SPECIAL ARTICLE

Physiological Features of Aging Persons

Oliver O. Aalami, MD; Tony D. Fang, MD; HanJoon M. Song, MD; Randall P. Nacamuli, MD

B
etween 1960 and 1994, the population of those 85 years and older in the United States
grew 274%.1 Similarly, the fastest-growing sector of surgical patients older than 65 years
is those older than 85 years.2 These figures are critical because elderly persons have
the highest mortality in the adult surgical population (5.8%-6.2% in those ⬎80 years
in 500 consecutive patients requiring general or regional anesthesia and 8.4% in those ⬎90 years
in 795 in-house operations).3-5 Why do elderly persons face such high surgical mortality rates? In
addition to a higher incidence and prevalence of disease, elderly persons experience baseline physi-
ological changes associated with senescence.6 It is vital for the modern surgeon to be aware of the
physiological changes associated with aging to minimize morbidity and mortality in the aging sur-
gical population.

Multiple theories of aging exist, all of
which are controversial and largely un-
proved. In general, theories of aging are
divided into either extrinsic (stochastic)
or intrinsic (developmental-genetic)
causes. The stochastic theories point to
cumulative cellular damage from free
radicals and radiation, errors in protein
synthesis, and protein cross-linking.7-9 De-
velopmental-genetic theories hypoth-
esize intrinsic, preprogrammed, genetic
control of cellular aging. The neuroendo-
crine and immunologic theory and the
concept of aging genes fit into this latter
category.10-12 Hayflick13 studied cellular se-
nescence across multiple species, and
noted that the maximum lifespan of a fi-
broblast varied among species. Specifi-
cally, there was a linear relationship be-
tween the maximum fibroblast population
doubling and the maximum lifespan of a
given species. Other cellular studies14 have
introduced the concept of telomere short-
ening representing an internal cellular
clock.
In this review, critical physiological
changes of systems associated with aging
From the Departments of Surgery, University of California, San Francisco–East Bay
(Drs Aalami and Nacamuli), and Stanford University School of Medicine, Stanford,
Calif (Drs Fang and Song).
are discussed. In addition, the blunted re-
sponses of each system in the face of pe-
rioperative stresses are examined.
ALTERATIONS IN
CARDIOVASCULAR
PHYSIOLOGICAL FEATURES
Normal physiological changes occur in the
cardiovascular system with aging. There is
a progressive loss of myocytes with a recip-
rocal increase in myocyte volume in both
ventricles.15 The large vessels stiffen, as does
the myocardium. As a result, afterload is in-
creased and early diastolic filling is im-
paired. The ␤-adrenergic responsiveness of
the heart decreases, limiting the maxi-
mum achievable heart rate (HR). In addi-
tion, the number of pacemaker cells in the
sinus node decreases with age. The dura-
tion of myocardial contractility is length-
ened, but force does not decrease signifi-
cantly in elderly persons. The heart partially
compensates for lower HRs and maximal left
ventricular (LV) contractility with exercise-
induced dilatation of the left ventricle.16 De-
spite these compensatory mechanisms, and
because of the prevalence of cardiac dis-
ease, myocardial infarctions have been re-
ported as the leading cause of postopera-
tive death among 80-year-old patients.4

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 Cross-sectional echocardiographic studies17 sug-
gest that LV wall thickness progressively increases with
age independent of cardiovascular risk factors such as
hypertension. Furthermore, a histomorphometric analy-
sis18 has revealed that enlarging cardiac myocytes (hy-
pertrophy) rather than an increase in number (hyper-
plasia) accounts for ventricular wall thickening; however,
the absolute number of myocytes actually decreases over
time. In addition, the local collagen concentration and
its properties are altered in elderly persons. The num-
ber of collagen fibers increases along with increases in
nonenzymatic cross-linking. Although the myocyte-
collagen ratio remains relatively unchanged, this is mainly
because of increased myocyte size; as a result, hypertro-
phy rather than hyperplasia is more prominent in eld-
erly persons. These anatomical and structural changes
contribute to an increase in myocardial stiffness and a
decrease in compliance.
Previous reports17 have estimated that the LV early
diastolic filling rate progressively decreases and reaches
only 50% of the peak rate by the age of 80 years. The LV
end-diastolic volume does not reduce with age, but does
mildly increase while at rest and during upright exer-
cise.16 This is mainly because of increased atrial contrac-
tion during the latter phase of ventricular filling. The in-
creased contractility of the atrium will lead to hypertrophy
and enlargement of the chamber, which can be detected
by an atrial gallop on auscultation.19 Although the LV ejec-
tion fraction ([LV end-diastolic volume−LV end-systolic
volume]/LV end-diastolic volume) is relatively preserved
with age, the maximum LV ejection fraction (the ejection
fraction during exhaustive upright exercise) decreases. This
is because of the dramatic reduction in ejection fraction
reserve during aging.17 The stroke volume remains un-
changed over time, and is achieved by increasing end-
diastolic volume and maximally using the Starling curve.
The resting HR does not change with age, but the
maximum achievable HR decreases, with the maximal HR
that an 85-year-old person can achieve being approxi-
mately 70% of that of a 20-year-old person.17 Because the
stroke volume does not change over time, the maximum
cardiac output (stroke volume⫻HR) decreases during ag-
ing, indicating that the overall cardiac reserves diminish
with age. The dysfunction of sympathetic modulation of
the cardiovascular system with advanced age is consis-
tent with increased spillover of catecholamine and im-
paired responses to ␣-adrenergic receptor stimula-
tion.20,21 This results in further reduction of the contractility
of the myocardium.17 Aging also affects the LV afterload
and vascular-ventricular load matching. This mismatch
leads to failures of LV elasticity (contractility) in re-
sponse to increased afterload.22 In addition, the diastolic
pressure decreases with age, compromising myocardial per-
fusion and worsening overall cardiac function.
Normal aging affects the arterial system. Intimal hy-
perplasia and thickening, with a concomitant decrease
in vascular compliance and increased stiffness, develop
with advanced age,23,24 with the intimal thickness of the
carotid artery increasing 2 to 3 times between the ages
of 20 and 90 years.25 Multiple studies19,25 have demon-
strated that intimal thickening is a risk factor for silent
coronary artery disease, and it is, therefore, considered
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a component of subclinical vascular disease. Microscopi-
cally, there are alterations in the vascular media. In-
creased nonenzymatic collagen cross-linking, similar to
collagen-associated changes in the myocardium, is seen.
The elastin content in the media decreases with age. This
contributes to decreased vascular elasticity (compli-
ance) and increased stiffness. Pulmonary vessels of el-
derly persons have a lower elastin content and experi-
ence a decrease in collagen content by 1% a year.26 Lower
extremity arteries of patients older than 50 years com-
monly demonstrate medial calcifications and sclero-
sis.27 Dysfunctional endothelial vascular smooth muscle
tone regulation (eg, a decrease in nitric oxide produc-
tion with age) contributes to stiffer arterial walls inde-
pendent of atherosclerotic changes.28,29
Peripheral vascular resistance and central artery stiff-
ness are 2 main determinants of arterial blood pressure.
Increases in peripheral vascular resistance lead to an in-
crease in systolic and diastolic pressure, while increases
in central artery stiffness lead to an elevation in systolic
pressure but a reduction in diastolic pressure.25 Although
blood pressure in younger individuals is primarily dic-
tated by peripheral vascular resistance, with aging cen-
tral arterial stiffness becomes the main determinant of pres-
sure.25 Investigators30 have demonstrated that systolic blood
pressure increases in adults of all ages, well into the 80s,
while diastolic blood pressure peaks in the 50s and sub-
sequently declines. Thus, the overall effect of aging (dis-
allowing for hypertension) is an increase in systolic pres-
sure and a decrease in diastolic pressure, which manifests
as a widened pulse pressure. The most common form of
hypertension in adults older than 50 years is isolated sys-
tolic hypertension.31 Increased systolic pressure, al-
though used as a screening variable for increased cardio-
vascular disease risk, is not as good a predictor of coronary
disease as is increased pulse pressure.32-34
ALTERATIONS IN PULMONARY
PHYSIOLOGICAL FEATURES
Normal aging results in changes in pulmonary mechan-
ics, respiratory muscle strength, gas exchange, and ven-
tilatory control. Increased rigidity of the chest wall and
a decrease in respiratory muscle strength with aging re-
sult in an increased closing capacity and a decreased forced
expiratory volume in 1 second (FEV1).35 The partial pres-
sure of oxygen, arterial, decreases progressively with age
because of the age-induced ventilation-perfusion mis-
match, diffusion block, and anatomical shunt.36 Also, el-
derly patients have a diminished ventilatory response to
hypercapnia and hypoxia.37
The large airways grow slightly with age, but the re-
sulting increase in dead space is insignificant.38 The res-
piratory bronchioles and alveolar ducts, on the other hand,
increase in size significantly over time, particularly after
the age of 60 years. The fraction of lung consisting of al-
veolar ducts increases progressively over time. As the al-
veoli grow, the cumulative surface area available for gas
exchange decreases by 15% by the age of 70 years.39
Changes associated with aging result in a diminish-
ing pulmonary elastic recoil pressure.40 The fusion of ad-
jacent alveoli, which occurs with aging, decreases sur-
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 face tension forces and pulmonary elastic recoil.38 In
addition, chest wall stiffness increases with advancing age,
decreasing compliance. Chest wall stiffness increases be-
cause of the calcification of intercostal cartilages, arthri-
tis of the costovertebral joints, and gradual atrophy and
weakening of the intercostal muscles with advanced age.
A patient with kyphosis or osteoporosis has an even more
significant decrease in chest wall compliance.41 Elastin
fiber concentration surprisingly increases with age, and
is not believed to contribute to the age-related decrease
in lung elasticity.42
Gradual atrophy and weakening of the intercostal
muscles during aging demands greater contributions from
the diaphragm and abdominal muscles for breathing. Un-
fortunately, the strength of the diaphragm declines with
age, as measured by the maximum transdiaphragmatic
pressure.43,44
Pulmonary function test changes are most affected
by the age-related decreased compliance of the pulmo-
nary system and muscle strength. Burr et al45 showed that
the FEV1 and the forced vital capacity decline progres-
sively with age. Knudson et al35 estimated that the FEV1
decreases by 30 and 23 mL/y in nonsmoking men and
women, respectively, with an even greater decrease after
the age of 65 years. This is equivalent to an 8% to 10%
decline in FEV1 each decade. The forced vital capacity
in nonsmokers is estimated to decrease about 15 to 30
mL/y.46,47 The vital capacity progressively decreases and
the residual volume gradually increases, leading to a rela-
tively unchanged total lung capacity (vital capacity+residual
volume). The functional residual capacity also increases
with age, although it is not as significant because of the
counteraction of the increased stiffness of the chest wall.48
Immunohistochemical staining of type IV collagen in
alveoli showed increased thickness of the alveolar base-
ment membrane.49 Thickening of the alveolar basement
membrane decreases gas-diffusing capabilities. The diffus-
ing capacity of the lung is decreased about 2.03 mL/min
per millimeter of mercury in men per decade and 1.47 mL/
min per millimeter of mercury in women per decade.50 The
resulting ventilation-perfusion mismatch leads to higher
alveolar-arterial oxygen gradients. The partial pressure of
oxygen, arterial, decreases during rest and exercise with
age, becoming more prominent during exercise.
Collectively, the normal aging process changes the
anatomical structures and tissue properties affecting res-
piratory physiological features in several aspects. Most
important, expiratory flow rates decrease with age, as does
the partial pressure of arterial oxygen. Both of these func-
tional variables have been reported as risk factors for pul-
monary complications.51 Age-related pulmonary func-
tion changes result in decreasing respiratory reserves. In
the perioperative period, special care must be taken not
to compromise the patient’s respiratory function. Pre-
venting aspiration and fluid overload and encouraging
pulmonary toilet are just some examples.
ALTERATIONS IN RENAL
PHYSIOLOGICAL FEATURES
The kidneys grow from 50 to 250 g in the first 50 years of
life. In contrast, their weight decreases from the age of 50
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years to 180 g.52 Dunnill and Halley53 have demonstrated
that this absolute volume loss is primarily due to cortical
tissue loss. The renal medulla, in comparison, maintains
most of its volume. Cortical loss is due to glomeruloscle-
rosis (acellular obliteration of glomerular capillary
architecture).54 Shunts form around sclerotic glomeruli,
decreasing cortical blood flow while maintaining flow to
the medulla and the collecting system parenchyma.55,56 Hy-
pertension, diabetes mellitus, and atherosclerosis accel-
erate the process of glomerulonephrosis.54 In addition, tu-
bular senescence is seen in the elderly population.57
Histologically, tubular length decreases, interstitial fibro-
sis is seen, and tubular basement membrane constitution
and anatomical features change with age.
Glomerulosclerosis directly affects the glomerular
filtration rate (GFR). After the age of 40 years, the GFR
decreases 1 mL/min per year.58 Because of the concomi-
tant decrease in creatinine production in elderly per-
sons, serum creatinine levels remain normal despite sig-
nificantly reduced GFRs.54 The elderly patient undergoing
surgery has a low filtration reserve and is, therefore, more
sensitive to any ischemic or nephrotoxic insults. Fluid,
electrolyte, and acid-base abnormalities result, with the
onset of acute renal failure.
Tubular senescence blunts the reabsorption and se-
cretion of solutes. Specifically, the capacity to reabsorb
sodium decreases, as does the secretion of potassium and
hydrogen ions.59 The juxtaglomerular apparatus in el-
derly patients produces less renin than in young pa-
tients, blunting the response to aldosterone.60 As a con-
sequence, elderly patients are more susceptible to
electrolyte and acid-base abnormalities. Antidiuretic hor-
mone response is also attenuated in elderly persons, mak-
ing sodium and water conservation difficult.61,62
Reduced renal reserve is seen in the disease-free el-
derly population. Glomerulosclerosis and senescence of
tubules are the 2 main causes of decreased GFR with ag-
ing. In the face of surgery, fluid, electrolyte, and acid-
base balance must be monitored closely to correct any
abnormalities. Elderly patients poorly tolerate dehydra-
tion and volume loads. They are more likely to accumu-
late potassium, and have a blunted renin response. The
response to aldosterone and vasopressin is also blunted.
In addition, because of the diminished GFR of elderly per-
sons, drugs that are cleared via the kidneys require dose
modification based on creatinine clearance.63 If such pre-
cautions are not taken, toxic levels will accumulate in
the circulation.
ALTERATIONS IN GASTROINTESTINAL
PHYSIOLOGICAL FEATURES
Alterations in normal gastrointestinal physiological fea-
tures can be generally broken down into 3 areas: changes
in neuromuscular function, changes in the structure of
the gastrointestinal tract itself, and changes in the ab-
sorptive and secretory functions of the bowel. Neuro-
muscular changes primarily affect the upper gastrointes-
tinal tract, particularly the esophagus, and can lead to
symptoms consistent with numerous disease processes,
such as reflux and achalasia. Changes in the structure of
the bowel wall are most notable distally in the colon, and
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 are responsible for the most common age-related co-
lonic disorder, diverticula.64 Functional alterations in se-
cretion and absorption are predominantly found in the
stomach (secretion) and small bowel (absorption), al-
though it is difficult to consistently link these age-
related changes with pathological features.
Changes in Neuromuscular Function
Changes in function with aging of the oropharynx and
esophagus are primarily related to neuromuscular de-
generation and subsequent alterations in the ability to
coordinate the complex reflexes that lead to successful
swallowing and propulsion of food along the esopha-
gus. Aberrant contraction can also be caused by weak-
ness in the muscles. Failure to coordinate the reflexes
regulating proper motility can lead to numerous patho-
logical features, including diffuse esophageal spasm, acha-
lasia, and reflux. Because these age-associated problems
with esophageal motor function can also be caused by
primary neurological conditions, it is especially impor-
tant to delineate deficits in neurological function caused
by cerebrovascular accidents and true central nervous sys-
tem degenerative processes from age-related changes.65
The cricopharyngeus muscle, the primary muscle of the
upper esophageal sphincter, is particularly susceptible to
alterations in motility and may lead directly to prob-
lems such as aspiration, dysphagia, and pharyngoesoph-
ageal diverticula.66,67 Neuromuscular deficits of the lower
esophagus include a decreased or even absent response
to normal upper esophageal peristalsis, with a general
weakness and slowing of contractions. Insufficient rest-
ing pressure in the lower esophageal sphincter can lead
to gastroesophageal reflux and symptoms simulating hi-
atal hernia and achalasia.68
The other portion of the gastrointestinal tract thought
to experience altered neuromuscular function with age
is the stomach. However, the exact effect that aging has
is unclear. Studies69,70 investigating the gastric empty-
ing times of young and elderly patients have demon-
strated increases and decreases in the rate of emptying.
Furthermore, it has been challenging to link any alter-
ation in gastric emptying with patient complaint or patho-
logical features.68 At best, these data suggest that there
may be perturbations in the homeostatic mechanisms
regulating gastric emptying in elderly persons. The small
bowel has been demonstrated to have unaltered rates of
transit.69
Changes in Gastrointestinal Wall Structure
The upper alimentary tract does not experience signifi-
cant structural changes as age progresses. As mentioned
previously, weakening of the musculature of the orophar-
ynx and upper esophagus can contribute to the forma-
tion of pharyngoesophageal diverticula and can cause
functional problems. Similarly, although the gastric mu-
cosa becomes atrophic with age, correlations between his-
tologic change and disease processes, including atro-
phic gastritis, have been hard to establish.71 The primary
structures affected by age in the small bowel are intesti-
nal villi. Starting around the age of 60 years, there is a
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progressive decrease in the height of the villi, with a con-
comitant decrease in surface area available for absorp-
tion.68 Fibrous connective tissue can also be seen replac-
ing normal mucosal parenchyma and smooth muscle cells.
The colon is the most consistently affected portion
of the gastrointestinal tract with regard to age-related
structural alterations. Mucosal changes are noted, but do
not affect the absorptive capabilities of the colon.68 The
primary process seen in the colon is a thickening of the
muscular layers, particularly the muscularis propria and
the muscularis mucosa. This thickening is due to elas-
togenesis and a buildup of elastin between myocytes in
the bowel wall, not due to muscle cell hyperplasia or hy-
pertrophy (although these may be caused by inflamma-
tion and fibrosis).64,72 Thickening is present throughout
the life cycle, but becomes more rapid after the age of 60
years. The tinea coli are affected more than the circular
muscle layers, and it is contraction in the longitudinal
direction secondary to elastin accumulation that con-
tributes to hard stool, constipation, and fecal impac-
tion. Diverticular disease, the most common age-related
colonic disease, occurs as a result of concomitant weak-
ening of the muscularis propria at locations where ar-
teries and veins cross the bowel wall.73
Changes in Secretion and Absorption
It is a common misconception that age-associated xe-
rostomia is due to a primary deficit in the production of
saliva. Although the composition of saliva is altered in
elderly persons (they have higher levels of mucin, re-
sulting in a more viscous secretion), overall production
and flow rates are normal.74,75 Diminished salivation is
almost always attributable to secondary factors, such as
medication. Secretion of gastric acid and pepsin de-
clines with age. This is more noticeable in women, and
is manifested as an attenuation of peak and basal acid se-
cretion.71 However, serious problems, such as achlorhy-
dria, are not usually attributable to age alone and, thus,
the underlying pathological features in patients with this
type of condition must be determined. Decreases in pep-
sin secretion correlate with those patients in whom age-
related mucosal atrophy is present.68
In the small bowel, a decrease in the height of villi
and a reduction in surface area can lead to disorders of
absorption. Specifically, absorption of calcium, carbo-
hydrate, and D-xylose is impaired, although this may be
inconsistent and may not be clinically significant.68,76 There
are no significant changes in the absorptive capacity of
the colon attributable to age.
ALTERATIONS IN HEPATOBILIARY
PHYSIOLOGICAL FEATURES
Several changes in liver physiological features occur with
aging. The size of the liver decreases after the age of 50
years, declining from roughly 2.5% of total body mass
to a nadir of just more than 1.5%. Alterations in blood
flow parallel this decrease. Interestingly, although the to-
tal number of hepatocytes in an aged liver is decreased,
there is an increase in the mean cell volume, which some68
have interpreted as a cellular response to an increased
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 biological demand on the remaining cells. Despite this
potential increased demand, most liver function test re-
sults remain normal in elderly persons, as do standard
function test results, such as those for hepatic filtration,
detoxification, ethanol elimination, and conjugation.68,77
Hepatic synthesis of several proteins, including clotting
factors, can be reduced, although this does not impair base-
line function. However, perhaps because of the larger ana-
bolic burden placed on fewer hepatocytes, hepatic syn-
thesis of these factors is unable to increase significantly
beyond baseline when challenged.78
No direct link between aging and major gallblad-
der function has been established, including absorp-
tion, mucosal physiological features, and contractile prop-
erties. Although there is an increase in the incidence of
cholelithiasis in elderly persons (theoretically attrib-
uted to an increase in the ratio of lipid-cholesterol in bile),
the underlying process by which this occurs has not been
elucidated.68,79
ALTERATIONS IN ENDOCRINE, IMMUNE,
AND STRESS RESPONSES
Age-related changes that occur in various endocrine func-
tions have been well documented in the literature. Per-
haps the best studied of these include postmenopausal
changes, resulting in an estrogen-deficient state. Meno-
pause is characterized by a cessation of menses and a de-
cline in estrogen levels with a concomitant increase in
luteinizing hormone and follicle-stimulating hormone lev-
els.80 During the first decade after the initiation of meno-
pause, women undergo rapid bone loss, most likely re-
flecting diminished estrogen levels. Thereafter, a slow
phase of bone loss occurs, primarily from a loss of es-
trogen-mediated calcium homeostasis.81 The decrease in
skeletal mass associated with menopause occurs in con-
junction with normal age-related bone loss, further com-
pounding the problems of osteoporosis and pathologi-
cal bone fractures in elderly persons. In addition to its
effects on bone, menopause removes estrogen’s cardio-
protective effect, increasing low-density lipoprotein level,
decreasing high-density lipoprotein level, and increas-
ing overall atherogenesis.82 Further effects of low estro-
gen levels experienced in menopause include changes in
vasomotor symptoms, urogenital atrophy, increased mood
swings, and loss of libido.83,84 Hormone therapy allevi-
ates many of these estrogen-deficient symptoms, al-
though well-known risks have been documented, in-
cluding increased risks of venous thrombosis, stroke, and
breast cancer.85-87
In men, serum testosterone, estradiol, dehydroepi-
androsterone, and dehydroepiandrosterone sulfate lev-
els slowly decline with advancing age, while sex hormone–
binding globulin, luteinizing hormone, and follicle
stimulating hormone levels increase.88 The decrease in
sex hormone–binding globulin further decreases the level
of free active testosterone. Low testosterone levels are as-
sociated with decreased libido, decreased hematocrit,
muscle atrophy, osteoporosis, and possibly erectile dys-
function.83,89 In older men with testosterone-related hy-
pogonadism or markedly low levels of testosterone, tes-
tosterone replacement has been shown to improve sexual
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drive, increase lean body mass, and possibly improve ex-
ercise-induced coronary ischemia.90 The benefits of tes-
tosterone supplementation for older men with normal to
low-normal levels of testosterone without clinical signs
of hypogonadism are less clear. Overall, the long-term
effects of testosterone therapy are inconclusive and war-
rant further investigation.90-92
In terms of pituitary function, an age-related de-
crease in growth hormone and its anabolic mediator, in-
sulinlike growth factor 1, may be associated with the de-
creased lean body and bone mass and increased percentage
body fat observed in aging persons.93,94 Rather than a de-
fect in growth hormone release from the pituitary gland,
changes in growth hormone–related regulatory hor-
mones, such as growth hormone–releasing hormone and
somatostatin, seem to mediate the age-related decrease
in growth hormone.95 As for other pituitary hormones,
baseline prolactin levels are similar as individuals age,
although the increase in prolactin levels in response to
mild surgical stress (eg, inguinal hernia repair) seems to
be blunted in older individuals.96
For nondiabetic individuals, progressive impair-
ment of glucose tolerance occurs with advancing age, in-
dependent of obesity and sex.83 A previous investiga-
tion97 comparing the response of older (those in their 80s)
with that of younger (those in their 20s) individuals to
oral glucose tolerance tests reported a 45% rate of im-
paired tolerance in older individuals. The pathogenesis
of this age-related decline in glucose handling seems to
result from increased insulin resistance rather than an
impairment of insulin secretion.98 Possible explana-
tions for this age-related insulin resistance include a de-
crease in fat-free mass, dietary and physical activity
changes, neurohormonal changes, and a decreased ca-
pacity of the glucose uptake system.98,99 Overall, there is
an age-related increase in fasting and postprandial glu-
cose levels.83,100 As for enzymatic function of the pan-
creas, pancreatic lipase may be mildly decreased, possi-
bly accounting for the slight impairment of fat absorption
observed in elderly persons.68
The anatomical features and function of the thy-
roid also undergo age-related changes. The thyroid gland
in elderly persons is characterized by mild atrophy, in-
creased fibrosis, and decreased size of the follicles.101 Func-
tionally, there is less peripheral conversion of thyroxine
to triiodothyronine, decreased uptake of iodine, and over-
all lower levels of thyroxine and free thyroxine.68,101 How-
ever, whether the age-related decline in thyroid func-
tion translates to clinical relevance is unclear. Similar to
the thyroid, the neighboring parathyroid glands also un-
dergo age-related changes. Several studies102 have dem-
onstrated an increase in parathyroid hormone level with
age and increased parathyroid hormone release in re-
sponse to serum calcium compared with younger indi-
viduals. The increased baseline levels and augmented re-
sponse of parathyroid hormone to stimuli have been
implicated in osteoporosis and bone loss in elderly per-
sons.103 In contrast to parathyroid hormone, calcitonin
levels seem to decrease with age.
Interestingly, adrenal function in advanced age leads
to changes in the diurnal pattern of cortisol, which shifts
earlier in the day and produces higher evening cortisol
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 levels.68,104 Clinically, these sleep disturbances are mani-
fested by a relatively earlier bedtime and awakening com-
pared with younger individuals. In addition, there is a
positive correlation between increases in baseline levels
of epinephrine and norepinephrine and age; however, the
response of epinephrine and norepinephrine release to
stimulation is blunted.83,105 The attenuated sympathetic
response of body stress manifests in several ways. For in-
stance, older individuals have less cutaneous vasocon-
striction to cold stimuli compared with younger indi-
viduals, making them more susceptible to hypothermia
(also described in the “Neurological Changes” section).106
Also, less reserve in elderly persons translates into de-
creased capacity to efficiently regulate pulse rate, blood
pressure, blood pH, and oxygen use.
Apart from decreased sympathetic responsiveness
during stress in elderly persons, immune function also
has an age-related decline. Advanced age leads to a func-
tional impairment of T-lymphocyte–mediated immu-
nity and an increased susceptibility to infections.107 The
response of T lymphocytes to interleukin 2 also seems
to be impaired in older individuals, as is the stress-
related increase in natural killer cell activity.83,108 Fur-
thermore, markers of the systemic response to surgical
stress (tumor necrosis factor ␣, interleukin 6, and CD11b/
CD18 expression) have been elevated after surgical stress
in older compared with younger individuals.109 Investi-
gators have, thus, postulated that activation of mono-
cytes and the increases in cytokine responses to surgical
stress may potentially contribute to systemic inflamma-
tory response syndrome and an increased incidence of
postoperative complications in elderly persons. Inter-
leukin 6, an inflammatory cytokine, has been particu-
larly well studied, and its age-related increase has been
well documented.110 In terms of function, interleukin 6
has been postulated to modulate the endocrine re-
sponse, with activation of the hypothalamic-pituitary-
adrenal axis, stimulation of plasma cortisol levels, and
augmentation of bone loss.83,111 The role of interleukin
6 has also been reported to be sex specific.112
NEUROLOGICAL CHANGES
Traditional theories of normal neuronal loss with aging
have been challenged.113 Histological studies114 of brain
specimens from subjects without dementia or other ce-
rebral pathological features have shown minimal neu-
ronal loss with normal aging. Neurodegenerative pro-
cesses (Alzheimer, Parkinson, and Huntington diseases),
though, are strongly associated with neuronal loss.115-117
Cortical atrophy has been repeatedly demonstrated to
progress with age.118-120 A 6% to 11% loss of brain weight
has been demonstrated in subjects older than 80 years.121
Coffey et al119 performed quantitative magnetic reso-
nance imaging studies of the brain in subjects matched
by Mini-Mental State Examination score and found sta-
tistical decreases in cerebral hemisphere volume, fron-
tal region area, temporoparietal region area, and parieto-
occipital region area with age. Increased lateral ventricle
and third ventricle volumes in elderly persons were also
shown in the same study.119 Cortical atrophy is said to
precede neurodegeneration, if dementia has not already
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ensued.121 In patients with Alzheimer disease, Mouton
et al122 have demonstrated a 20% to 25% greater cortical
atrophy compared with age-matched control subjects. In-
terestingly, higher levels of education have been shown
to protect against dementia.123 This concept is known as
the reserve hypothesis.
Cerebral blood flow and cerebral oxygen consump-
tion have been shown to decrease with age, particularly
in areas with decreased gray and white matter.124-126 This
increases the risk for cerebrovascular accidents with as-
sociated vascular disease. Vision, auditory function, and
vibrotactile sensation are blunted with age.121 The recep-
tor cells of the retina, rods, and cones have been re-
ported to undergo changes with aging.127 Stiffening of the
tympanic membrane and sensory loss of the cochlea are
a few examples of changes in the auditory system.128 De-
creased mechanoreceptor density and sensitivity, and de-
creased peripheral nerve conductivity, have been shown
in elderly patients with decreased vibrotactile sensa-
tion.129 Loss of labyrinth hair cells, nerve fibers, and ves-
tibular ganglion cells has been shown to affect the ves-
tibulo-ocular reflex in elderly persons.130 Decreased tactile
and proprioceptive sensation has been reported in eld-
erly persons.128,131 Kokmen et al132 reported decreased joint
motion sensation in healthy aged individuals. They found
a decrease in reflex time with age, but no difference in
nerve fiber numbers.132
The autonomic neural responses are blunted in
elderly persons. Collins et al133 found healthy elderly sub-
jects to have significantly diminished beat-to-beat varia-
tion in response to postural change, decreased vasocon-
strictor response to cooling, and reduced baroreflex
sensitivity. Peripheral vascular resistance is maintained
with postural changes in healthy community-dwelling eld-
erly individuals, despite blunting of the baroreflexes with
age.134,135 Orthostatic intolerance is far more common in
debilitated patients older than 70 years who are institu-
tionalized for the long term.136 Pfeifer et al137 reported an
age-related increase in cardiovascular sympathetic ac-
tivity and a decrease in cardiac parasympathetic activity.
Brodde and Michel138 attribute the diminished sympa-
thetic tachycardia response and the diminished vagal
bradycardia response of the aging heart to the reduced
responsiveness of ␣-adrenergic and muscarinic recep-
tors, respectively. Thermoregulatory mechanisms be-
come less responsive with age, predisposing elderly per-
sons to hypothermia in cold environments.43,139-141 The 2
primary responses to a cold challenge, vasoconstriction
and shivering, are less effective.141,142 After a cold iso-
tonic sodium chloride solution infusion in elderly pa-
tients, Frank et al143 reported a decreased maximum re-
sponse intensity for vasoconstriction, total body oxygen
consumption, and norepinephrine. In addition, de-
creased vasomotor responsiveness to norepinephrine and
subjective sensory thermal perception were noted.143
Elderly persons have an increased threshold for
pain.144 Adequate pain control is critical to minimize the
risk for myocardial ischemia, tachycardia, hyperten-
sion, and pulmonary complications. In addition, effec-
tive analgesia encourages early patient mobilization, short-
ens hospital stays, and decreases medical costs.51 At the
same time, caution must be taken not to overmedicate
WWW.ARCHSURG.COM
 elderly persons. Overmedication with various agents may
lead to hypoxia, hypercapnia, hypotension, or delirium.
Agents with shorter elimination half-lives are recom-
mended.145
In summary, cortical atrophy lowers the threshold
to neurodegeneration in patients. The most common post-
operative neural complications are cerebrovascular ac-
cidents and delirium. Perioperative insults, such as hy-
potension, hypoxia, hypothermia, and malnutrition, pose
a greater risk to the central nervous system of elderly per-
sons compared with young persons. The blunted sym-
pathetic and parasympathetic responses to stimuli re-
sult in more moderate responses to stress and typically
longer recovery times to baseline functionality.
CONCLUSIONS
Elderly persons experience normal physiological changes
associated with aging in all of their solid organ systems.
Together, these changes lead to a diminished physiologi-
cal reserve. Patients with advanced age have the highest
mortality rate within the adult surgical population.3 A ma-
jor risk factor for perioperative mortality is, therefore, con-
sidered to be advanced age.146 The effects of postopera-
tive stresses are more detrimental to some organ systems
than others. Myocardial infarctions have been reported
as the leading cause of postoperative death among 80-
year-old patients.4 Among patients older than 60 years,
the incidence of postoperative myocardial infarction af-
ter noncardiac surgery is reported to be 0.1% to 0.15%,
with a subsequent mortality of 50% to 83%.147 Mortality
secondary to pulmonary complications is reported as be-
tween 0% and 0.6%, depending on risk factors.148,149 Pul-
monary complications, including pneumonia, hypoven-
tilation, hypoxia, and atelectasis, are reported to occur
in 2% to 10% of elderly patients.3 Cerebrovascular-
related mortality in elderly patients undergoing urologi-
cal procedures was reported to be 0.05%.3 Postoperative
delirium varies between 5% and 61%, but only 1% of pa-
tients have persistent symptoms.150,151
The perioperative risk for mortality is heightened
in the postoperative period.3 The postoperative period
is physiologically most stressful, because this is when there
are the greatest shifts in fluid, body temperature, adren-
ergic activity, and pulmonary function.152 Thorough pre-
operative assessment of organ function and reserve, in-
traoperative control of disease, close postoperative
monitoring, and pain management are recommended to
effectively decrease perioperative mortality.51
Accepted for publication April 27, 2003.
Corresponding author: Randall P. Nacamuli, MD, Chil-
dren’s Surgical Research, 257 Campus Dr, Stanford, CA
94305 (e-mail: Nacamuli@stanford.edu).
REFERENCES
1. Bureau of the Census. Sixty-five Plus in the United States: Statistical Brief 95.
Available at: http://www.census.gov/apsd/www/statbrief/sb95_8.pdf.
2. Weintraub M, Kekoler L. Demographics of Aging. Baltimore, Md: Williams &
Wilkins; 1997.
3. Pedersen T, Eliasen K, Henriksen E. A prospective study of mortality associ-
(REPRINTED) ARCH SURG/ VOL 138, OCT 2003
1074
©2003 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Mexico | Access Provided by JAMA User on 03/31/2021
ated with anaesthesia and surgery: risk indicators of mortality in hospital. Acta
Anaesthesiol Scand. 1990;34:176-182.
4. Djokovic JL, Hedley-Whyte J. Prediction of outcome of surgery and anesthesia
in patients over 80. JAMA. 1979;242:2301-2306.
5. Hosking MP, Lobdell CM, Warner MA, et al. Anaesthesia for patients over 90
years of age: outcomes after regional and general anaesthetic techniques for
two common surgical procedures. Anaesthesia. 1989;44:142-147.
6. Rosenthal R, Zenilman M, Katlic M. Principles and Practice of Geriatric Sur-
gery. New York: Springer-Verlag NY Inc; 2001.
7. Harmon D. Aging: a theory based on free radical and radiation chemistry. J Ger-
ontol. 1956;11:298-300.
8. Orgel L. The maintenance of accuracy of protein synthesis and its relevance to
aging. Proc Natl Acad Sci U S A. 1963;49:517-521.
9. Bjorksten J. The cross linkage theory of aging. J Am Geriatr Soc. 1968;16:408-
427.
10. Mobbs C. Neuroendocrinology of aging. In: Rowe J, ed. Handbook of the Bi-
ology of Aging. San Diego, Calif: Academic Press Inc; 1996:234-282.
11. Walford RL. Immunologic theory of aging: current status. Fed Proc. 1974;33:
2020-2027.
12. Finch CE, Ruvkun G. The genetics of aging. Annu Rev Genomics Hum Genet.
2001;2:435-462.
13. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell
Res. 1965;37:614-636.
14. Harley CB. Telomere loss: mitotic clock or genetic time bomb? Mutat Res. 1991;
256:271-282.
15. Olivetti G, Melissari M, Capasso JM, et al. Cardiomyopathy of the aging human
heart: myocyte loss and reactive cellular hypertrophy. Circ Res. 1991;68:1560-
1568.
16. Fleg JL, O’Connor F, Gerstenblith G, et al. Impact of age on the cardiovascular
response to dynamic upright exercise in healthy men and women. J Appl Physiol.
1995;78:890-900.
17. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardio-
vascular disease enterprises, part II: the aging heart in health: links to heart dis-
ease. Circulation. 2003;107:346-354.
18. Olivetti G, Giordano G, Corradi D, et al. Gender differences and aging: effects
on the human heart. J Am Coll Cardiol. 1995;26:1068-1079.
19. Lakatta EG. Arterial and cardiac aging: major shareholders in cardiovascular
disease enterprises, part III: cellular and molecular clues to heart and arterial
aging. Circulation. 2003;107:490-497.
20. Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol
Rev. 1993;73:413-467.
21. Esler MD, Turner AG, Kaye DM, et al. Aging effects on human sympathetic neu-
ronal function. Am J Physiol. 1995;268(pt 2):R278-R285.
22. Schulman SP, Gerstenblith G. Relationship of age and sex on ventricular vas-
cular coupling at rest and exercise. Circulation. 2000;102(suppl II):602.
23. Lidman D. Histopathology of human extremital arteries throughout life: includ-
ing measurements of cystolic pressures in ankle and arm. Acta Chir Scand. 1982;
148:575-580.
24. Banks J, Booth FV, MacKay EH, Rajagopalan B, Lee GD. The physical properties
of human pulmonary arteries and veins. Clin Sci Mol Med. 1978;55:477-484.
25. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardio-
vascular disease enterprises, part I: aging arteries: a “set up” for vascular dis-
ease. Circulation. 2003;107:139-146.
26. Mackay EH, Banks J, Sykes B, et al. Structural basis for the changing physical
properties of human pulmonary vessels with age. Thorax. 1978;33:335-344.
27. Mazess RB, Forman SH. Longevity and age exaggeration in Vilcabamba, Ecua-
dor. J Gerontol. 1979;34:94-98.
28. Avolio A. Genetic and environmental factors in the function and structure of
the arterial wall. Hypertension. 1995;26:34-37.
29. Gimbrone MA Jr. Vascular endothelium, hemodynamic forces, and atherogen-
esis. Am J Pathol. 1999;155:1-5.
30. Franklin SS, Gustin WT, Wong ND, et al. Hemodynamic patterns of age-related
changes in blood pressure: the Framingham Heart Study. Circulation. 1997;96:
308-315.
31. Sagie A, Larson MG, Levy D. The natural history of borderline isolated systolic
hypertension. N Engl J Med. 1993;329:1912-1917.
32. Franklin SS, Larson MG, Khan SA, et al. Does the relation of blood pressure to
coronary heart disease risk change with aging? the Framingham Heart Study.
Circulation. 2001;103:1245-1249.
33. Sesso HD, Stampfer MJ, Rosner B, et al. Systolic and diastolic blood pressure,
pulse pressure, and mean arterial pressure as predictors of cardiovascular dis-
ease risk in men. Hypertension. 2000;36:801-807.
34. Franklin SS, Khan SA, Wong ND, et al. Is pulse pressure useful in predicting
risk for coronary heart disease? the Framingham Heart Study. Circulation. 1999;
100:354-360.
WWW.ARCHSURG.COM
 35. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maxi-
mal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis.
1983;127:725-734.
36. Sorbini CA, Grassi V, Solinas E, et al. Arterial oxygen tension in relation to age
in healthy subjects. Respiration. 1968;25:3-13.
37. Kronenberg RS, Drage CW. Attenuation of the ventilatory and heart rate re-
sponses to hypoxia and hypercapnia with aging in normal men. J Clin Invest.
1973;52:1812-1819.
38. Campbell E. Physiologic changes in respiratory function. In: Katlic M, ed. Prin-
ciples and Practice of Geriatric Surgery. New York: Springer-Verlag NY Inc; 2001:
396-405.
39. Thurlbeck WM, Angus GE. Growth and aging of the normal human lung. Chest.
1975;67(2 suppl):3S-6S.
40. Pride NB. Pulmonary distensibility in age and disease. Bull Physiopathol Respir
(Nancy). 1974;10:103-108.
41. Turner JM, Mead J, Wohl ME. Elasticity of human lungs in relation to age.
J Appl Physiol. 1968;25:664-671.
42. Pierce J, Hocott J, Ebert R. The collagen and elastin content of the lung in em-
physema. Ann Intern Med. 1961;55:210-222.
43. Polkey MI, Harris ML, Hughes PD, et al. The contractile properties of the eld-
erly human diaphragm. Am J Respir Crit Care Med. 1997;155:1560-1564.
44. Tolep K, Kelsen SG. Effect of aging on respiratory skeletal muscles. Clin Chest
Med. 1993;14:363-378.
45. Burr ML, Phillips KM, Hurst DN. Lung function in the elderly. Thorax. 1985;40:
54-59.
46. Tockman MS, Erozan YS, Gupta P, et al, for the the LCEWDG Investigators, Lung
Cancer Early Detection Group. The early detection of second primary lung can-
cers by sputum immunostaining. Chest. 1994;106(suppl):385S-390S.
47. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using tech-
niques and equipment that meet ATS recommendations. Am Rev Respir Dis.
1981;123:659-664.
48. Johnson BD, Reddan WG, Pegelow DF, Seow KC, Dempsey JA. Flow limitation
and regulation of functional residual capacity during exercise in a physically
active aging population. Am Rev Respir Dis. 1991;143(pt 1):960-967.
49. D’Errico A, Scarani P, Colosimo E, Spina M, Grigioni WF, Mancini AM. Changes
in the alveolar connective tissue of the ageing lung: an immunohistochemical
study. Virchows Arch A Pathol Anat Histopathol. 1989;415:137-144.
50. Neas LM, Schwartz J. The determinants of pulmonary diffusing capacity in a
national sample of US adults. Am J Respir Crit Care Med. 1996;153:656-664.
51. Jin F, Chung F. Minimizing perioperative adverse events in the elderly. Br J An-
aesth. 2001;87:608-624.
52. Roessle R, Roulet F. Nieren: In Mass und Zahl in der Pathologie. Berlin, Ger-
many: J Springer; 1932.
53. Dunnill MS, Halley W. Some observations on the quantitative anatomy of the
kidney. J Pathol. 1973;110:113-121.
54. Ryan J, Zawada E. Renal Function and Fluid and Electrolyte Balance. 767-779.
New York: Springer-Verlag NY Inc; 2001.
55. Takazakura E, Sawabu N, Handa A, et al. Intrarenal vascular changes with age
and disease. Kidney Int. 1972;2:224-230.
56. Epstein M. Effects of aging on the kidney. Fed Proc. 1979;38:168-171.
57. Darmady EM, Offer J, Woodhouse MA. The parameters of the ageing kidney.
J Pathol. 1973;109:195-207.
58. Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progres-
sive nature of kidney disease: the role of hemodynamically mediated glomeru-
lar injury in the pathogenesis of progressive glomerular sclerosis in aging, re-
nal ablation, and intrinsic renal disease. N Engl J Med. 1982;307:652-659.
59. Epstein M. Renal Physiologic Changes With Age. Littleton, Colo: PSG Publish-
ing; 1985.
60. Weidmann P, De Myttenaere-Bursztein S, Maxwell MH, et al. Effect on aging
on plasma renin and aldosterone in normal man. Kidney Int. 1975;8:325-333.
61. Epstein M, Hollenberg NK. Age as a determinant of renal sodium conservation
in normal man. J Lab Clin Med. 1976;87:411-417.
62. Dontas A, Marketos S, Papanayiotou P. Mechanisms of renal tubular defects in
old age. Postgrad Med J. 1972;48:295-303.
63. Duchin K. Pharmacodynamics and Pharmacokinetics of Drugs in the Elderly.
Littleton, Colo: PSG Publishing; 1985.
64. Whiteway J, Morson BC. Pathology of the ageing: diverticular disease. Clin Gas-
troenterol. 1985;14:829-846.
65. Khan TA, Shragge BW, Crispin JS, Lind JF. Esophageal motility in the elderly.
Am J Dig Dis. 1977;22:1049-1054.
66. Pelemans W, Vantrappen G. Oesophageal disease in the elderly. Clin Gastro-
enterol. 1985;14:635-656.
67. Sivarao DV, Goyal RK. Functional anatomy and physiology of the upper esoph-
ageal sphincter. Am J Med. 2000;108(suppl 4a):27S-37S.
68. Adkins RB, Marshall BA. Anatomic and physiologic aspects of aging. In: Ad-
(REPRINTED) ARCH SURG/ VOL 138, OCT 2003
1075
©2003 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Mexico | Access Provided by JAMA User on 03/31/2021
kins RB, Scott HW, eds. Surgical Care for the Elderly. 2nd ed. Philadelphia, Pa:
Lippincott-Raven Publishers; 1998:xxi, 531.
69. Kupfer RM, Heppell M, Haggith JW, et al. Gastric emptying and small-bowel
transit rate in the elderly. J Am Geriatr Soc. 1985;33:340-343.
70. Evans MA, Triggs EJ, Cheung M, et al. Gastric emptying rate in the elderly: im-
plications for drug therapy. J Am Geriatr Soc. 1981;29:201-205.
71. Andrews GR, Haneman B, Arnold BJ, Booth JC, Taylor K. Atrophic gastritis in
the aged. Australas Ann Med. 1967;16:230-235.
72. Whiteway J, Morson BC. Elastosis in diverticular disease of the sigmoid colon.
Gut. 1985;26:258-266.
73. Drummond H. Sacculi of the large intestine with special reference to their re-
lations to the blood vessels of the bowel wall. Br J Surg. 1916;4:407-413.
74. Astor FC, Hanft KL, Ciocon JO. Xerostomia: a prevalent condition in the elderly.
Ear Nose Throat J. 1999;78:476-479.
75. Fischer D, Ship JA. Effect of age on variability of parotid salivary gland flow
rates over time. Age Ageing. 1999;28:557-561.
76. Holt PR. The small intestine. Clin Gastroenterol. 1985;14:689-723.
77. Vestal RE, McGuire EA, Tobin JD, et al. Aging and ethanol metabolism. Clin Phar-
macol Ther. 1977;21:343-354.
78. Salem SA, Rajjayabun P, Shepherd AM, et al. Reduced induction of drug me-
tabolism in the elderly. Age Ageing. 1978;7:68-73.
79. Valdivieso V, Palma R, Wunkhaus R, et al. Effect of aging on biliary lipid com-
position and bile acid metabolism in normal Chilean women. Gastroenterol-
ogy. 1978;74:871-874.
80. Overlie I, Moen MH, Morkrid L, Skjaeraasen JS, Holte A. The endocrine tran-
sition around menopause—a five years prospective study with profiles of go-
nadotropines, estrogens, androgens and SHBG among healthy women. Acta
Obstet Gynecol Scand. 1999;78:642-647.
81. Riggs BL. Endocrine causes of age-related bone loss and osteoporosis. No-
vartis Found Symp. 2002;242:247-264.
82. Matthews KA, Wing RR, Kuller LH, et al. Influence of the perimenopause on
cardiovascular risk factors and symptoms of middle-aged healthy women. Arch
Intern Med. 1994;154:2349-2355.
83. Perry HM 3rd. The endocrinology of aging. Clin Chem. 1999;45:1369-1376.
84. Greendale GA, Judd HL. The menopause: health implications and clinical man-
agement. J Am Geriatr Soc. 1993;41:426-436.
85. Johnson SR. Menopause and hormone replacement therapy. Med Clin North
Am. 1998;82:297-320.
86. Kuller LH. Hormone replacement therapy and risk of cardiovascular disease:
implications of the results of the Women’s Health Initiative. Arterioscler Thromb
Vasc Biol. 2003;23:11-16.
87. Notman MT, Nadelson C. The hormone replacement therapy controversy. Arch
Women Ment Health. 2002;5:33-35.
88. Schulman C, Lunenfeld B. The ageing male. World J Urol. 2002;20:4-10.
89. Demers LM. Andropause: an androgen deficiency state in the ageing male. Ex-
pert Opin Pharmacother. 2003;4:183-190.
90. Gruenewald DA, Matsumoto AM. Testosterone supplementation therapy for older
men: potential benefits and risks. J Am Geriatr Soc. 2003;51:101-115.
91. Janssens H, Vanderschueren DM. Endocrinological aspects of aging in men: is
hormone replacement of benefit? Eur J Obstet Gynecol Reprod Biol. 2000;92:
7-12.
92. Hermann M, Berger P. Hormonal changes in aging men: a therapeutic indica-
tion? Exp Gerontol. 2001;36:1075-1082.
93. Corpas E, Harman SM, Blackman MR. Human growth hormone and human ag-
ing. Endocr Rev. 1993;14:20-39.
94. Khan AS, Sane DC, Wannenburg T, et al. Growth hormone, insulin-like growth fac-
tor-1 and the aging cardiovascular system. Cardiovasc Res. 2002;54:25-35.
95. Muller EE, Rigamonti AE, Colonna Vde G, Locatelli V, Berti F, Cella SG. GH-
related and extra-endocrine actions of GH secretagogues in aging. Neurobiol
Aging. 2002;23:907-919.
96. Arnetz BB, Lahnborg G, Eneroth P, et al. Age-related differences in the serum
prolactin response during standardized surgery. Life Sci. 1984;35:2675-2680.
97. McConnell JG, Buchanan KD, Ardill J, et al. Glucose tolerance in the elderly:
the role of insulin and its receptor. Eur J Clin Invest. 1982;12:55-61.
98. Barbieri M, Rizzo MR, Manzella D, et al. Age-related insulin resistance: is it an
obligatory finding? the lesson from healthy centenarians. Diabetes Metab Res
Rev. 2001;17:19-26.
99. Fink RI, Wallace P, Olefsky JM. Effects of aging on glucose-mediated glucose
disposal and glucose transport. J Clin Invest. 1986;77:2034-2041.
100. Samos LF, Roos BA. Diabetes mellitus in older persons. Med Clin North Am.
1998;82:791-803.
101. Sirota DK. Thyroid function and dysfunction in the elderly: a brief review. Mt
Sinai J Med. 1980;47:126-131.
102. Haden ST, Brown EM, Hurwitz S, et al. The effects of age and gender on par-
athyroid hormone dynamics. Clin Endocrinol (Oxf). 2000;52:329-338.
WWW.ARCHSURG.COM
 103. Bilezikian JP, Silverberg SJ. Parathyroid hormone: does it have a role in the
pathogenesis of osteoporosis? Clin Lab Med. 2000;20:559-567.
104. Van Cauter E, Leproult R, Plat L. Age-related changes in slow wave sleep and
REM sleep and relationship with growth hormone and cortisol levels in healthy
men. JAMA. 2000;284:861-868.
105. Mazzeo RS. Aging, immune function, and exercise: hormonal regulation. Int J
Sports Med. 2000;21(suppl 1):S10-S13.
106. Smolander J. Effect of cold exposure on older humans. Int J Sports Med. 2002;
23:86-92.
107. Effros RB. Ageing and the immune system. Novartis Found Symp. 2001;235:
130-149.
108. Naliboff BD, Benton D, Solomon GF, et al. Immunological changes in young
and old adults during brief laboratory stress. Psychosom Med. 1991;53:121-
132.
109. Ono S, Aosasa S, Tsujimoto H, et al. Increased monocyte activation in elderly
patients after surgical stress. Eur Surg Res. 2001;33:33-38.
110. Wei J, Xu H, Davies JL, et al. Increase of plasma IL-6 concentration with age in
healthy subjects. Life Sci. 1992;51:1953-1956.
111. Giuliani N, Sansoni P, Girasole G, et al. Serum interleukin-6, soluble interleu-
kin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-
related changes. Exp Gerontol. 2001;36:547-557.
112. Zietz B, Hrach S, Scholmerich J, et al. Differential age-related changes of hy-
pothalamus-pituitary-adrenal axis hormones in healthy women and men: role
of interleukin 6. Exp Clin Endocrinol Diabetes. 2001;109:93-101.
113. Brody H. An Examination of Cerebral Cortex and Brainstem in Aging. New York,
NY: Raven Press; 1976.
114. Terry R, De Teresa R, Hansen L. Neocortical cell counts in normal human adult
aging. Ann Neurol. 1987;21:530-539.
115. Coleman P, Flood D. Neuron numbers and dendritic extent in normal aging and
Alzheimer’s disease. Neurobiol Aging. 1987;8:521-545.
116. Meier-Ruge W, Hunziker O, Iwangoff P, et al. Alterations of Morphological and
Neurochemical Parameters of the Brain Due to Normal Aging. Amsterdam, the
Netherlands: Elsevier North-Holland; 1987.
117. Flood D, Coleman P. Hippocampal plasticity in normal aging and decreased plas-
ticity in Alzheimer’s disease. Prog Brain Res. 1990;83:435-443.
118. Coffey CE, Lucke JF, Saxton JA, et al. Sex differences in brain aging: a quanti-
tative magnetic resonance imaging study. Arch Neurol. 1998;55:169-179.
119. Coffey CE, Saxton JA, Ratcliff G, et al. Relation of education to brain size in nor-
mal aging: implications for the reserve hypothesis. Neurology. 1999;53:189-
196.
120. Long DM. Aging in the nervous system. Neurosurgery. 1985;17:348-354.
121. DeLaTorre J, Fay L. Effects of aging on the human nervous system. In: Rosenthal
R, Zenilman M, Katlic M, eds. Principles and Practice of Geriatric Surgery. New
York: Springer-Verlag NY Inc; 2001:926-948.
122. Mouton PR, Martin LJ, Calhoun ME, et al. Cognitive decline strongly correlates
with cortical atrophy in Alzheimer’s dementia. Neurobiol Aging. 1998;19:371-
377.
123. Friedland RP. Epidemiology, education, and the ecology of Alzheimer’s dis-
ease. Neurology. 1993;43:246-249.
124. Yamaguchi T, Kanno I, Uemura K. Reduction in regional cerebral metabolic rate
of oxygen during human aging. Stroke. 1986;17:1220-1228.
125. Dastur D. Cerebral blood flow and metabolism in normal human aging, patho-
logical aging, and senile dementia. J Cereb Blood Flow Metab. 1985;5:1-9.
126. Fazekas J, Alivan R, Bessman A. Cerebral physiology of the aged. Am J Med
Sci. 1952;223:245-257.
127. Marshall J, Grindle J, Ansell P, et al. Convolution in human rods: an aging pro-
cess. Br J Ophthalmol. 1979;63:181-187.
(REPRINTED) ARCH SURG/ VOL 138, OCT 2003
1076
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128. Skinner HB, Barrack RL, Cook SD. Age-related decline in proprioception. Clin
Orthop. April 1984:208-211.
129. Verrillo RT. Age related changes in the sensitivity to vibration. J Gerontol. 1980;
35:185-193.
130. Paige GD. The aging vestibulo-ocular reflex (VOR) and adaptive plasticity. Acta
Otolaryngol Suppl. 1991;481:297-300.
131. Kaplan FS, Nixon JE, Reitz M, et al. Age-related changes in proprioception and
sensation of joint position. Acta Orthop Scand. 1985;56:72-74.
132. Kokmen E, Bossemeyer RW Jr, Barney J, Williams WJ. Neurological manifes-
tations of aging. J Gerontol. 1977;32:411-419.
133. Collins KJ, Exton-Smith AN, James MH, et al. Functional changes in auto-
nomic nervous responses with ageing. Age Ageing. 1980;9:17-24.
134. Smith JJ. Circulatory response to the upright posture. Boca Raton, Fla: CRC
Press LLC; 1990:187.
135. Gribbin B, Pickering TG, Sleight P, et al. Effect of age and high blood pressure
on baroreflex sensitivity in man. Circ Res. 1971;29:424-431.
136. Lipsitz LA. Orthostatic hypotension in the elderly. N Engl J Med. 1989;321:952-
957.
137. Pfeifer MA, Weinberg CR, Cook D, et al. Differential changes of autonomic ner-
vous system function with age in man. Am J Med. 1983;75:249-258.
138. Brodde OE, Michel MC. Adrenergic and muscarinic receptors in the human heart.
Pharmacol Rev. 1999;51:651-690.
139. Frank SM, Beattie C, Christopherson R, et al. Epidural versus general anesthe-
sia, ambient operating room temperature, and patient age as predictors of in-
advertent hypothermia. Anesthesiology. 1992;77:252-257.
140. Inoue Y, Nakao M, Araki T, Ueda H. Thermoregulatory responses of young and
older men to cold exposure. Eur J Appl Physiol Occup Physiol. 1992;65:492-
498.
141. Wagner JA, Robinson S, Marino RP. Age and temperature regulation of hu-
mans in neutral and cold environments. J Appl Physiol. 1974;37:562-565.
142. Khan F, Spence VA, Belch JJ. Cutaneous vascular responses and thermoregu-
lation in relation to age. Clin Sci (Lond). 1992;82:521-528.
143. Frank SM, Raja SN, Bulcao C, et al. Age-related thermoregulatory differences
during core cooling in humans. Am J Physiol Regul Integr Comp Physiol. 2000;
279:R349-R354.
144. Harkins SW, Chapman CR. Detection and decision factors in pain perception in
young and elderly men. Pain. 1976;2:253-264.
145. McLeskey CH, ed. Geriatric Anesthesiology. Baltimore, Md: Williams & Wilkins;
1997.
146. Priebe HJ. The aged cardiovascular risk patient. Br J Anaesth. 2000;85:763-
778.
147. Plumlee JE, Boettner RB. Myocardial infarction during and following anesthe-
sia and operation. South Med J. 1972;65:886-889.
148. Bluman LG, Mosca L, Newman N, et al. Preoperative smoking habits and post-
operative pulmonary complications. Chest. 1998;113:883-889.
149. Olsson GL, Hallen B, Hambraeus-Jonzon K. Aspiration during anaesthesia: a
computer-aided study of 185,358 anaesthetics. Acta Anaesthesiol Scand. 1986;
30:84-92.
150. Chung F. Postoperative mental dysfunction. In: McLeskey CH, ed. Geriatric An-
esthesiology. Baltimore, Md: Williams & Wilkins; 1997:487-495.
151. Dai YT, Lou MF, Yip PK, et al. Risk factors and incidence of postoperative de-
lirium in elderly Chinese patients. Gerontology. 2000;46:28-35.
152. Mangano DT, Wong MG, London MJ, et al, for the Study of Perioperative Is-
chemia (SPI) Research Group. Perioperative myocardial ischemia in patients
undergoing noncardiac surgery, II: incidence and severity during the 1st week
after surgery. J Am Coll Cardiol. 1991;17:851-857.
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