3
Physiology of Aging
George E. Taffett
Aging, from maturity to senescence, results in an appar-
ent depletion of physiologic reserves that has been
termed homeostenosis. This term suggests a narrowing of
homeostatic reserve mechanisms. Homeostenosis leads
to the increased vulnerability to disease that occurs with
aging. Primary aging changes, upon which we focus here,
are those that occur as a result of the passage of time and
are independent of disease state, although there may be
overlap between disease and these changes. The age
changes may be accelerated or slowed by lifestyle but are
usually evident by the fourth or fifth decade and are
gradual and inexorable. Overall, primary aging changes
result in little change in function when the older individ-
ual (or animal) is assessed in the unstressed state, but
these age changes become readily evident when the older
individual is stressed or moved away from homeostasis.
Because disease produces such stresses, the impact, pre-
sentation, and natural history of diseases are modified
with age because the substrate, perhaps more than the
disease pathophysiology, has been modified.
The concept of homeostenosis—the characteristic, pro-
gressive constriction of homeostatic reserves that occurs
with aging in every organ system—was recognized by the
famous physiologist Walter Cannon in the 1940s.1 Figure
3.1 graphically displays the traditional thinking about
homeostenosis. With aging, the capacity of older persons
to bring themselves back to homeostasis after a chal-
lenge becomes smaller. All challenges to homeostasis are
movements off the baseline, and larger challenges require
greater physiologic reserves to return to homeostasis.
Aging itself brings the individual closer to the precipice
or threshold by the loss of physiologic reserves. The
“precipice” may be defined, for example, as death or ill
enough to have a cardiac arrest or for hospital admission.
The precipice may also be the appearance of common
and protean symptoms, such as confusion, weight loss,
sleep disorder, or weakness.
Although empirically this paradigm is true, direct evi-
dence for this model may be derived from studying the
physiologic deviation from normal using the APACHE
severity of illness scales.2 Acute physiologic assessment
points are generated by increased deviation from home-
ostatic values for 12 variables, including vital signs,
oxygenation, pH, electrolytes, hematocrit, white count,
and creatinine. A normal person at homeostasis will have
a zero score. A greater departure from homeostasis is
measured by a greater point total.
Figure 3.2 shows young and old patients who experi-
enced a cardiac arrest. The younger group (mean age, 59
years) had significantly higher (by 20%) acute physio-
logic assessment scores than the older group (mean age,
75).3 The data represent the worst values available in the
24 h prearrest. These data support the concept that the
threshold, in this case being “sick” enough to have a
cardiac arrest, is closer to homeostasis for the older than
for the younger group. In practice, the creators of the
APACHE II or III scales recognized that advanced age
adds to risk of physiologic impairment with intercurrent
illness. Another way to say this is that age reduces reserve
capacity and makes us less resilient. APACHE scales give
“bonus points” for age so that the total scores are not
different between the younger and older groups.3
Despite the summative evidence, there is high vari-
ability in these processes. Variation in the age effects on
any parameter is large, and the variability appears to
increase with age. These variations are present from indi-
vidual to individual at the same age, within a given indi-
vidual from organ system to system, and even from cell
to cell isolated from the same person. For example, inves-
tigators of the Baltimore Longitudinal Study of Aging
performed serial measurements of glomerular filtration
rate (GFR) measured as creatinine clearance in healthy
people. Overall, the mean GFR decreased 1 ml/year;
however, almost 30% of patients showed no decrement
in function in repeated studies over as long as 30 years.
Others showed decreases in GFR of 2 ml/year or more.4
Similarly, when lymphocytes are isolated from an older
person and then studied in vitro, some of the cells func-
27
28 G.E. Taffett

Figure 3.1. Standard schematic of homeostenosis.

As the individual ages, there is no change in home-
ostasis, but the amount of physiologic reserves
“The Precipice ” available to counter any challenge to homeostasis
decreases with aging. Challenges to homeostasis are
depicted as arrows moving away from the baseline.
The “precipice” may be any clinically evident
marker such as death, confusion, or cardiac arrest.
Physiologic
Reserves

Increasing Age

tion as well as those from a younger person5; of course, physiologic reserves have not “disappeared,” as sug-
others function poorly, and it is the relative ratio of the gested in Figure 3.1, but they remain unavailable to
two groups that impacts overall function. Therefore, as counter additional challenges. I focus on examples from
opposed to the pediatrician who can within a few weeks the cardiovascular system, such as heart rate, cardiac
anticipate when a baby will start to walk, the geriatrician hypertrophy, and diastolic function, because the data in
has a much harder time predicting when senescent this area provide an ample molecular, biochemical, and
changes will become clinically evident. physiologic foundation to reinterpret the traditional
Another reason for the variability in the physiologic approach to homeostenosis.
changes associated with aging is the contribution of Although resting heart rate in unchanged with age,
behavioral factors such as exercise and diet, both of maximum heart rate attained with exercise or pharma-
which are strong influences on healthy aging. Epidemiol- cologic manipulation decreases with age. Baltimore
ogists describe the growing rate of obesity, especially Longitudinal Study data, obtained from healthy, highly
among older men, as an increasingly sedentary existence screened individuals, give a regression equation of
of most people beyond 30 years of age. For many of the
variables listed in Table 3.1, exercise or other choices are
known to attenuate but not totally abrogate aging effects.
Some, such as the decrease in maximum heart rate
attained with exercise, appear to be more predictable.
Table 3.1 summarizes many of the major changes in
systems receiving further elucidation in respective sec-
tions of this volume. Data from the cardiovascular system
are expanded here because the data in this area provide
ample rationale to justify the necessity to reinterpret the
traditional approach to homeostenosis. This reinterpre-
tation helps one understand the phenomenon of frailty, a
central concern of geriatrics. Frailty is the state when
physiologic reserves are reduced to the point at which
susceptibility to disability is increased. Frailty is, there-
fore, the clinical manifestation of the later stages of
homeostenosis, an intolerance of homeostatic challenges.
Additionally, the reinterpretation of homeostenosis
makes those caring for the elderly appreciate and under-
stand the complexities they face.
In the elderly, as in youth, maintaining homeostasis is
a dynamic, active process. The reinterpretation of Figure
Figure 3.2. Age decreases the level of physiologic derange-
3.1 shown in Figure 3.3 is based on the concept that older ment associated with cardiac arrest. Acute physiologic assess-
persons are actively employing some of their physiologic ment (APA) scores (from the APACHE II severity of illness
reserves just to maintain homeostasis. Their available scale) are shown from patients who subsequently experienced
reserves appear depleted because they in are already in cardiac arrest and a resuscitation attempt. The data show the
use by the old heart (or other organ or system) to com- APA scores were significantly higher in the younger patients
pensate for primary age-related or other changes. The who arrested than the older ones (p < 0.05; Beer et al. 19943).
3. Physiology of Aging 29

Table 3.1. Major changes in system.

Endocrine system
Impaired glucose tolerance (fasting glucose increased 1 mg/dl/decade; postprandial increased 10 mg/dl/decade)
Increased serum insulin and increased HgbA1C nocturnal growth hormone peaks lost, decreased 1GF-1
Marked decrease in dehydroepiandrosterone (DHEA)
Decreased free and bioavailable testosterone
Decreased T3
Increased parathyroid hormone (PTH)
Decreased production of vitamin D by skin
Ovarian failure, decreased ovarian hormones
Increased serum homocysteine levels
Cardiovascular
Unchanged resting heart rate (HR), decreased maximum HR
Impaired left ventricular filling
Marked dropout of pacemaker cells in SA node
Increased contribution of atrial systole to ventricular filling
Left atrial hypertrophy
Prolonged contraction and relaxation of left ventricle
Decreased inotropic, chronotropic, lusitropic response to beta-adrenergic stimulation
Decreased maximum cardiac output
Decreased hypertrophy in response to volume or pressure overload
Increased serum atrial natriuretic peptide (ANP)
Large arteries increase in wall thickness, lumen, and length, become less distensible, and compliance decreases
Subendothelial layer thickened with connective tissue
Irregularities in size and shape of endothelial cells
Fragmentation of elastin in media of arterial wall
Peripheral vascular resistance increases
Blood pressure
Increased systolic blood pressure (BP), unchanged diastolic BP
Beta-adrenergic-mediated vasodilatation decreased
Alpha-adrenergic-mediated vasoconstriction unchanged
Brain autoregulation of perfusion impaired
Pulmonary
Decreased FEV1 and FVC
Increased residual volume
Cough less effective
Ciliary action less effective
Ventilation–perfusion mismatching causes PaO2 to decrease with age: 100 - (0.32 * age)
Trachea and central airways increase in diameter
Enlarged alveolar ducts due to lost elastic lung parenchyma structural support result in decreased surface area
Decreased lung mass
Expansion of thorax
Maximum inspiratory and expiratory pressures decrease
Decreased respiratory muscle strength
Chest wall stiffens
Diffusion of CO decreased
Decreased ventilatory response to hypercapnia
Hematologic
Bone marrow reserves decreased in response to high demand
Attenuated reticulocytosis to erythropoeitin administration
Renal
Decreased creatinine clearance and GFR 10 ml/decade
Decrease of 25% in renal mass, mostly from cortex with a relative increased perfusion of juxtamedullary nephrons
Decreased sodium excretion and conservation
Decreased potassium excretion and conservation
Decreased concentrating and diluting capacity
Impaired secretion of acid load
Decreased serum renin and aldosterone
Accentuated ADH release in response to dehydration
Decreased nitric oxide production
Increased dependence of renal prostaglandins to maintain perfusion
Decreased vitamin D activation
(Continued)
30 G.E. Taffett

Table 3.1. Continued

Genitourinary (GU)
Prolonged refractory period for erections for men
Reduced intensity of orgasm for men and women
Incomplete bladder emptying and increased postvoid residuals
Decreased prostatic secretions in urine
Decreased concentrations of antiadherence factor Tamm–Horsfall protein
Temperature
Impaired shivering
Regulation
Decreased cutaneous vasoconstriction and vasodilation
Decreased sweat production
Increased core temperature to start sweating
Muscle
Marked decrease in muscle mass (sarcopenia) due to loss of muscle fibers
Aging effects smallest in diaphragm (role of activity), more in legs than arms
Decreased myosin heavy chain synthesis
Small if any decrease in specific force
Decreased innervation, increased number of myofibrils per motor unit
Infiltration of fat into muscle bundles
Increased fatigability
Decrease in basal metabolic rate (decrease 4%/decade after age 50) parallels loss of muscle
Bone
Slower healing of fractures
Decreasing bone mass in men and women, both trabecular and cortical bone
Decreased osteoclast bone formation
Joints
Disordered cartilage matrix
Modified proteoglycans and glycosaminoglycans
Peripheral nervous system
Loss of spinal motor neurons
Decreased vibratory sensation, especially in feet
Decreased thermal sensitivity (warm–cool)
Decreased sensory nerve action potential amplitude
Decreased size of large myelinated fibers
Increased heterogeneity of axon myelin sheaths
Central nervous system
Small decrease in brain mass
Decreased brain blood flow and impaired autoregulation of perfusion
Nonrandom loss of neurons to modest extents
Proliferation of astrocytes
Decreased density of dendritic connections
Increased numbers of scattered neurofibrillary tangles
Increased numbers of scattered senile plaques
Decreased myelin and total brain lipid
Altered neurotransmitters, including dopamine and serotonin
Increased monoamine oxidase activity
Decrease in hippocampal glucocorticoid receptors
Decline in fluid intelligence
Slowed central processing and reaction time
Gastrointestinal (GI)
Decreased liver size and blood flow
Impaired clearance by liver of drugs that require extensive phase I metabolism
Reduced inducibility of liver mixed-function oxidase enzymes Mild decrease in bilirubin
Hepatocytes accumulate secondary lysosomes, residual bodies, and lipofuscin
Mild decrease in stomach acid production, probably due to nonautoimmune loss of parietal cells
Impaired response to gastric mucosal injury
Decreased pancreatic mass and enzymatic reserves
Decrease in effective colonic contractions
Decreased calcium absorption
Decrease in gut-associated lymphoid tissue
3. Physiology of Aging 31

Table 3.1. Continued

Vision
Impaired dark adaptation
Yellowing of lens
Inability to focus on near items (presbyopia)
Minimal decrease in static acuity, profound decrease in dynamic acuity (moving target)
Decreased contrast sensitivity
Decreased lacrimation
Smell
Detection decreased by 50%
Thirst
Decreased thirst drive
Impaired control of thirst by endorphins
Balance
Increased threshold vestibular responses
Reduced number of organ of Corti hair cells
Audition
Bilateral loss of high-frequency tones
Central processing deficit
Difficulty discriminating source of sound
Impaired discrimination of target from noise
Adipose
Increased aromatase activity
Increased tendency to lipolysis
Immune system
Decreased cell-mediated immunity
Lower affinity antibody production
Increased autoantibodies
Facilitated production of anti-idiotype antibodies
Increased occurrence of MGUS (monoclonal gammopathy of unknown significance)
More nonresponders to vaccines
Decreased delayed-type hypersensitivity
Impaired macrophage function (Interferon-gamma, TGF-beta, TNF, IL-6, IL-1 release increased with age)
Decreased cell proliferative response to mitogens
Atrophy of thymus and loss of thymic hormones
Accumulation of memory T cells (CD-45+)
Increased circulating IL-6
Decreased IL-2 release and IL-2 responsiveness
Decreased production of B cells by bone marrow

208 - (0.95 ¥ age) for maximum heart rate attained with
exercise. It is likely that women have lower maximum
heart rates at age 30 and a more gentle fall with aging
than this equation predicts. This decrease in maximum
heart rate responsiveness results from a combination of
factors. First, primary aging decreases the intrinsic heart
rate (the heart rate in the absence of sympathetic and
parasympathetic stimulation), as well as invokes
reserves just to maintain resting heart rate. Data from
Jose,6 although regretfully including only a modest
number of elders, show a decrease in intrinsic heart rate
from 120–130/min to less than 80. There is no difference

“The Precipice ”

Physiologic
Reserves
Figure 3.3. Revised schematic of homeostenosis. Available
In comparison to Figure 3.1, this diagram shows
that maintaining homeostasis is a dynamic process. Physiologic
The older person employs or consumes physiologic Reserves
reserves just to maintain homeostasis, and therefore Already In Use
there are fewer reserves available for meeting new
challenges. Increasing Age
32
in resting heart rate with age, so the extent of parasym-
pathetic tone, slowing heart rate at rest, is decreased.
Removal of parasympathetic tone, the first mechanism
invoked to increase heart rate with exercise, is then less
effective for the elderly because vagal tone is already
diminished at rest; this is consistent with the attenuated
heart rate response of healthy elders to administration of
atropine. The decreased yield from lysis of parasympa-
thetic tone is added to decreased beta-adrenergic
chronotropic responsiveness to contribute to the overall
decreased maximal heart rate in response to exercise
(Fig. 3.4).
Importantly, the same limitation in maximum heart
rate with exercise applies to that in response to other
stimuli, such as infection or anemia. Therefore, an 80-
year-old man with a sinus tachycardia of 120, mounting
close to a maximum heart rate response, could be con-
sidered as a young man who had a heart rate of 170. In
the setting of an infection, although a 120 heart rate
would hardly raise eyebrows, a 170 would surely provoke
serious concern. For their respective age groups, both
values roughly represent an equivalent of 75% of
maximum response.
A similar set of observations, that reserves are invoked
to maintain homeostasis in the old, are seen following the
response to another challenge, pressure overload induced
by banding the aorta (Fig. 3.5).7 In older male rats (18
months of age), there is only trivial increase in left ven-
tricular mass in response to pressure overload. This same
manipulation results in a 40% hypertrophy of the left
ventricle in adult (9-month) animals. The molecular
response to the pressure overload was markedly attenu-
Figure 3.5. Decreased response to pressure stimulus in the old
heart. After aortic banding in the young and old rat, there is a
decreased elaboration of RNA for “early immediate response
genes” (fos and jun) in the old heart, followed by decreased con-
tractile protein response (skeletal actin). Ventricular atrial
G.E. Taffett
Sympathetic Stimulation
Actual Heart Rate
Intrinsic Heart Rate
Vagal Tone
Age 20 Age 80
Resting Heart Rate
Figure 3.4. Resting and exercise heart rates. There are no dif-
ferences in resting heart rate between the older and young
person, but the extent of the resting vagal tone, slowing heart
rate (dark gray bar), is decreased in the older person. With exer-
tion, the removal of the vagal tone results in smaller increment
in heart rate and the beta-adrenergic chronotropic responsive-
ness is also decreased (light gray bar), all contributing to the
decreased maximum heart rate in the old. The straight line rep-
resents the intrinsic heart rate (absence of any sympathetic or
vagal tone).
ated in the old heart, with little induction of the immedi-
ate early response genes c-jun and c-fos. Skeletal actin,
which precedes cardiac actin when new contractile ele-
ments are laid down in the heart, was not increased in the
older, banded heart. All these molecular markers con-
firmed the absence of hypertrophic response to banding
in the old heart.
natriuretic peptide (ANP), a marker for myocyte hypertrophy,
is increased in the control and old hearts, suggesting prior invo-
cation of the hypertrophic response (Takahashi et al. 19927 with
permission.)
3. Physiology of Aging
In contrast, atrial natriuretic peptide (ANP), a marker
for myocyte hypertrophy when it is expressed by the
ventricular myocyte, is increased significantly after
banding in the young heart. The ventricular ANP is not
detectable in the control young heart. ANP is signifi-
cantly elevated in the ventricle from both the banded and
control older hearts, providing evidence that the old heart
has already invoked the hypertrophic response even
before the banding is applied.
Morphologic evidence of myocyte hypertrophy in
aging is provided by examining myocyte size. Myocytes
from the ventricles of older persons and animals are
larger than those from young adults, consistent with
ongoing myocyte hypertrophy in response to uncertain
stresses. Various investigators report 25% increase in
myocyte length and 50% or more increases in myocyte
width.8 There is likely a maximum size for the myocyte;
therefore, myocytes in the old heart may be unable to
hypertrophy further because they have already
responded to prior or ongoing challenges.
With aging in animals and man, there are impairments
in early cardiac relaxation, largely caused by alterations
in cellular calcium flux. The increased dependence on
transsarcolemmal calcium flux (in and out of the cell)
seen in the old rat heart maintains adequate calcium
availability for contraction. This adaptation appears to be
a compensation for decreased transsarcoplasmic reticu-
lum calcium flux. Therefore, the compensation comes at
a cost, the lengthening of contraction by both slowing the
development of force and slowing cardiac relaxation.
Using gene therapy, a key sarcoplasmic reticulum calcium
pump can be restored in old rats to levels found in the
young heart, and cardiac relaxation improves signifi-
cantly.9 One manifestation of the impaired relaxation is
the decreased effectiveness of early diastolic filling of the
left ventricle. As a compensation to maintain ventricular
filling, contribution of atrial systole to diastolic filling
increases from 10% to 15% at age 20 to almost 50% at
age 80.10 In addition to explaining why atrial fibrillation
(and the loss of atrial systole) becomes so devastating in
the elderly, the ability to augment the atrial contribution
to further increase cardiac output is limited. Therefore,
the Frank–Starling mechanism is invoked; filling pres-
sures increase to augment cardiac output.
There are numerous other changes in the cardiovascu-
lar system (CVS) that follow the paradigm just described,
and the pattern is not at all limited to the CVS, such as
the limited heat shock protein elaboration in response to
certain stimuli. These changes support rethinking the
concept of frailty. Frailty is not a static state of increased
vulnerability to stressors; rather, it is a dynamic state in
which the older person tolerates additional challenges
poorly because reserves are already engaged in battles,
seen or unseen. From a therapeutic standpoint, this
suggests that efforts to disengage reserves may result
33
in decreasing vulnerability. To date, evidence for this
opportunity to increase reserves remains unproven.
Older persons are frailer, more likely to cross a given
“precipice” after a stress, not only because they have lost
some reserves because of aging, but because they are
already utilizing other reserves to compensate for those
lost just to maintain homeostasis. Older people are more
likely to drown when thrown a brick, not because they
cannot swim but because they are already treading water.
It is well known that the mortality associated with
myocardial infarction (MI) increases dramatically with
age. Although absolute death rates have improved with
treatment for all ages, the 10-fold increase in mortality
after MI from ages 40 to 80 has not been modified. This
age-related increase in mortality has been variously
attributed to increased infarct size in the old, comorbid
conditions, less aggressive therapy for the old, noncom-
pliance with medical regimens, or increased existence of
multivessel coronary artery disease. Some of the points
may be true, but in studies where all these factors are con-
trolled, the mortality is still much higher in the older
groups. Age is the key component, and I hypothesize that
it is the age-related inability to respond to challenge,
homeostenosis in the cardiovascular system, that results
in the increased mortality.
A similar set of implications can be made relevant to
the increased frequency of falls in response to challenge
in the elderly. Decreases in baroreceptor sensitivity, arte-
rial compliance, cardiac compliance (and greater depend-
ence on cardiac filling to maintain cardiac output),
renal sodium conservation, plasma volume, vasopressin
response to standing, and renin, angiotensin, and aldos-
terone levels all contribute to the propensity to fall with
postural change. Many of the problems with medications
in the elderly, once attributed to altered pharmaco-
dynamics, may be explained by this apparent depletion
of physiologic reserves.
Data from the MacArthur Study of Aging support the
concept that healthy elders are actively compensating
just to maintain homeostasis and that the presence of
invoked compensation is associated with poor out-
comes.11 Only 7% of those aged 70 to 79 had no evidence
of such compensation, and the lack of compensation was
associated with highest level of function. Seeman refers
to this activation as “allostatic load,” and while some of
the markers, such as elevated cholesterol and systolic
blood pressure, are known risk factors for CV events and
death, others reflect the activity of sympathetic nervous
system or the hypothalamic–pituitary–adrenal axis.
Those patients with high allostatic load had decreased
physical and cognitive function at 2-year follow-up.
There is some evidence that the inverse may also be
true. Masoro believes that one mechanism by which the
beneficial, life-prolonging effects of caloric restriction
occur is precisely that the decreased availability of calo-
34
Continence
Orientation
Physiologic
Reserves
Available
Physiologic
Reserves
Already In Use
Increasing Age
ries is a low-intensity stress.12 The beneficial effects of low-
dose radiation may also be via this mechanism. Persistent,
harmless stresses, such as caloric restriction or radiation,
may be good for us; larger stresses may be harmful.
Invoking compensatory mechanisms has the additional
effect of constraining the complexity of many variables.
Heart rate variability decreases with aging, and this con-
striction of heart rate may be due to decreased parasym-
pathetic tone and possible activation of the sympathetic
nervous system while at rest.13 A similar constriction is
seen in blood pressure variability. The decrease in vari-
ability may correspond with the ongoing activation of
compensatory reserves.
The concept of threshold is also useful in understand-
ing the altered presentations of disease in the elderly. The
extent that any threshold from Figure 3.1 or Figure 3.3
approaches homeostasis may determine whether that
threshold is crossed by a given challenge. For example,
delirium is a very common atypical presentation of a wide
variety of illness in the elderly, a marker of the uneasy
truce that the old brain maintains with its environment.
The precarious balance is clearly evident but is not
limited to the cholinergic pathways. While it seems
strange that a given older person may have the same
presentation (confusion) for a urinary tract infection, gas-
trointestinal bleeding, and a myocardial infarction, this
phenomena may be relatively common because the sys-
temic responses to these differing illnesses may be
similar, involving cytokines, catecholamines, etc. In these
patients, at homeostasis their “anticonfusion reserves”
may be exhausted so the distance from homeostasis to
the “precipice” becomes minimal and is easily crossed
(Fig. 3.6).
Finally, the lines on these schematics (Figs. 3.1, 3.3, 3.6)
are straight for convenience’s sake, not because any of
the processes described in Table 3.1 are necessarily linear.
For example, the loss in muscle mass approaches 40% as
one ages from 30 to 80, yet most of that loss happens after
G.E. Taffett
Figure 3.6. Altered presentation of illness may be
another manifestation of homeostenosis. With age,
the precipices may approach homeostasis at dif-
fering rates so that modest challenges produce
clinically evident events, in this case, new onset of
incontinence, and in others, disorientation or
confusion.
age 60, indicating the rate of loss increases with increas-
ing age. Strength follows mass in this pattern. It is likely
that most age-related physiologic changes are not linear
functions of age.
In summary, there is an apparent loss of physiologic
reserves that leads to an intolerance of challenges to the
homeostasis of older persons. One should appreciate that
this frailty is, in part, present because the older person
is continually expending reserves to compensate for
primary age changes and other unseen processes absent
or trivial in the younger individual.
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American Physiological Society. New York: Oxford Press;
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