s cholesterol and maintaining its array of myelin sheaths render them particularly vulnerable to stress. Positron emission tomography imaging of the aging brain has revealed and mapped the plethora of changes in blood flow and neurotransmitter metabolism that occurs with advancing years.
Special Senses The special senses related directly to the cranial nerves (vision, hearing, taste, and smell) experience age-related change. With respect to vision, the most typical of all biological aging changes is presbyopia, or the loss of accommodation function for the ocular lens with loss of capacity of the associated musculature. The consequence is loss of near-vision, which leads to the need for reading glasses or bifocal spectacles. A more important aging change related to the lens is the opacification that leads to cataract formation. The eye is designed to translate light energy into visual images, but the energy of light, particularly the ultraviolet b-rays of solar energy, damages ocular tissue. Thus, there is as a strong environmental component to the disarranging of the laminar stacking of the fibrillar proteins of the lens, which imparts its clear, transparent basis; consumption of diets high in antioxidant vitamins has been associated with the delay in cataract formation. Age-related hearing loss is a feature of biological aging. It affects the cochlear neural structures and leads to loss of acuity, especially for higher pitched tones. It is speculated that apoptosis of the most vital neural cells drives this hearing loss, based on mutations in the mitochondria due to life-long free-radical stress. Taste and smell acuity decline with aging, both in sensitivity and in accuracy of recognition. Because these combined senses account for the recognition of flavors, their diminution with age could affect appetite and reduce the enjoyment of meals.
Cognitive Function The intellectual, reasoning, and memory functions of the cerebral cortex decline with increasing age. This has been a universal observation in general elderly populations. The debate is whether this is a consequence of neurodegenerative diseases (pathological change) or a biological correlate of aging (senescence). Continued intellectual stimulation has been posited as an approach to retard cognitive decline, and a role for B-complex vitamins and antioxidants has been advanced.
Peripheral Nervous System Vibratory perception in the peripheral extremities is the classical index of peripheral nervous decline with aging. Less well appreciated is the effect of aging on pain perception, in which there can be a numbing of sensation or, less commonly, an accentuation of perception. Pain perception from the visceral organs is often dulled, which can have adverse implications for the early detection of organic diseases. All of the peripheral nerve dysfunction can result from the compensatory sprouting
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of axonal limbs to compensate for the loss of motor neurons. This is well directed at first, but with further aging, the synaptic connections are poorly directed and motor function suffers as a consequence.
Drug Metabolism The metabolism of drugs and pharmacological agents is not the purview of any single organ system. Older persons tend to be prescribed increasing numbers of medications with advancing age. Important changes in drug metabolism occur with aging. Metabolism and disposition of drugs change with age. This involves age-associated decrease in the function of some, but not all, cytochrome P-450 enzymes. Among the pharmacokinetic and pharmacodynamic changes that occur with advancing age are reductions in renal and hepatic clearance and an increased effective half-life of lipid-soluble drugs. The older population shows increased sensitivity to some psychotropic drugs and anticoagulants, with the frail elderly being more susceptible than healthy elders.
Synthesis and Conclusion The number of older people is increasing in all regions and all societies of the world. Advancing age produces senescent changes in cellular function that are reflected in a declining capacity of all physiological systems. The increased prevalence of disease in older population aging is a major risk factor for disease but does not necessarily lead to age-related diseases. All physiological systems are intrinsically interrelated in maintaining the health and function of the organism. Aging is associated with a loss of complexity in the dynamics of many physiological systems. It has been speculated that the basis for the syndrome of frailty in older persons may result from a reduced ability to adapt to internal and external stresses of
daily life due to the loss of dynamic coordination among the interrelated physiological systems. The alterations in physiological functions with aging have important implications for absorbing, retaining, and utilizing nutrients. The extent to which dietary patterns and nutrient intakes are accelerating or retarding the rates of functional decline is a matter of ongoing investigation in gerontological nutrition and physiology.
See also: Aging. Brain and Nervous System: Biology, Metabolism, and Nutritional Requirements. Cytokines: Nutritional Aspects. Older People: Nutritional Management of; Nutritional Requirements. Osteoporosis: Nutritional Factors. Vitamin K
Further Reading Ahluwalia N (2004) Aging, nutrition and immune function. Journal of Nutrition, Health and Aging 8: 2–6. Balin AK (ed.) (1994) Practical Handbook of Human Biologic Age Determination. Boca Raton: CRC Press. Harman SM (2004) What do hormones have to do with aging? What does aging have to do with hormones? Annals of the New York Academy of Science 1019: 299–308. Hayflick L (2003) Living forever and dying in the attempt. Experimental Gerontology 38: 1231–1241. Hutchinson ML and Munro HN (1986) Nutrition and Aging: Bristol-Meyer Nutrition Symposia, vol. 5, Academic Press. Leveille SG (2004) Musculoskeletal aging. Current Opinion in Rheumatology 16: 114–118. Lipsitz LA (2004) Physiological complexity, aging, and the path to frailty. Science of Aging Knowledge Environment 16: 16. Mishra SK and Misra V (2003) Muscle sarcopenia: An overview. Acta Myol 22: 43–47. Park HL, O’Connell JE, and Thomson RG (2003) A systematic review of cognitive decline in the general elderly population. Internation Journal of Geriatric Psychiatry 18: 1121–1134. Timiras PS (1994) Physiological Basis of Aging and Geriatrics, 2nd edn. Baton Raton: CRC Press.