Age-Related Physiological Changesand Their Clinical SignificanceGERRY R. BOSS, MD, and J. EDWIN SEEGMILLER, MD, La Jolla, California

Physiological changes occur with aging in all organ systems. The cardiacoutput decreases, blood pressure increases and arteriosclerosis develops. Thelungs show impaired gas exchange, a decrease in vital capacity and slowerexpiratory flow rates. The creatinine clearance decreases with age althoughthe serum creatinine level remains relatively constant due to a proportionateage-related decrease in creatinine production. Functional'changes, largelyrelated to altered motility patterns, occur in the gastrointestinal system withsenescence, and atrophic gastritis and altered hepatic drug metabolism arecommon in the elderly. Progressive elevation of blood glucose occurs withage on a multifactorial basis and osteoporosis is frequently seen due 'to a lineardecline in bone mass after the fourth decade. The epidermis of the skinatrophies with age and due to changes in collagen and elastin the skin loses itstone and elasticity. Lean body mass declines with ag'e and this is primarily dueto loss and atrophy of muscle cells. Degenerative changes occur in manyjoints and this, combined with the loss of muscle mass, inhibits elderly patientslocomotion. These changes with age have important practical implications forthe clinical management of elderly patients: metabolism is altered, changesin response to commonly used drugs make different drug dosages necessaryand there is need for rational preventive programs of diet and exercise in aneffort to delay or reverse some of these changes.

NORMAL AGING affects all physiological processes.Subtle irreversible changes in the function of mostorgans can be shown to occur by the third andfourth decades of life, with progressive deteriora-

Refer to: Boss GR, Seegmiller JE: Age-related physiologicalchanges and their clinical significance, In GeriatricMedicine. West J Med 135:434-440, Dec 1981

Dr. Boss is Assistant Professor of Medicine, Division of Gen-eral Internal Medicine, Department of Medicine, and Dr. Seeg-miller is Professor of Medicine and Chief, Arthritis Division, De-partment of Medicine, University of California, San Diego, Schoolof Medicine, La Jolla, California.

Reprint requests to: Gerry R. Boss, MD, Department of Medi-cine, University Hospital, 225 Dickinson Street, San Diego, CA92103.

tion with age. The rapidity of the decline in func-tion varies with the organ system under consid-eration but is relatively constant within a givensystem. Thus, the rate of aging is the same for a45-year-old man as it is for an 85-year-old man;the difference is that by 85 years of age more age-related changes have accumulated. An importantconcept not widely appreciated is the distinctionthat must be made between the normal attritionof function occurring in all persons with advancingage and the loss of function that marks the onset

434 DECEMBER 1981 * 135 * 6

of pathological changes from one or more of thediseases encountered with increased prevalence inthe older age group. Failure to recognize thisdifference can lead to progressive disability fromtreatable diseases in many cases.

In this review we will discuss some of thephysiological changes that occur with aging in thecardiovascular, respiratory, renal, gastrointestinal,endocrine, skin and musculoskeletal systems andtheir consequence for various therapeutic ap-proaches in the day-to-day management of pa-tients. We will concentrate mostly on changes thatare of clinical importance and not discuss theincreased incidence of such disorders as neoplasiathat are well known to occur in all these systems.The attrition of the neurological and immunesystems with age are discussed in other sectionsof this issue.

Cardiovascular SystemHeart

Cardiac output decreases linearly after the thirddecade at a rate of about 1 percent per year innormal subjects otherwise free of cardiac disease.'Due to the small decrease in surface area withage the cardiac index falls at a slightly slowerrate of 0.79 percent per year. The cardiac outputof an 80-year-old subject is approximately halfthat of a 20-year-old. The basis of this decreasein cardiac function is unknown but may relate toone of several factors.

First, senescent cardiac muscle has a decreasedinotropic response to catecholamines, both en-dogenous and exogenous, and, perhaps of moreclinical significance is a decreased response tocardiac glycosides.' Second, with aging there is anassociated increase in diastolic and systolic myo-cardial stiffness, perhaps due to increased inter-stitial fibrosis in the myocardium.3 Third, there isa progressive stiffening of arteries with age, par-ticularly of the thoracic aorta, leading to anincreased afterload of the heart.4 And finally, inautopsy studies as many as 78 percent of subjectsolder than 70 have been shown to have amyloiddeposits in the myocardium, predominantly in theatria, but also in the ventricles and pulmonaryvessels.' When amyloid is present in the ventriclesand vessels it may lead to congestive failure, oftenwith conduction defects. Cardiac amyloidosis maybe a relative contraindication to treatment withdigoxin since there appears to be an increasedrisk of arrhythmias.

GERIATRIC MEDICINE

HypertensionA progressive increase in blood pressure after

the first decade of life has long been regarded asa normal consequence of aging and was the basisfor ignoring the presence of hypertension in theelderly. Only in the past decade or so have pros-pective studies provided evidence of the graveportents of hypertension for the older age groupas well as the young and the potential preventivevalue of early treatment. The elevation with ageis more pronounced for systolic than diastolicpressure. When hypertension is defined as a sys-tolic blood pressure of greater than 160 mm ofmercury and simultaneously a diastolic of greaterthan 95 mm of mercury, approximately 16 per-cent of the general adult population is hyper-tensive but about 50 percent of those over age65 are hypertensive.The Framingham Study clearly established that

high blood pressure is a significant risk factor forstroke, coronary artery disease and congestiveheart failure.6 Moreover, cardiovascular diseasewas a more frequent cause of death and morbidityin the hypertensive subjects older than 65 yearsof age than in the younger subjects. More recentlythe Hypertension Detection and Follow-up Pro-gram confirmed these findings and showed, as didthe Veterans Administration Cooperative Study,that treatment was beneficial.7 All of these studies,as well as the European Working Party on HighBlood Pressure in the Elderly, have shown thatblood pressure in the elderly can be safely loweredwhen the antihypertensive therapy is chosen care-

fully and monitored regularly. The main questionthat needs to be answered at present is whetherisolated systolic hypertension needs to be treatedin elderly patients. Not enough data are yet avail-able to answer this question and large-scale clinicaltrials are desperately needed. The discovery ofnearly a dozen population isolates throughout theworld among whom blood pressure does not in-crease with advancing age is provocative. In eachisolate the culture had no access to added salt inthe diet, suggesting an additional possible preven-tive approach that needs evaluation in our ownculture.

Arteriosclerosis and Coronary Artery DiseaseThickening of the walls of arteries with hyper-

plasia of the intima, collagenization of the mediaand accumulation of calcium and phosphate inelastic fibers progressively occurs with aging. Inaddition, the lipid content of nonatherosclerotic

THE WESTERN JOURNAL OF MEDICINE 435

portions of vessels increases, particularly ofcholesterol.8 Although none of these age-relatedchanges has definitely been shown to be a precur-sor of arteriosclerosis, atherosclerosis clearly in-creases with aging. Raised fibrous plaques thatcontain lipid, atheromas, of the abdominal aortaincrease linearly from onset at about age 20 toreach approximately 30 percent by -age 70. Ingeneral, atherosclerosis occurs earlier in the aortaand carotid arteries than in the coronary andcerebral arteries and peripheral vascular diseaseappears later. Myocardial infarction from coro-nary artery disease increases dramatically withage and although many risk factors are known,age itself is probably the most significant. Preven-tion at present is aimed at amelioration of theother factors, such as hypertension, obesity andcigarette smoking.

Respiratory SystemLung VolumeA linear decrease of vital capacity is found

that amounts to a decrement of about 26 mlper year for men and 22 ml per year for womenstarting at age 20.'3 The total lung capacity re-mains constant, however, and thus the residualvolume increases with age. The ratio of residualvolume to total lung capacity (RV/TLC) is about20 percent at age 20 and increases to 35 percentby age 60, with most of this increase in RV/TLCoccurring after age 40.10 In most studies thefunctional residual capacity also increases, al-though not as rapidly as the residual volume.

Gas ExchangeAlthough alveolar oxygen tension remains con-

stant with age, arterial oxygen pressure shows aprogressive decrease, thus increasing the alveolar-arterial oxygen difference (A-a).0.9 Most of thisdecrease in arterial oxygen pressure results froma mismatch of ventilation and perfusion. Theelastic recoil of the lungs decreases with age andthus there is a greater tendency for airwaysto collapse. This is measured as an increase in"closing volume" which increases linearly abovethe age of 20.11 Airway closure occurs predomi-nantly in the dependent zones of the lung and inthe upright position this will result in a ventilation-perfusion mismatch because more perfusion occursin the lower lobes. Although an age-related de-crease in carbon monoxide diffusing capacity hasbeen shown, it is unclear whether this contributesto the reduction in arterial oxygen pressure.

Flow RatesThere is a 20 percent to 30 percent decrease

in maximum voluntary ventilation, forced expira-tory volume in one second, maximal expiratoryflow rate and maximum midexpiratory flow dur-ing adult life.9 The basis for these changes is notknown but again may relate to a decrease in theelastic recoil properties of the lung. This wouldresult in both a decreased ability to generate nor-mal expiratory pressures as well as increased re-sistance to expiration due to abnormally earlyairway collapse.Infections

It is well known that elderly patients have apronounced increase in incidence of pneumonia,both bacterial and viral, compared with youngerpersons. Although much of this may be due to ageneral depression of immune system function,other more specific factors may play a role. Pneu-monia generally results from aspiration of orophar-yngeal secretions and such aspiration appearsmore frequent in the elderly. Perhaps of evengreater importance, the normal mechanical clear-ing of the tracheobronchial tree by the mucociliaryapparatus is significantly slower in nonsmokingolder persons than in their younger counterparts.Finally, due perhaps to poor oral hygiene, de-creased flow of saliva or difficulty with swallowing,older persons have a higher rate of colonizationof their oropharynx with Gram-negative bacillithan do younger persons.

Genitourinary SystemKidneysA gradual decrease in the volume and weight

of the kidneys occurs with aging so that by theninth decade renal size is about 70 percent ofthat of the third decade. Moreover, there is adecline in the total number of glomeruli perkidney from about 1,000,000 below the ageof 40 to about 700,000 by age 65.12 13 With thereduction in the number of glomeruli there is aconcomitant age-related decrease in the creatinineclearance (C,.) and the decline is according tothe following equation14:

C,., (ml/minute) = 135.0-0.84 X age (years).The serum creatinine concentration, however,changes little with age.11 This is because of anage-related decrease in creatinine production dueto a reduction in muscle cell mass that parallels-the decrease in glomerular filtration rate.

This attrition in renal function has significant

436 DECEMBER 1981 * 135 * 6

GERIATRIC MEDICINE

consequences for the clinical management ofelderly patients. Thus, drugs such as aminogly-cosides, digoxin, penicillin and tetracycline whichare primarily cleared by glomerular filtration willhave a prolonged half-life in an elderly personeven when the dosage is modified through thestandard use of the serum creatinine concentra-tion. In fact, in one study the half-life of thesedrugs in older subjects with a normal serumcreatinine concentration was about twice that inyounger persons.'" Although the serum creatinineconcentration does not change, there is a smallbut significant age-dependent increase in the bloodurea nitrogen (BUN) concentration and the rateof rise is approximated by the following equation17:

BUN (mg/dl) = 7.56 + 0.119 X age.

This increase in the blood urea concentration isnot always seen, however, since there is frequentlya decrease in the intake of protein as well.

Tubular function also declines with aging. Themaximal reabsorption of glucose follows a lineardecrease such that the glucose threshold rangesfrom 130 to 310 mg/dl in elderly persons.Glycosuria may therefore be misleading in thediagnosis and management of diabetes mellitus inolder persons. Both the concentrating and dilutingability of the kidneys also slowly deteriorates.This may contribute to the increased proclivityfor dehydration and hyponatremia seen in olderpatients although excessive use of diuretics prob-ably plays a more major role. Interestingly,in the absence of congestive heart failure orurinary tract obstruction or infection, the noc-turia of old age appears to be primarily of a cen-tral nonrenal origin due to a disturbance in thenormal diurnal rhythm of excretion.18

BladderUrinary incontinence has been found in 17 per-

cent of men and 23 percent of women older than65 years.'9 In about half of the women and afifth of the men this was due to stress incontinencealone. The capacity of the bladder decreases withage from about 500 to 600 ml for persons youngerthan 65 to 250 to 600 ml for those older than65. Perhaps more important, in younger personsthe sensation of needing to void occurs when thebladder is little more than half filled but in manywho are older the sensation occurs much later orsometimes not at all, leading to overflow incon-tinence. These changes appear to be due more

often to central nervous system disease than tobladder dysfunction.

Prostate

Enlargement of the prostate occurs in mostolder men; by age 80 more than 90 percent ofmen have symptomatic prostatic hyperplasia withvarying degrees of bladder neck obstruction andurinary retention. Prostate surgery is required in5 percent to 10 percent of all men at some time.Recently the cause of the hyperplasia has beenmore clearly defined; the concentration of dihy-drotestosterone (DHT) increases in prostatic cells.'0The increase in the intraprostatic concentra-tion of DHT is due to two age-related changes:an estrogen-mediated enhancement of androgenreceptors on prostatic cells as well as a decreasein the intracellular catabolism of DHT. Futuretreatment of benign prostatic hyperplasia may beendocrinologic, aimed at reducing the intracellularconcentration of DHT by competitive steroidantagonists.

Gastrointestinal SystemEsophagus

Age-related changes of esophageal function, so-called presbyesophagus, are due primarily to dis-turbances of esophageal motility. The esophagusin an older person may have a decreased peri-staltic response, an increased nonperistaltic re-sponse, a delayed transit time or a decreasedrelaxation of the lower sphincter on swallowing.The decrease in peristalsis and delay in transittime may lead to dysphagia with a voluntary cur-tailment of caloric consumption. Nonperistalticcontractions are found almost exclusively in theelderly. They occur in the lower two thirds of theesophagus and are the cause of the "corkscrew"esophagus seen on barium swallow studies. De-creased relaxation of the lower esophageal sphinc-ter on swallowing is the basis of achalasia and ismore common in the elderly population.

StomachThe incidence of atrophic gastritis increases

significantly with age. In a Scandinavian studyapproximately 40 percent of apparently healthysubjects older than 65 had evidence of atrophicgastritis.2" At present, atrophic gastritis is dividedinto type A which is confined to the body andfundus sparing the antrum and type B which isassociated with atrophy of both antral and fundic

THE WESTERN JOURNAL OF MEDICINE 437

glands. Both types increase in frequency withadvancing years. Severe atrophic gastritis resultsin achlorhydria, deficient intrinsic factor secretion,decreased pepsinogen production and, in type A,hypergastrinemia due to lack of acid inhibition ofgastrin cell secretion. Type A atrophic gastritisappears to be an autoimmune disease, whereastype B may be due to local environmental factorssuch as chronic enterogastric bile reflux. Bothtypes of atrophic gastritis are premalignant lesions.

ColonA decrease in intestinal motility occurs with

age. The colon becomes hypotonic, which leads toincreased storage capacity, longer stool transittime and greater stool dehydration. These are alletiologic factors in the chronic constipation thatplagues the aged. Laxative abuse therefore resultsand is the most common cause of diarrhea in theelderly. A high-fiber diet is the treatment of choiceand this can best be achieved by prescribing a dietrich in bran. Whether or not constipation is anetiologic factor in diverticulosis remains unclearbut age certainly is. Diverticula are uncommonbelow the age of 40 but steadily increase there-after until nearly 50 percent of those older than80 have diverticulosis. Symptoms are present inonly about 20 percent to 25 percent of those whoare affected and severe disease with inflammationand bleeding occurs in a much smaller number.2

Sphincter ControlLoss of control of the internal and external anal

sphincters in the elderly in the presence of essen-tially normal cognitive function is a most emotion-ally traumatic and demeaning experience. Theresulting fecal incontinence is one of the majorcauses for admission of many otherwise healthypersons to long-term care facilities. Recent studieshave shown the cause to be a loss of tone of theexternal rectal sphincter. Biofeedback techniquesallowed the regaining of sphincter and bowel con-trol in as many as 70 percent of a group ofpatients studied.23

Liver and Biliary TractThe liver decreases in weight by as much as

20 percent after the age of 50 but perhaps becauseof its large reserve capacity this attrition is notreflected by a decrease in the usual liver functiontests. Although tests of liver function show littleor no change with age, a large number of drugssuch as diazepam and antipyrine are known to

* The oral glucose dose was 1.75g per kilogram(kg) of body weight.

Figure 1.-Nomogram for correcting the glucose toler-ance test for age. (Reproduced from Andres24 with per-mission of publisher and author.)

be metabolized more slowly by the liver in theelderly. This alteration in hepatic drug metabolismmay be due to a decrease in the appearance,amount or distribution of the smooth endoplasmicreticulum. Biliary tract disease is unusual beforethe third decade and the incidence of cholelithiasisincreases greatly with age. In a large autopsyseries of subjects older than 70 years, 30 percenthad gallstones and another 5 percent had previ-ously had a cholecystectomy. In general, surgicaloperation is indicated in patients with gallstones,even if asymptomatic, since the risk of complica-tions in an elderly patient is greater than the riskof operation.Endocrine SystemGlucose Homeostasis

Increasing age results in a progressive deteriora-tion in the number and the function of insulin-producing beta cells.24 The capacity of these cellsto recognize and respond to changes in glucoseconcentration is impaired. In elderly subjects a

greater proportion of the insulin released into thecirculation in response to a glucose challenge is inthe form of the inactive precursor proinsulin thanin their younger counterparts. Of perhaps even

438 DECEMBER 1981 * 135 * 6

Age Two Hour Blood Glucose* Percentile(mg per 100mI) Rank

80 28075 260 o70 240

65 220

60 200

55 180

50 160

45 140

40 120 1035 100

30 9S 80

25-t 99/ 60

20

greater importance is the development of pro-gressive peripheral insulin resistance with age.Compared with younger persons the elderly havea relative decrease in lean body mass with a rela-tive increase in adiposity. Since little change in thetotal number of fat cells occurs with age, the in-creased adiposity appears due to an increase infat cell size. In general, as adipocytes enlarge theyturn down their insulin receptors. Thus, even innonobese elderly persons there is peripheral insulinresistance due to increased size of adipocytes witha relative decrease in insulin receptors. The com-bination of abnormal beta cell function withperipheral insulin resistance leads to increasedglucose intolerance in normal aged persons.25Figure 1 is a nomogram for correcting the glu-cose tolerance test for the age of the patient, animportant consideration in the diagnosis of dia-betes in the elderly.24

Although diabetic ketoacidosis and lactic acido-sis are uncommon in elderly diabetic persons,hyperosmolar nonketotic coma occurs with somefrequency.26 As already discussed, there is adecrease in the renal concentrating function withage as well as a decrease in the maximal reabsorp-tion of glucose. Thus, even mild hyperglycemiamay lead to osmotic diuresis. This will causefurther hyperglycemia and ultimately dehydra-tion. The dehydration may lead to vascular insuf-ficiency in elderly patients and they may becomeobtunded and refuse to drink; rapid progressionto coma may then ensue. This syndrome is fre-quently precipitated or exacerbated by a myo-cardial infarction, pneumonia or urinary tractinfection.

OsteoporosisOsteoporosis is a skeletal disorder characterized

by a decrease in bone mass which may result inmechanical failure of the skeleton. The decreasein bone mass is an age-related phenomenon. Be-ginning in the fourth decade there is a lineardecline in bone mass at a rate of about 10 percentper decade for women and 5 percent per decadefor men. Thus, by the eighth and ninth decades30 percent to 50 percent of the skeletal mass maybe lost. The decrease in bone mass is due to arelative increase of bone resorption over forma-tion but the basis of this is unknown. Hormonalfactors certainly play a role since women aremore susceptible than men and the rate of develop-ment of osteoporosis in women accelerates aftermenopause. Moreover, low-dose estrogen therapy

GERIATRIC MEDICINE

can arrest or retard bone loss if begun shortly afterthe menopause.27'28

MenopauseNowhere are the development of age-related

changes more apparent than in the human femaleclimacteric. Menopause occurs because of the dis-appearance of oocytes from the ovary throughovulation and atresia. Little is understood aboutthe process of ovarian atresia and whether it isdue to primary ovarian failure or secondary tohypothalamic-pituitary changes.

Several consequences of the menopause deservemention. First is the vasomotor instability orhot flashes. Two thirds to three quarters ofmenopausal women will experience flushing, with80 percent having the symptoms for longer thanone year and 25 percent to 50 percent for morethan five years. Changes in skin temperature,skin resistance, core temperature and pulserate occur during the flush. Besides being amajor disturbance while women are awake, thehot flashes may occur during sleep, leading towaking episodes. Insomnia with possible physi-ologic and psychologic disturbances may thusresult.

It is well known that arteriosclerotic cardio-vascular disease is unusual in women before themenopause. The precise protective mechanism ofovarian function is not known, but premenopausalwomen have a higher ratio of high-density lipo-proteins to low-density lipoproteins than do post-menopausal women. Osteoporosis with its relationto the menopause has already been discussed.Changes of the skin occur with age and the recentdemonstration of estrogen receptors in the skinof mice suggests that estrogens could have directeffects on aging of the skin (see below).

SkinEpidermis

Atrophy of the epidermis occurs with age andis most pronounced in exposed areas: face, neck,upper part of the chest, and extensor surface ofthe hands and forearms. In addition to the thin-ning of the epidermis there is notable flatteningof the dermal epidermal junction with effacementof both the dermal papillae and the epidermal retipegs. The turnover rate of cells in the stratumcorneum decreases with age and in persons olderthan 65 it takes 50 percent longer to reepitheli-alize blistered skin than in young adults. The

THE WESTERN JOURNAL OF MEDICINE 439

decrease in epidermal cell growth and division occur with aging, a distinction between the attri-causally contribute to the increased incidence tion in function of normal aging and pathologicalof decubitus ulcers in older patients.29 states must be clearly delineated. To do otherwise

jeopardizes a patient's prospect for receivingDermis

Dermal collagen becomes stiffer and less pliablewith age; elastin is more cross-linked and has ahigher degree of calcification. These changes causethe skin to lose its tone and elasticity, resulting insagging and wrinkling.30 An age-related decreasein the number of dermal blood vessels also de-velops. This relative ischemia of the skin may alsoplay a pathogenetic role in the development ofdecubitus ulcers.

Musculoskeletal SystemMuscle

The age-dependent decline in lean body massis well known and is primarily due to loss andatrophy of muscle cells. Some muscles, such asthe diaphragm, show few if any changes whileothers, such as the soleus, show pronounced infil-tration by collagen and fat.:" Age-related changesalso occur in the innervation of muscle but theexact pathologic process is not well understood.Although much of the decreased locomotion ofelderly subjects is due to skeletal changes (seebelow), a substantial part is probably secondaryto decreased muscle mass and function.

Skeletal

Degenerative joint disease occurs in 85 percentof persons older than 70 years of age and is amajor cause of disability. It affects both theperipheral and axial skeleton and is characterizedby degeneration of cartilage, subchondral bonethickening and eburnation, and remodeling ofbone with formation of marginal spurs and sub-articular bone cysts. Due to its predilection forweight-bearing joints, wear-and-tear type mecha-nisms must be operative. When the degenerativechanges are pronounced, pain can be severe,greatly limiting the activity status of an elderlypatient. Fortunately, adequate drug and surgicaltreatments exist but old people are truly restrictedby their joints.

ConclusionWe have briefly discussed some of the major

changes that occur with age in several of the bodysystems. Although it is tempting to regard manyof the so-called diseases of the elderly as being theend stage of normal physiologic changes that

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