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Normal aging

Author: George E Taffet, MD

Section Editor: Kenneth E Schmader, MD
Deputy Editor: Lisa Kunins, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2018. | This topic last updated: Jan 09, 2017.

INTRODUCTION — Time modifies many biologic processes. Aging is characterized by progressive and broadly
predictable changes that are associated with increased susceptibility to many diseases. Aging is not a
homogenous process. Rather, organs in the same person age at different rates influenced by multiple factors,
including genetic make-up, lifestyle choices, and environmental exposures. A Danish twin study found that
genetics accounted for about 25 percent of the variation in longevity among twins, and environmental factors
accounted for about 50 percent [1]. However, with greater longevity (to age 90 or 100), genetic influences
became more important.

This topic will present an overview of normal aging. Effects of aging on the immune systems and abnormal aging
are discussed in more detail separately. (See "Immune function in older adults".)

AGE-ASSOCIATED PHYSIOLOGIC CHANGES

Physiologic rhythms — The organization of rhythmic physiologic processes is altered by aging. Age impacts
the circadian pattern of body temperature, plasma cortisol, and sleep and can cause desynchronization or
"internal phase drift." Phase advances can lead to the occurrence of some rhythmic functions (eg, the 24-hour
body temperature trough and sleep onset) one to two hours earlier in older adults. The pulsatile secretion of
gonadotropins, growth hormone, thyrotropin, melatonin, and adrenocorticotropic hormone (ACTH) are attenuated
with age [2]. One source of this dysfunction appears to be neuronal loss in the suprachiasmatic nucleus in the
hypothalamus [3]. In addition, age may delay the ability to reset physiologic rhythms to a new photoperiod.

Loss of complexity — Loss of complexity, a concept derived from the field of nonlinear dynamics, may be a
general principle of all aging systems [4]. This loss of complexity may result in decreased heart-rate variability,
blood-pressure variability, electroencephalographic frequencies, response to auditory frequencies, and response
to stress. Age-related loss of complexity may not be immutable, however; as an example, senior athletes show
greater heart rate variability than sedentary age-matched controls [5].

Homeostenosis — Homeostenosis refers to the concept that, from maturity to senescence, diminishing
physiologic reserves are available to meet challenges to homeostasis. This concept was first recognized by
Walter Cannon in the 1940s [6]. Homeostenosis leads to the increased vulnerability to disease that occurs with
aging.

A figure graphically displays the traditional thinking about homeostenosis (figure 1). The endpoint of this process
is frailty, where even the smallest challenge overwhelms the available reserves and results in disaster. The
"precipice" may be variably defined: death, cardiac arrest, hospital admission, or onset of a symptom such as
confusion or incontinence. Aging itself brings the individual closer to the precipice by the loss of physiologic
reserves. With aging, the area in which the older person can bring themselves back to homeostasis by invoking
their reserves narrows or becomes stenotic.

Evidence for this model is plentiful. As an example, the APACHE severity of illness scales, used to predict
prognosis for patients in intensive care, have a correction for age. The Acute Physiologic Assessment, a
component of the APACHE score, indicates deviation from homeostatic values for 12 variables, including vital
signs, oxygenation, pH, electrolytes, hematocrit, white blood count, and creatinine. A zero score indicates
homeostasis, and a greater point total indicates a larger deviation from homeostasis [7,8]. In a comparison of
young and old patients who had a cardiac arrest, the younger group (mean age 59) had significantly higher
Acute Physiologic Assessment scores in the 24 hours pre-arrest than the older group (mean age 75) [9]. These
data indicate that the deviation from homeostasis needed to cross a critical threshold (cardiac arrest) is less in
the old. In practical terms, the creators of the APACHE scales recognize this by giving "age points" so that total
scores are equalized between the groups. (See "Predictive scoring systems in the intensive care unit", section on
'Acute Physiologic and Chronic Health Evaluation (APACHE)'.)

Maintaining homeostasis is a dynamic, active process. Frailty is the state when physiologic reserves are
maximally invoked just to maintain homeostasis and any challenge will cross some threshold. Increased severity
of illness and frailty have independent effects on patient outcomes [10]. (See "Frailty".)

The "family of precipices" concept is useful in understanding altered presentations of disease in older adults. As
an example, delirium is a common presentation of a wide variety of illness in the older individual, a marker of the
uneasy truce that the old brain maintains with the environment. A given older person may have the same
presentation (confusion) for a urinary tract infection, gastrointestinal bleeding, or a myocardial infarction. The
systemic responses to these differing illnesses may be similar, involving catecholamines and mediators of
inflammation. The "anti-confusion reserves" are exhausted so the distance from homeostasis to this "precipice" is
easily crossed.

In summary, an apparent loss of physiologic reserves in older adults leads to intolerance to challenges to their
homeostasis. This increased vulnerability is in part because the older person is continually expending reserves to
compensate for primary age changes, as well as other processes that are absent or trivial in the younger
individual.

HEMATOPOIETIC SYSTEM — In the absence of additional challenges, the hematopoietic system maintains
adequate function throughout an individual's lifespan [11]. Red cell life span, iron turnover, and blood volume are
unchanged with age. However, bone marrow mass decreases and fat in the bone marrow increases with
increasing age [12,13]. Therefore, functional reserves are reduced with age. Thus, advanced age may be an
important consideration for determining suitability as a donor for hematopoietic cell transplantation [14] or
tolerance of chemotherapy.

The compensatory hematopoietic response to phlebotomy, hypoxia, and other challenges is delayed and less
vigorous in the healthy older person [15]. This is due to changes in both populations of progenitor cells and the
bone marrow environmental matrix. When young mice are transfused with a cellular mixture of marrow from
older and younger mice, the young marrow assumes the bulk of the repopulation burden [16]. Studies comparing
the bone marrow of healthy older and younger patients found a 35 percent decrease in the colony size of the
stimulated erythroid progenitor cells (CFU-E) in older individuals [17]. Another study suggests that inability to
produce critical stimulatory hormones (stem cell factor, granulocyte macrophage colony-stimulating factor [GM-
CSF], and interleukin [IL]-3) is the major factor accounting for functional difference between bone marrow from
older and younger people [18]. The presence of abnormalities both intrinsic to older progenitor cells, as well as
the milieu, is consistent with findings from a study that progenitor cells isolated from young animals
demonstrated a decreased ability to repopulate bone marrow in old animals, while cells from old animals had a
decreased ability to repopulate young animals; the donor age effect was about equal in magnitude to the host
age-effect and the worst yield was when old marrow was given to an old host [19].

Total circulating white cells counts do not change with age in healthy older people, but the function of several cell
types is reduced. Analysis of circulating white cells reveal a greater propensity for clonal expansion with
increasing age and this correlates with increased likelihood of development of hematologic malignancies [20].
Age-related changes in the immune system are discussed separately. (See 'Immune system' below and "Immune
function in older adults".)

Age is a significant risk factor for myelotoxicity due to chemotherapy regimens for malignancies [21]. However,
consistent with many other changes, heightened sensitivity to chemotherapy and impaired recovery of the bone
marrow is not a uniform finding in all older adults. This underscores the importance of heterogeneity among older
people in their functional status as well as their homeostatic reserves. (See "Systemic chemotherapy for cancer
in elderly persons".)

Though the number of platelets is unchanged with age, platelet responsiveness to a number of thrombotic
stimulators is increased. Reduced availability of nitric oxide and increased oxidative damage have been
implicated in age-associated platelet hyperresponsiveness [22]. This results in a small but consistent decrease in
bleeding time with age. Old age should be considered a procoagulant state. Fibrinogen, factor V, factor VII, factor
VIII, factor IX, high molecular-weight kininogen, and prekallikrein increase with age in healthy humans, possibly
related to the low-grade inflammation that is part of normal aging [23]. Fibrin degradation fragments (D-dimers)
are elevated twofold in healthy older subjects with no evidence of thrombosis and may be even higher in
hospitalized older adults, such that an age-incorporating formula for D-dimer interpretation has been suggested
[24]. Plasminogen activator inhibitor-1, the major inhibitor of fibrinolysis, increases dramatically with aging [25-
27]. Overall, age is an important risk factor for deep venous thrombosis.

GASTROINTESTINAL TRACT — The overall effects of aging on the gastrointestinal system are modest; aging
itself does not cause malnourishment. Nonetheless, age-related changes in gastrointestinal systems affect the
incidence and presentation of multiple gastrointestinal problems in older adults.

Oropharynx — The epithelial lining of the oral mucosa thins with age. The gums recede, exposing the tooth
cementum, which is more prone to decay, and predisposing older persons to root caries and incomplete
mastication [28]. Edentate patients are at greater risk for inadequate nutritional intake compared with those with
partial or full retention of their teeth [29].

Modest age-associated changes occur in the salivary glands, including a small decrease in the number of acinar
cells and up to a 50 percent decrease in maximal saliva production from parotid salivary glands [30], although
accessory salivary gland production is unchanged. Up to 50 percent of older patients have subjective complaints
of dry mouth, which can impact chewing and swallowing. However, some of these complaints may be attributed
to medication side-effects rather than aging itself [31].

Transfer of the food bolus to the pharynx is altered in the majority of older patients. Loss of esophageal muscle
compliance results in increased resistance to flow across the upper esophageal sphincter [32]. Up to 60 percent
of older patients without dysphagia have abnormal transfer to the pharynx on videofluoroscopy [33]. Less
effective mastication and decreased food clearance from the pharynx lead to increased aspiration risk in older
adults.

Esophagus — Anatomic changes in the esophagus include hypertrophy of the skeletal muscle at the upper
third, decrease in myenteric ganglion cells that coordinate peristalsis, and perhaps increased smooth muscle
thickness [28]. The amplitude of esophageal contractions during peristalsis decreases, but the movement of food
is not impaired. Abnormal peristalsis after swallowing and non-peristaltic repetitive contractions, at one time
attributed to old age and called "presbyesophagus," are now thought to be due to disease processes.

Secondary esophageal contractions (induced by esophageal distention) appear to be greatly reduced [28].
Secondary contractions contribute to clearance of refluxed acid. Diminution of these contractions, combined with
decreased lower esophageal sphincter tone, results in increased gastric acid exposure [28]. Sensation of
distention, and possibly tissue damage, in the distal esophagus is also impaired with age [34]. Thus, many older
patients with severe reflux esophagitis seen at endoscopy have surprisingly little symptomatology. Nevertheless,
indigestive symptoms can impair nutritional status [29].

Stomach — Early studies suggested that gastric acid production decreased dramatically with age, with a
decrease in parietal cells and an increase in interstitial leukocytes [35]. Subsequent studies challenge those
findings and suggest that 90 percent of people aged 65 and over are able to acidify gastric contents in the basal
unstimulated state [36,37]. Helicobacter pylori infection may account for the discrepancies between early and
more recent work [38]. Over 50 percent of older people are infected with H. pylori, with the prevalence increasing
with advancing age [39]. (See "Bacteriology and epidemiology of Helicobacter pylori infection", section on
'Epidemiology'.)

Increased rates of gastritis and increased sensitivity to gastric irritants, such as nonsteroidal antiinflammatory
medications or bisphosphonates, in older adults may be related to several age-related physiologic changes:
decreased prostaglandin synthesis, decreased bicarbonate and nonparietal fluid secretion, delayed gastric
emptying, and impaired microcirculation [40]. In addition to an increased sensitivity to gastric insults, rates of
healing are impaired by a host of mechanisms in older people [41]. Gastric motility is determined by the
combined effects of the enteric nerves, smooth muscle, and the interstitial cells of Cajal. The number and volume
of the interstitial cells of Cajal bodies decreases by over 10 percent per decade in normal people without motility
complaints [42]. In aging rat models, sensory neural function is decreased, delaying recognition of experimentally
induced mucosal injury [28].

Small intestine — The small intestine undergoes modest anatomic changes, including moderate villus atrophy
and coarsening of the mucosae. The absorption of several micronutrients (eg, xylose, folic acid, B12, copper)
may decrease with age but remain adequate for homeostasis [43]. The efficiency of calcium absorption from the
gut lumen decreases because of decreased vitamin D receptors in the gut and decreased levels of circulating
25(OH) vitamin D. Typically, women over age 75 absorb 25 percent less of a given dose of calcium than younger
women, especially if there is reduced acid secretion [44]. Iron may also be less well-absorbed, but overall aging
impacts the absorption of macronutrients minimally [43].

Consumed carbohydrates result in significantly more hydrogen excretion in the older adults, suggesting
malabsorption and subsequent bacterial metabolism of the carbohydrate in the aging gut [45]. Up to 15 percent
of residents in senior congregate housing have evidence of bacterial overgrowth as assessed by breath
hydrogen testing [46]. Bacterial overgrowth and associated malabsorption can affect nutritional status and
micronutrient absorption. Additionally, the barrier function of the small intestine may be compromised and local
inflammation activated in response [47].

Decreases in sensory and myenteric neurons contribute to the increased frequency of painless ulcers with
increased age [28,48]. Interestingly, in several animal studies, caloric restriction has been shown to decrease
myenteric neuronal loss with age [49].

Large intestine — Anatomic changes with aging in the large intestine include mucosal atrophy, cellular and
structural abnormalities in the mucosal glands, hypertrophy of the muscularis mucosa, and atrophy of the
muscularis externa. Functional changes include altered coordination of contraction and increased opioid
sensitivity that may predispose the older person to drug-induced constipation.

Studies have not been consistent regarding alterations in colonic motility, but the general consensus is that
colonic propulsive motility is reduced with age and about one-fourth of those over 65 years suffer from chronic
constipation [29]. One factor contributing to reduced motility is an age-related reduction in myenteric plexus
neurons and a decline in the interstitial cells of Cajal similar to that seen in the stomach Intrinsic sensory neurons
that respond to physicochemical changes may degenerate disproportionately compared with motor enteric
neurons. The loss of sensory input into local reflex pathways could contribute to reduced propulsive motility [50].
(See "Etiology and evaluation of chronic constipation in adults".)

The loss of intrinsic sensory neurons may also contribute to the decreased visceral response to bowel
perforation or ischemia that is classically observed in the older patient. As an example, the rigid surgical
abdomen after appendiceal perforation is a less frequent finding in those over 75, leading to delayed diagnosis
[51].

Older women may be more predisposed to fecal incontinence than older men as the resting pressure and
squeeze pressure decrease with age, resulting in decreased anal sphincter tone [52]. In one study, both male
and female patients aged greater than 70 years had 30 to 40 percent decreases in sphincter pressures
compared with controls less than 30 years of age [53]. The internal anal sphincter of continent older people is
thickened, perhaps to compensate for decreased resting and maximum pressures in the anal canal with age.
However, thinning of the external sphincter correlated with fecal incontinence more than age [54].

Diverticuli are common in Western populations over age 65, with prevalence ≥65 percent [55]. The prevalence of
diverticuli is lower in other populations, presumably with other diets, but nonetheless there remains a strong age-
dependence [56]. The formation of colonic diverticuli is attributed to decreased muscle wall strength, decreased
bowel wall compliance, and increased intra-abdominal pressure required for stool excretion [55]. Slower large
bowel transit and increased segmental contractions (as opposed to propulsive contractions) result in increased
water reabsorption, leaving harder stools and increasing the likelihood of wall failure [28]. (See "Colonic
diverticulosis and diverticular disease: Epidemiology, risk factors, and pathogenesis".)

The risk of colon cancer increases with age. In addition to prolonged exposure to potential carcinogens, aging is
associated with increased proliferation and decreased apoptosis in the colonic mucosa [57]. The biology of these
changes is a rich area for exploration. (See "Colorectal cancer: Epidemiology, risk factors, and protective
factors".)

The barrier function of colonic epithelium also appears to be compromised and has been implicated in promoting
the proinflammatory state, “inflammaging”. Isolated specimens from normal aging baboon colon showed
increased permeability to potential toxins, decreases in the key structural components of the tight junctions, and
enhanced downstream inflammatory responses [58].

Hepatobiliary system — Liver mass decreases between 20 and 40 percent with age, and perfusion and blood
flow decreases up to 50 percent between the third and tenth decades of life [59]. Lipofuscin accumulates in
hepatocytes with age and is also seen in young patients with severe malnutrition, accounting for an appearance
that has been described as "brown atrophy." Older livers have more macrohepatocytes (large cells), and
increased polyploidy [60].

The following findings are relevant to liver function in older adults:

● Although many liver functions decline (diminished erythromycin demethylation, galactose elimination, and
reduced caffeine clearance), standard "liver function tests" (transaminases, alkaline phosphatase) are
minimally affected by age [28,61].

● Findings are contradictory regarding albumin synthesis in older livers; animal studies found reductions
consistent with a loss of liver mass [62], although this was not confirmed in a study in healthy older people
[63]. Serum albumin declines slightly with normal human aging [64]. Interestingly, studies have shown that
mortality of nursing home residents correlates with albumin levels, even within the normal range [65].

● The metabolism of low-density lipoprotein (LDL) cholesterol decreases with a reduction in LDL receptors in
older patients [66], which could contribute to the higher serum LDL levels in older adults [62].

● Cytochrome P450 content decreases with age, with one study finding a 32 percent decrement comparing
individuals over 70 years with a group 20 to 29 years of age [67]. This may account for the finding that
metabolic clearance of many drugs is 20 to 40 percent slower in older people [68]. (See "Drug prescribing
for older adults".)

● The lower amounts of vitamin K antagonists needed to anticoagulate older people are consistent with age-
related decreased synthesis of vitamin-K-dependent clotting factors [69].

● Although function and anatomy of the gall bladder are well-preserved in old age, the bile composition has a
higher lithogenic index, predisposing the older person to cholesterol gallstone formation [70].

Younger livers show a robust regenerative response to liver injury characterized by mitogen-activated protein
kinase activity. This declines with age in animals and people [66].

Exocrine pancreas — The exocrine pancreas undergoes only modest alterations with age. Minor atrophic and
fibrotic changes have essentially no impact on pancreatic exocrine function [45]. Noninvasive pancreatography
indicates greater incidence of cysts and side branches of the pancreatic ducts, and a decrease in stimulated
pancreatic flow with advancing age [71]. Aged animals showed decreased output of lipase and amylase in
response to meals that were high in fat or carbohydrates [28].

THE RENAL SYSTEM — There are multiple effects of aging on the renal system (table 1). Renal mass
decreases by 25 to 30 percent between the ages of 30 and 80 years, with the steepest decline after age 50. In
addition, fat and fibrosis replace some of the remaining functional parenchyma. Loss occurs primarily in the renal
cortex and preferentially affects those nephrons most important to maximal urine concentration.

Normal aging is associated with diffuse sclerosis of glomeruli such that 30 percent of glomeruli are destroyed by
age 75 [72]. The remaining glomeruli have impaired filtering ability. Intrarenal vascular changes include spiraling
of the afferent arterioles, narrowing of the larger arteries, intimal fibrosis [73], and shunts between afferent and
efferent arterioles allowing blood flow to bypass the glomeruli [74]. Nephrosclerosis (global glomerulosclerosis,
interstitial fibrosis, and arteriosclerosis) was identified in donor kidneys to be used for transplantation in 3 percent
of donors 18 to 29 years old and 73 percent of donors 70 to 77 years old [75].

At baseline, renal plasma blood flow is 40 percent lower in healthy normotensive older men than in young men
and this difference is magnified under conditions that stimulate renal vasodilation [76]. Studies suggest that older
kidneys may be maintained in a state of vasodilation to compensate for loss of vasculature [76,77]. Vasodilating
prostaglandins are increased at baseline in normal older adults [78], and this contributes to the increased
(roughly doubled) risk of renal injury with use of nonsteroidal antiinflammatory drugs (NSAIDs) in older people
[79,80].

Creatinine clearance decreases with age (7.5 to 10 mL per minute per decade), although there is wide variability
in decline seen in longitudinal studies of healthy older adults [81]. As many as one-third have no change at all in
the glomerular filtration rate (GFR), one-third have a slight decline, and one-third have a more marked decline.
Creatinine production also decreases with age and tubular secretion of creatinine increases, so that the serum
creatinine may remain stable despite decreases in the GFR [82]. All of the commonly used equations for
estimating creatinine clearance factor age into the formulae; however, the estimated GFR (eGFR) provided by
some electronic health records need to be utilized cautiously, especially with those over 90 [83,84]. Cystatin C-
based estimates of renal function may be useful when accurate assessment in an older person is necessary [85].
In healthy older people, an increase of roughly 50 percent in Cystatin C levels is seen from age 40 to age 80
[86]. (See "Calculation of the creatinine clearance".)

Fluid and electrolyte homeostasis are maintained relatively well with aging, in the absence of challenges.
However, the ability to maximally dilute urine and excrete a water load is impaired and compromises volume
regulation under conditions of stress. In the setting of dehydration, the minimum urine flow rate is twice as great
in those over 70 compared with those under 40, and the maximum urine osmolality is also reduced with age [87].
In addition to this impaired ability to retain water and solute, the older kidney also is impaired in its ability to retain
amino acids and glucose.

Other functional changes in the renal system are a reduction of urine acidification and impairment in excreting an
acid load. The older kidney is more prone to nephrotoxicity related to medications or intravenous contrast
[88,89]. Additionally, the injured older kidney is less likely to recover from acute insult [90]. The older kidney is
also more vulnerable to ischemic insult, with a greater number of cells undergoing apoptosis following ischemia
than in the young kidney. Tubular cells appear to have diminished ability to entirely repopulate the tubules after
an acute ischemic insult.

In animal studies, hormonal functions of the kidney are affected by aging, such as decreasing hydroxylation of
vitamin D [91] and downregulation of the renin-angiotensin system [92]. The production of erythropoietin in
response to hemoglobin, however, appears to be unchanged with age [93].

CARDIOVASCULAR SYSTEM — Advancing age increases the risk for hypertension and coronary artery
disease. The prevalence of coronary artery disease at autopsy may reach 75 percent after the sixth decade in
men and two decades later in women [94]. Therefore, to isolate age-related cardiovascular change from disease-
related change, studies must carefully select older individuals with no underlying cardiovascular condition. The
Baltimore Longitudinal study studied highly screened older individuals and found only a minimal impact of aging
on resting cardiovascular function such as left ventricular ejection fraction (LVEF) [95]. This reflects the adequacy
of the compensatory strategies used by the old heart (and vascular system) to counteract subtle and gradual
age-associated physiologic, molecular, and biochemical changes. However, by invoking available compensatory
mechanisms to maintain resting function, the older person is less able to compensate for subsequent challenges
[96]. (See 'Homeostenosis' above.)

Many older people perform little physical activity. Typical age changes may therefore also reflect the impact of
factors related to lifestyle and comorbidity, and the contribution of age alone may be difficult to determine.

Minimal anatomic changes occur in the right side of the heart. By contrast, the left atrium enlarges and the left
ventricle stiffens with aging. Left atrial volume, corrected for body size, increases roughly 50 percent from the
third decade to the eighth [97]. The left ventricle also hypertrophies with age, with an average increase in left
ventricular wall thickness of 10 percent [98].

Both the aortic valve and mitral annulus thicken and develop calcific deposits [99]. Mitral annular calcification
may predispose the older person to cardiac conduction problems. (See "Valvular heart disease in elderly adults".)

Ventricular cardiomyocytes hypertrophy, in part as a response to the increased afterload produced by large
artery stiffening [100,101]. The largest myocytes are also the most vulnerable to challenge [101]. Loss of
myocytes with age has been reported to occur by both apoptosis and necrosis; the total number of
cardiomyocytes may be reduced significantly in healthy human hearts [100,102,103]. As well, substantial cellular
dropout occurs in the sinoatrial (SA) node and more modest cellular loss at the atrioventricular node. This may
underlie increased sensitivity of the older SA node to calcium channel blockers [104].

There is a negligible age-related decrease in the resting heart rate but a marked decrease in the maximum heart
rate in response to exercise or other stressors. The intrinsic heart rate (the rate without sympathetic or
parasympathetic input to the heart) decreases by five to six beats per minute each decade. The response to both
parasympathetic antagonists (atropine) and beta-adrenergic agonists (isoproterenol) is decreased in healthy
older people [105].

Heart rate reflects the combined effects of sympathetic and parasympathetic tones. The target maximum heart
rate is calculated as "220 – age." Women may have a more gradual decline and a correction factor of 0.90-0.85
may adjust the target heart rate for women, although this is not always applied. Exercise training does not modify
the age-associated decline in maximum heart rate. Heart rate variability, perhaps due to decreased
parasympathetic tone and decreased sympathetic responsiveness, also decreases with age [106].

The prevalence of atrial premature beats increases with age but is not associated with increased cardiac risk
[107]. An increase in isolated ventricular ectopic beats is also seen in healthy older individuals and is part of the
normal aging process [108].

The culmination of age-associated cardiovascular changes is a decrease in maximum work, measured as

maximum oxygen utilization (VO2max) on exercise testing. Exercise training in sedentary older individuals can
improve this parameter, but a decline with age is seen even in highly trained individuals.

Resting LVEF is not changed in healthy older people, but there are smaller increases in LVEF in response to
exercise [109]. At maximum effort, LVEF in the young is above 80 percent while by age 80 it is 70 percent [95].
Older hearts also have impaired early left ventricular filling with a compensatory greater contribution from atrial
systole than younger hearts [110]. This may in part explain why atrial fibrillation is more likely to precipitate heart
failure in older adults. An atrial gallop (S4) is a normal finding on physical examination in individuals in sinus
rhythm over 75, a manifestation of the increased contribution of left atrial systole to ventricular filling.
The old heart is a vulnerable heart. For example, mortality and the probability of developing heart failure after a
myocardial infarction increase dramatically with age. While myocardial infarction is not a part of normal aging,
response to this systemic challenge is impaired because of the aging process.

RESPIRATORY SYSTEM — Aging, in the absence of additional challenges, does not result in hypoxia or
pneumonia. However, age-related anatomic and functional changes in the respiratory system contribute to the
increased frequency of pneumonia, increased likelihood of hypoxia, and decreased maximum oxygen uptake in
the older person.

The lung undergoes a number of anatomic changes [111]. Alveolar ducts enlarge due to loss of elastic tissue,
resulting in a decreased surface area for gas exchange. Overall, about one-third of the surface area per volume
of lung tissue is lost over the life span, and anatomic dead space increases [112]. The loss of lung elastic tissue
decreases recoil and results in modest reduction in the expiratory boundary of the maximal flow-volume
envelope. During maximal exercise, this may limit expiratory airflow and produce dynamic lung hyperinflation
[113]. Surfactant composition is also altered by age [114], and alveolar fluid has a greater content of
proinflammatory proteins and a reduced antiinflammatory profile [115]. Carbon monoxide diffusion studies find
that diffusion capacity decreases approximately 5 percent per decade [116].

Age increases ventilation-perfusion mismatching because airways in dependent portions of the older lung, areas
that are better perfused than elsewhere, are closed during all or part of the respiratory cycle. This is a critical
factor in the declining arterial PO2 with age. Alveolar PO2 does not change with age, but age increases the
alveolar-arterial (A-a) oxygen gradient. The effect of the ventilation-perfusion mismatch is more marked in the
supine than sitting position because of positional changes in thoracic mechanics [117]. The decrease in arterial
PO2 (PaO2) may not be linear but appears to decline from age 30 until 70 or 75 and thereafter remains almost
constant. While age-related changes do not result in hypoxia at sea level, older adults may approach hypoxia at
altitude [118]. The fall on PaO2 is slightly greater in women than men [117,119]. Older people may have little
reserve for further decrements in pulmonary function before important hemoglobin desaturation occurs.

In contrast to the decrease in PaO2 and increase in the A-a oxygen gradient, carbon dioxide excretion is not
impaired with age; changes in PaCO2 are due to disease and should not be attributed to age alone [120].

The chest wall also changes with age; increased stiffness of the chest wall predominates over an increase in
compliance of the lung parenchyma. Overall chest wall compliance decreases by one-third from age 30 to 75
[121]. Intercostal muscle contraction accounts for less chest expansion in older individuals, with a relatively
greater contribution from abdominal muscles. Abdominal muscles are only partially effective in ventilating in the
seated (or supine) position. Thus, full airway expansion occurs only in the standing position in older adults.
Atelectasis can result in an increased A-a gradient.

As the chest remodels with age, the diaphragm flattens and becomes less efficient. The diaphragmatic changes
likely contribute to the increase in the work of breathing during exercise, which can increase 30 percent [122].

The effect of age on traditional pulmonary function tests is shown in the graph (figure 2). With advancing age,
functional reserves decrease. In nonsmoking men, forced vital capacity (FVC) decreases between 0.15 and 0.3
liters per decade, and forced expiratory volume in 1 second (FEV1) decreases by 0.2 to 0.3 liters per decade,
with steeper decline in the seventh and eight decades [123,124]. Age-related changes in women decline less
steeply. Total lung capacity (proportional to height) does not change significantly with age; however, the residual
volume (air left in the lung at the end of full expiration) increases by as much as 10 percent per decade because
of a higher closing volume. Of note, however, the ability to properly perform pulmonary function tests (and use
inhalers) decreases in older adult patients [125].

The Cardiovascular Health Study population experienced age-related decreases in maximal inspiratory force and
a smaller decrement in maximal expiratory force parameters [126]. Both the inspiratory force and expiratory force
are significantly greater in physically active older people. Diaphragm thickness was also greater in the active old
group [127]. Thus, some of the decrements described above are due to sedentary lifestyle.

Older persons have decreased responses to hypoxemia, hypercapnia, and mechanical loading, such as
breathing through a small-diameter endotracheal tube [128]. The central drive to the respiratory muscles is
decreased [129]. Many of these changes are minimized with exercise; the implication is that central or peripheral
receptor hyporesponsiveness may be due in part to deconditioning, and that exercise training can induce
compensation for age-related changes.

Cough is less vigorous in the older person because of the age effects on respiratory muscle strength and greater
closing volumes that prevent clearing of increasing proportions of the lungs [126]. Mucociliary clearance is slower
and less effective, and recovery of mucociliary clearance after insult (typically viral infection) is slowed with age.
In addition to impaired clearance from large airways, clearance of inhaled particles from the small conducting
airways is also impaired with age [130].

The rate of decline in the peak aerobic capacity in healthy older persons with age, especially men, is not
constant. The Baltimore Longitudinal Study of Aging found a 3 to 6 percent decrease in peak aerobic capacity
per decade in the 30s and more than 20 percent decrease in peak aerobic capacity per decade in the 70s and
beyond [131]. The decrease in FEV1 with age correlates strongly with the worsening peak aerobic performance
[132].

GENITOURINARY SYSTEM — Aging changes in the genitourinary system increase the older person's risk of
urinary incontinence, urinary tract infection, erectile dysfunction, and dyspareunia.

Bladder — The prevalence of urinary incontinence increases with age. Until age 80, incontinence is more
common in women than men, but the prevalence differences by gender subside after age 80 [133]. Urinary
incontinence is related to decreases in detrusor muscle contractility, maximum bladder capacity, maximum flow
rate, and the ability to withhold voiding, with an increase in postvoid residual (PVR) [134]. These functional
changes are due in part to decreased innervation of the detrusor muscle [135] and in part due to changes in the
brain [136]. (See "Urinary incontinence in men" and "Evaluation of women with urinary incontinence".)

Withdrawal of estrogen in women results in decline in urethral length as well as decreased maximal urethral
closure pressure. The urethra becomes a less effective barrier from bacterial contamination with age, especially
in women [137]. Topical estrogens, especially in addition to pelvic floor exercises, may lead to restoration of
urethral function [138].

Male reproductive system — Surveys of sexual activity among older men have found varying rates of activity.
In one multinational survey, over 80 percent of men aged 60 to 69 and 70 percent of those aged 70 to 79
reported that they were sexually active [139]. By contrast, two representative samples from the United States
found that 39 percent of men aged 75 to 85 years reported sexual activity [140]. The older penis needs greater
stimulation to attain an erection, spontaneous erections are less frequent, erections are less firm, refractory times
between erections (or ejaculations) become prolonged and ejaculation is less forceful with smaller ejaculate
volumes. These changes are the sum of age-related neurologic, vascular, and endocrinological changes [141].
(See "Overview of male sexual dysfunction".)
A gradual decline in male reproductive ability occurs with age. Germ cells are formed continually, but sperm
production decreases. The sperm from older testes have an increased frequency of chromosomal abnormalities
and impaired motility and decreased ability to fertilize even when administered by intrauterine artificial
insemination [142]. The seminiferous tubules also degenerate and Leydig cell number decreases. Changes in
the epididymis and seminal vesicles are characterized by deposition of pigmented granules in the epithelial walls
and amyloid in the seminal vesicle wall, which may be associated with amyloid deposition elsewhere in the body
[143].

Enlargement of the prostate gland occurs with age. Prostate gland hyperplasia is discussed in detail separately.
(See "Epidemiology and pathogenesis of benign prostatic hyperplasia" and "Clinical manifestations and
diagnostic evaluation of benign prostatic hyperplasia".)

Female reproductive system — The ovary ages with a decline in oocyte numbers as women enter their late
fourth decade, and menopause (amenorrhea for 12 months after the final menstrual period) ensues at an
average age of 51 years. In women of advanced age undergoing in vitro fertilization (IVF) treatment (defined
here as after 45), the implantation, clinical pregnancy, and live birth rates all occur at reduced frequency [144].
Changes related to menopause and estrogen depletion are discussed separately. (See "Clinical manifestations
and diagnosis of menopause".)

Once menopause has occurred, more gradual age-related postmenopausal processes are seen. The vagina
loses elasticity. The clitoris, like the older penis, needs greater stimulation and becomes less engorged [145].
Subcutaneous fat in the pelvis is lost. Vaginal dryness and atrophy are mostly estrogen-dependent but may be
compounded by age-related diminished blood flow to the vagina. Cervicovaginal secretions, especially during
arousal, become sparser. Vaginal pH rises, allowing colonization by enteric microflora. (See "Overview of sexual
dysfunction in women: Epidemiology, risk factors, and evaluation".)

MUSCULOSKELETAL SYSTEM

Muscle — Although there is great variability, muscle mass decreases in relation to body weight by about 30 to
50 percent in both men and women. The loss is not linear, but it accelerates with increasing age. Sarcopenia,
age-related loss of muscle mass and strength, is defined as a decrease in appendicular muscle mass two
standard deviations below the mean for young healthy adults [146]. Sarcopenia is an independent risk factor for
mortality in longitudinal studies [147].

In many sites, muscle quality decreases with infiltration of fat and connective tissue into the old muscle [148].
The presence of intramuscular and intermuscular fat has been termed "myosteatosis." Myosteatosis at the thigh
has been associated with decreased strength, slower gait speed, and decreased survival in the AGES-Reykjavik
study [149,150]; a mortality relationship was not seen with the calf myosteatosis [151]. Critically, myosteatosis
needs to be taken in context, as trained individuals acquire muscle fat as a ready energy supply [152], and in that
setting increased muscle fat is associated with better performance and exercise training in older people [153].

The loss of muscle mass is not uniform; in general, the loss from the legs is greater than from the arms. Type I
slow-twitch fibers are less affected by age than fast-twitch fibers. In any muscle bundle, the size of the myofibrils
decreases, followed by the number of myofibrils. Innervation of skeletal muscle decreases in men over 50; the
number of motor units in any given muscle decreases with a compensatory increase in motor unit size. While this
synaptic remodeling occurs at all ages, the "new" neuromuscular innervations are unstable [154]. Some have
implicated motor neuron changes as the primary cause of sarcopenia [155]. The loss of muscle contributes to
age-related insulin resistance, age-related changes in body composition, and volumes of distribution for water
soluble drugs.

The presence of atrophied or partially or completely denervated muscle fibers can be seen on cross-section of
muscle from an older person. Time to peak tension with ankle dorsiflexion is slowed, as is time to muscle
relaxation [156]. Strength also decreases dramatically with age, partially explained by loss in muscle mass. From
age 30 to age 80, a typical person's grip strength decreases 60 percent; however, activity plays an important
mitigating role. Overall, lower-extremity strength is lost at a relatively faster rate than upper-extremity strength;
activity may decrease the rate of decline but will not completely prevent it [148]. The older muscle is more easily
fatigued as well [157].

The recovery of older muscle after injury is slowed and frequently incomplete. At least some of this impairment is
locally mediated, perhaps by nerve regeneration, as old muscles transplanted into young animals regenerate
fairly well, while muscles taken from young animals and transplanted into old ones do not regain mass and
generate force as effectively [158].

Skeletal muscle from older adults shows altered energetics. The decrease in enzyme activity of glycolytic
enzymes is greater than that of oxidative enzymes. Physical activity plays a significant role in the decrease in
these enzyme activities. In older animals, an acute bout of exercise is associated with relative hypoperfusion of
the most oxidatively active exercising muscles [159].

Age-related hormonal changes in growth hormone, androgen, and possibly others may contribute to the age-
associated alterations muscle mass and function. Parabiosis studies (where old and young syngenic mice are
connected so that they share circulations) suggest circulating factors may restore many of these age-associated
decrements in muscle [160,161]. Additionally, proinflammatory cytokines increase with age and stimulate the rate
of skeletal muscle protein degradation [148]. The effects of many of these agents, especially insulin-like growth
factor (IGF)-1, may be mediated by neuromuscular effects, suggesting that both hormonal and neuronal
approaches to preventing sarcopenia may be efficacious [155].

Bone — Aging in both men and women increases the probability of fracture and the rate of repair is slowed,
once fracture occurs. The increased proinflammatory environment in healthy older adults promotes bone loss.
Anatomically, the weightbearing cortical bones lose substance from the endosteal surface. Computed
tomography (CT) or magnetic resonance imaging (MRI) indicate that the marrow lumen of the femur is larger, the
cortex thins, and fat fills much of the marrow cavities. The aging loss of mineral occurs in both cortical (peripheral
skeleton) and trabecular (axial skeleton) bone. There is a progressive decline in osteoblast number and activity,
but osteoclasts remain unchanged with age. Overall, the decline in bone mass is approximately 0.5 percent per
year in healthy older people [162]. Age-related changes in women are compounded by menopausal changes in
bone mass and function. Vitamin D deficiency, common in older people, further accelerates bone loss. (See
"Pathogenesis of osteoporosis".)

Weightbearing exercise is frequently reduced in older adults, contributing to a negative calcium balance and loss
of bone mineral [163]. Increasing weightbearing time or increasing loading forces may increase bone mineral and
prevent age-related bone loss [164].

Once bones fracture, the repair mechanisms are impaired in aging. In older animals, fractures produce less local
blood vessel formation and less osteogenic differentiation of progenitor cells and require at least twice as long to
regain prefracture biomechanical properties, including strength, than in younger adult animals [165]. Cells
isolated from old bones are less responsive to vitamin D than young ones. The matrix in old individuals may
stimulate less bone formation than matrix from younger people. This suggests that growth factors (eg, IGF-1)
may be deficient or inhibitory factors may be present in the old matrix. Supplementation with vascular endothelial
growth factor (VEGF), parathyroid hormone, vitamin D and calcium, statins, and some of the bone morphogenic
proteins have all shown promise in facilitating bone healing in various experimental paradigms [166].

CENTRAL NERVOUS SYSTEM

Anatomical and physiological changes — The volume of the brain decreases about 7 cm3 per year after age
65, with greatest loss in the frontal and temporal lobes [167] and greater loss of white matter than grey matter in
cognitively normal older adults [168]. Cerebral blood flow decreases heterogeneously by 5 to 20 percent, with
deterioration of mechanisms that maintain cerebral blood flow with fluctuation in blood pressure [169].

Age-related neuronal loss is most prominent in the largest neurons in the cerebellum and cerebral cortex. The
hypothalamus, the pons [170], and the medulla [171,172] have modest if any neuron or volume losses with
normal aging. Age-related neuron dropout is likely due to apoptosis (ie, programmed cell death) rather than
inflammation, ischemia, or another mechanism [173]. Age also affects neurons that persist, with loss of the
dendritic tree, shrinkage of processes, and decrease of synapses [174]. Such changes may contribute more to
the age-related loss of brain volume than the loss of neurons. In some areas, however, the dendritic connections
may increase, perhaps as a result of repatterning of the brain invoked to compensate for cellular dropout.
Neurons continue to form new synapses, and new neurons are formed throughout the lifespan, but the rates of
loss are greater than the gains [175].

Lipofuscin accumulates in certain areas of the brain, particularly the hippocampus and frontal cortex, but the
impact of lipofuscin on function is unknown [176]. Neurofibrillary tangles and senile plaques occur in certain
areas of the brain in normal aging but to a lesser extent than in Alzheimer disease. Thus, interpretation of beta
amyloid seen on amyloid imaging in individuals of advanced age poses a challenge [177]. Similar issues may be
raised for tau imaging [178].

Multiple nonhomogenous changes in brain enzymes, receptors, and neurotransmitters occur with age.
Acetylcholine availability decreases due to decrease in cholinergic and muscarinic neurons, and reduced release
and synthesis of acetylcholine [174,179]. As well, dopamine and corresponding receptors in the striatum and
substantia nigra may be decreased in normal aging [180]. Interestingly, dopamine may facilitate episodic memory
persistence [181], and providing dopamine as L-DOPA to normal old brains can improve performance on some
cognitive tasks [182].

Age-related changes seen on functional brain scanning with fluorodeoxyglucose positron emission tomography
(FDG-PET) are heterogeneous [183]. For many tasks, the old brain seems to work harder than the young one,
recruiting more neurons and with higher energetic expense as shown by PET scan [184]. For a simple recall test
of letters, a greater volume of activation was seen in old brains. The amount of brain activated for a given task
may be an insight into cognitive reserve, brain vulnerability, and tradeoffs made to maintain cognitive function
with age.

Cognitive and behavioral changes associated with normal aging — Certain memory performances on
cognitive testing, like procedural, primary, and semantic memory, are well-preserved with age [185]. Skills, ability,
and knowledge that are overlearned, well-practiced, and familiar, like vocabulary or general knowledge, remain
stable or improve up to 0.2 standard deviations per decade through the seventh decades, but even these
processes can begin to decrease with further aging [186]. The ability to recognize familiar objects and faces, as
well as to maintain appropriate visual perception of objects, remains stable over the lifetime.
Episodic and working memory and executive function are the specific domains of cognition most affected by
"normal" aging [187]. These are late-life changes, occurring after the sixth decade and have a linear or
accelerating decline with further aging [188]. Processing speed decreases with age and can have a global effect
on the testing performance of other neurocognitive domains in any timed test [189].

Executive function is critical to engagement in purposeful, independent, and self-preserving behavior and is
necessary for an older person to successfully manage their own medical illnesses. Executive function declines
with age, and more dramatically after age 70 [190].

Attention span decreases with even simple attentive tasks [191]. In particular, there is decrease in the ability to
focus on a task in a busy environment and ability to perform multiple tasks at one time [190]. These impairments,
similar to processing speed, may lead to decreased testing performance in other neurocognitive domains.

Problem-solving, reasoning about unfamiliar things, processing and learning new information, and attending to
and manipulating one's environment show a steady decline (by about -0.02 standard deviations per year) after
peaking around age 30. Language abilities (verbal fluency and the ability to name objects) demonstrate some
late-life decline, particularly after age 70.

Despite measurable changes seen on cognitive testing with normal cognitive aging, the successfully aging 95-
year-old individual remains able to function in society, the workplace, and/or at home. Few real-life situations
require performance at maximum levels, especially with time pressure or acquired knowledge. The impact of
cognitive loss can often be compensated by noncognitive factors that do not decline with age [186].

Cognitive retraining — Novel neural challenges increase recruitment of additional brain regions in young
healthy subjects; with repetition of the challenge, recruitment of these brain regions subsides and activity is seen
in skill-specific regions [192-194]. Neural recruitment in the aging brain is used to accomplish less novel tasks.
This process, referred to as "compensatory scaffolding," may be a strategy the brain uses to maintain function
and cognition [195].

Repeated use of "compensatory scaffolding" by engaging in social, leisure, and cognitive activities (learning a
new language, pursuing higher education) may decrease the risk of Alzheimer disease or delay its onset [196]
and slow the progress of normal aging changes [197]. Specifically designed cognitive training activities for older
adults have also been shown to decrease decline in ability to perform instrumental activities of daily living, per
subject self-reports compared with controls [198]. In healthy volunteers, cognitive training can lead to gray matter
volume increases in the "exercised" areas [199]. Whether these efforts improve compensation or prevent age-
related decline in neurologic processes is uncertain.

SKIN — The normal aging of the skin leads to atrophy, decreased elasticity, and impaired metabolic and
reparative responses. These changes are separate from those due to sun exposure, so-called "photoaging."

The epidermis becomes thinner, and the dermoepidermal junction flattens, resulting in increased fragility of the
skin to shear stress [200]. Removing an adhesive dressing from an older person may dislodge the epidermis
because the dermoepidermal junction is weaker than the bond between the skin and the dressing. Bleeding into
the space between the dermis and epidermis occurs more frequently.

Loss of undulations at the dermoepidermal junction decreases the area available for nutrient transfer, including
protective lipids in the stratum corneum. This results in dry skin (xerosis) and a compromise in the barrier
function of the skin [201]. Epidermal turnover is slowed due to decreased division of keratinocytes and longer
migration from the basal layer to the skin surface [202]. The epidermal cellular composition changes, with
decreases in melanocytes, immunologically active Langerhans' cells, and a 50 percent overall reduction in nail
growth and reductions in sweat and sebaceous gland activity [203].

Additional changes associated with age rather than sun damage include the following:

● The dermis thins with decrease in vascularity and in the biosynthetic capacity of the resident fibroblasts
[204]. These changes contribute to delayed wound healing.

● The elastic fiber network degenerates as elastin biosynthesis declines significantly after the fourth decade.
Changes in the glycosaminoglycan macromolecules in the dermis lead to loss of hydration and decreased
skin resilience [205].

● The ability to deliver heat to the skin for excretion is impaired. With the loss of rete pegs at the
dermoepidermal junction and loss of dermal capillarity, the area for heat transfer to the epidermis is
decreased. Loss of subdermal fat decreases insulation and the ability of older people to conserve heat.
Tonic vasoconstriction in many older adults, as well as decreases in both number and production of sweat
glands, also contribute to impaired thermoregulation with age [206,207].

● Sensory perception of the skin decreases, particularly in the lower extremities [208]. Decreased sensation
involves both touch, due to decreased Meissner's corpuscles [209], and low frequency vibration, mediated
by the Pacinian corpuscles [210].

● The skin plays a critical role in vitamin D synthesis. Ultraviolet rays convert 7-dehydrocholesterol to pre-
vitamin D3 in the epidermis. Levels of 7-dehydrocholesterol decreased with age, thus decreasing the older
person's capacity for vitamin D synthesis [211].

● There is a decrease in subdermal fat. This loss of support contributes to the skin wrinkling and sagging, as
well as to increased susceptibility to trauma [212].

Topical administration of all-trans-retinoic acid (tretinoin) appears to reverse many of the age-related changes in
sun-protected skin (inner thigh). After nine months of daily treatment with topical tretinoin cream 0.025 percent,
the epidermis thickens, rete ridges become deeper, capillaries reappear, matrix proteins are redeposited, and
collagen and elastin increased [213]. Thus, these age-related changes appear to be mutable.

Photoaging is the result of chronic sun exposure and recurrent damage by the sun's ultraviolet light. Photoaging,
not physiologic aging, produces most of the cosmetically undesirable changes in skin. Cellular dysplasia, atypical
cells, a loss of polarity of the keratinocytes, and a significant disorganization in the epidermis are the result of
photoaging. In the dermis, photoaging leads to elastosis, aggregates of amorphous elastic fibers, a decrease in
collagen content, an increase in glycosaminoglycans, and a modest inflammatory infiltrate localized to the
perivascular areas. The photoaged skin looks wrinkled, lax, yellowed, rough, and sometimes leathery. Photoaged
skin has a higher tendency toward telangiectasias, and it is spottily hyperpigmented and hypopigmented.
Photoaging changes are also partially reversible by topical treatment with retinoic acid.

SENSORY SYSTEM

Eye — The structure of the eye changes with age. Periorbital tissues atrophy; eyelids become more relaxed. The
lower lid flaccidity may lead to ectropion (eyelid turns outward) or entropion (eyelid turns inward). Lacrimal gland
function, tear production, and goblet cell function all decrease [214]. Even though tear production decreases,
watering eyes becomes more common because tissue atrophy leads to displacement of the lacrimal punctum
and less effective drainage.

The conjunctiva atrophies and yellows. The sensitivity of the cornea to touch declines by 50 percent. Deposition
of cholesterol esters, cholesterol, and neutral fat in the cornea causes arcus senilis, an annular yellow-white
deposit on the peripheral cornea. The presence of arcus senilis correlated with shorter lifespans in women in the
Copenhagen City Heart Study [215]. The iris becomes more rigid, yielding a smaller, more sluggishly responsive
pupil. The lens yellows, in part because of photo-oxidation in lens protein and an accumulation of insoluble
protein. The yellowing of the lens causes decreased transmission of blue light [216].

Production of aqueous humor decreases and the vitreous humor and body also shrink. Separation between the
liquid and solid components of the vitreous may be due to collagen changes and manifest as flashes of light
[217]. The retina becomes thinner because of a loss of neurons.

The changes in lens and iris lead to "presbyopia." The distance needed to focus near objects increases because
of decreased lens elasticity and, to a lesser extent, weakening and loss of an effective angle of the ciliary muscle
[218]. Presbyopia has gradual onset in the fourth decade with steady deterioration in static acuity (object at rest)
and a more pronounced loss of dynamic visual acuity (ie, objects in motion). (See "Visual impairment in adults:
Refractive disorders and presbyopia".)

The older eye adapts more slowly to changes in lighting conditions; the pupil becomes rigid and the lens more
opaque. The rate of synthesis of photopigment slows with age, adding to slowed adaptation to lower light
conditions [219]. Lens alterations increase light scattering, making the older person more sensitive to glare. After
lens removal, the glare threshold becomes normal.

Finally, contrast sensitivity declines, so older persons need increased color contrast to discriminate between
target and background. This factor should be taken into account in the design of living environments.

Hearing — Age-related changes in the auditory system produce decrements in high-frequency hearing acuity
and impaired speech recognition in noisy environments. The loss of hearing acuity may result in social isolation
and increases risk for delirium during hospitalization. The cumulative effects of environmental or occupational
noise confound interpretation of age effects. (See "Etiology of hearing loss in adults".)

With age, the walls of the external auditory canal thin. The cerumen becomes drier and more tenacious,
increasing the risk of cerumen impaction in older people. Although the ossicular joints degenerate with age,
sound transmission by the ossicles is well-preserved.

The inner ear experiences at least five distinct changes that occur to varying degrees:

● Hair cells in the organ of Corti are lost, initially affecting those in the basal end of the cochlea that respond to
the highest frequencies

● Neurons innervating the cochlear and in the auditory centers of the brain are lost

● The basilar membrane underlying the sensory apparatus stiffens and may calcify

● The capillaries of the stria vascularis (the source of endolymph) thicken

● The spiral ligament degenerates

Which of these five changes is dominant will define subgroups of age-related hearing. The net results are loss of
hearing acuity, especially at higher frequencies (presbycusis), difficulty with speech discrimination, and problems
localizing the sources of sound [220,221].

Some older individuals who say they cannot hear in fact are having difficulty understanding what is said. Many of
the consonant sounds are in the higher frequencies (t, k, ch), and patients may not comprehend speech if they
cannot appreciate those sounds. Strategically and practically, it may be better to rephrase a question that is not
understood by an older person rather than repeat it in a louder voice, especially because pitch (frequency) is
often raised when volume is increased. Additionally older people may have difficulty discriminating target sound
from background noise, adding to challenges of communicating in social situations or noisy emergency
departments. In these patients, amplification of sound alone is not effective because both target and background
are amplified.

Taste and smell — There are visible changes in the taste buds with age, though they have modest impact on
the sense. Although the number of papillae on the tongue decreases with aging, neurophysiologic responses of
individual papillae are minimally altered, and there is no relation between gustatory acuity and number of taste
buds.

Loss of taste in older patients is in large part due to decreased olfaction rather than taste itself [28]. However,
taste sensitivity also decreases with age, as shown by a study in which older patients required 30 percent higher
concentrations of aspartame to detect this artificial sweetener [222,223].

Similarly, more salt (two- to threefold) needs to be added to tomato soup before it can be appreciated by an older
person [224]. The effects of age on the tongue need not be uniform, with regions of deficient gustatory sense
becoming more common with age.

The acuity of olfaction declines significantly with age. Detection thresholds are increased by more than 50
percent in healthy people by age 80; recognition of familiar smells decreases similarly, including the recognition
of spoiled food and of a gas stove left on. The cause of the decreased olfactory sense is unclear, but the
sensation area decreases, the number of sensing neurons decreases, and the ability of the older person to
replenish dying olfactory receptor neurons is compromised [224].

Decreased taste and smell sensation may result in decreased enjoyment of food and an age-related difficulty in
sorting tastes of mixed or combined foods. The role of olfaction in maintaining appetite is critical; for example,
some people with anosmia forget to eat.

IMMUNE SYSTEM — Of all the changes that occur with age, decrements in immune functions are among the
most critical, contributing to the increased frequency of infections, malignancies, and autoimmune disorders.
These changes are mentioned briefly here and reviewed in more detail separately. (See "Immune function in
older adults".)

Immunosenescence, or the aging of the immune system, does not impact all immune processes equally. Some
of the responses that are most affected by age include the ability of lymphocytes (both B and T cells) to work in
concert to generate effective immune responses upon exposure to new antigens, in the form of either infections
or vaccinations.

An important concept in immunosenescence is that of loss of precise regulation of inflammatory processes.

Older adults display cytokine profiles that are consistent with a chronic, low-level inflammatory state, which is
sometimes referred to as "inflammaging" [225]. (See "Immune function in older adults".)
MOLECULAR BASIS OF AGING

The molecular basis for age-related physiologic changes is a subject of intense active investigation. The process
of natural selection (in which genes that promote beneficial conditions in early or reproductive years are selected
for, and genes associated with harmful conditions are selected against), does not play a significant role in later
life. Despite the lack of selection for late-life genes, some processes that may provide benefit early in life could
be detrimental later in life, so-called antagonist pleiotropy.

For more than 50 years, the most robust means to increase survival and modify many age-related changes was
to use caloric restriction. Reducing caloric intake by 20 to 40 percent in laboratory some of the most common
strains of mice and rats increased median and maximum lifespan by 20 to 50 percent but did not increase
survival in about 50 percent of tested mouse strains [226]. Studies with non-human primates have been less
promising, and despite having lower cholesterol, better insulin sensitivity, etc, survival has not been increased
[227,228].

Several findings suggest that shortening of the telomere (nucleoprotein end caps on chromosomes) is involved in
increased vulnerability of aging cells to DNA damage and dysregulation [229-231]. The shortened telomeres, as
well as other replicative dysregulation, may lead to inadequate replacement of damaged or dead cells from their
respective precursor cell populations. Interestingly, many of these resting precursors cells start to differentiate
along adipocyte-like pathways, rather than into other tissue types [12].

Subpopulations of adipocytes, hepatocytes, fibroblasts, and other cells may enter senescence with aging and
develop the senescence associated secretory phenotype (SASP) [232]. SASP cells have the potential to release
proinflammatory cytokines and other potentially harmful factors as well as modify the activity of local normal cells
[233]. Other hypotheses implicate the p53 gene that is activated when DNA is damaged. This gene activation
may mediate several molecular processes affecting cell function and viability: normal cell growth and division is
halted, with apoptosis for cells that rapidly turnover; peroxisome proliferator-activated receptor gamma
coactivators PGC1-alpha and PGC1-beta are repressed and lead to loss of muscle mitochondria and buildup of free
radicals with loss of antioxidant defenses [234].

The mammalian target of rapamycin (mTOR) pathway regulates nutrient distribution and is believed to play an
important role in the ability of caloric restriction to extend lifespan. Rapamycin has been shown to produce
longevity in mice [235].

LONGEVITY — Longevity predictions are important in many aspects of medical care. Limited survival will impact
the benefits of initiating medications or performing procedures or screening tests. Decision-making regarding the
appropriateness of a specific intervention (eg, "Should this older person be given a bisphosphonate to prevent
osteoporosis?") requires recognition of both the likely survival time for an individual and how long it may take for
the intervention to have effect.

One classic study provides survival data on individuals in the United States, stratified into quartiles by survival for
each five-year period above age 65 years [236]. The absence of significant comorbid conditions, or the presence
of superior functional status for age, identifies older adults who are likely to live longer than average. Conversely,
individuals with functional dependencies in activities of daily living and/or significant comorbidity (eg, heart
failure, end-stage renal disease, oxygen-dependent chronic obstructive lung disease) have a life expectancy
substantially below the average for his/her age.

Age-related modification of risk-benefit relationships has broad applicability. In addition to the documentation of
the broad range of life-expectancy for a given age, a table has been developed to measure the likely benefit
against the potential risk (table 2).

For example, a typical 85-year-old man who has a symptomatic inguinal hernia is likely to have the problem for
another 4.7 years and thus may warrant a discussion of surgical repair. Note that the tables are based on a US
Caucasian population and may not be generalizable to other groups. Also, the tables do not account quality of
life for the specified years. Both of these issues may critically modify the interpretation of the tabular data.

Successful aging — The term "successful aging" is used to identify older individuals who are free from chronic
disease and continue to function well into old age, both physically and cognitively. The term "essentially healthy"
identifies those with no acute disease, no recent history of cancer, and with well-controlled chronic disease.
"Exceptionally healthy" identifies older adults who take no medications, have no chronic disease, are
normotensive, and have a normal body weight. Psychosocial and genetic factors contribute to successful aging
as well as longevity.

Predictors of high functional status in both physical and cognitive domains were evaluated in the longitudinal
Cardiovascular Health Study, following 1677 participants for 14 years (median age 85, range 77 to 102, at study
endpoint) [237]. Although all participants showed functional decline over time, 53 percent remained functionally
intact, and this group had a higher baseline health profile and lower vascular disease risk. Greater physical
impairment was found in women and in those with greater weight. Cardiovascular disease and hypertension
were predictors for both cognitive and physical impairment.

In another longitudinal study of nearly 6000 British civil service employees followed for 17 years, successful
aging was identified in 12.8 percent of men and 14.6 percent of women at follow-up [238]. The strongest
predictor of successful aging was socioeconomic position at midlife. After adjustment for socioeconomics, not
smoking, diet, exercise, moderate alcohol intake (in women), and work support (in men) predicted healthy aging.

The effect of genetics on longevity and life expectancy has been explored in observational studies and in animal
experiments. As noted above, twin studies suggest that 25 percent of longevity is genetic [1]. However, the
importance of genetics is substantially larger at the extremes of longevity and may be greater for men than for
women. In the New England Centenarian Study, male siblings of centenarians had a 17 times greater chance of
living to age 100 compared with birth cohorts, compared with eight times greater for females [239].

A polymorphism in the Cholesterol Ester Transfer Protein gene has been identified that is associated with
successful aging, increased longevity, preserved cognition, less cardiovascular disease, and larger sized high-
density lipoprotein (HDL) particles in Ashkenazi Jews [240]. Animal models suggest the potential for gene
manipulation to prolong longevity. For example, the median and maximum survival of the nematode
Caenorhabditis elegans can be increased threefold by mutating the daf-16 gene, a key regulator of
insulin/insulin-like growth factor (IGF)-like pathways in the worm [241].

Environmental factors are likely to interact with genetics. In Italy, the ratio of female to male centenarians is quite
variable, ranging from 2:1 in Sardinia to 7:1 in Northern Italy, suggesting a gene-environment interaction [242].
Okinawa, Japan, has the highest concentration of centenarians in the world. The longevity there has been
attributed to a "caloric restriction with optimal nutrition" diet, similar to diets that increase longevity by 50 percent
in mice and rats [243]. A genetic component is also possible, based on family studies of Okinawan centenarians
[244]. Extreme female longevity may be less dependent on genetics than male longevity and more related to a
healthier lifestyle and more favorable environmental conditions [242].
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articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written
at the 10th to 12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Sex as you get older (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Aging, characterized by progressive changes associated with increased susceptibility to many diseases, is
influenced by genetic factors, lifestyle choices, and environmental exposures. Several overarching
physiologic principles characterize aging: loss of complexity as seen in less variability in heart rate
responses, altered circadian patterns, and loss of physiologic reserves needed to cope with challenges to
homeostasis. (See 'Age-associated physiologic changes' above.)

● Functional bone marrow reserves are reduced, with delayed response to blood loss or hypoxia. White blood
cell function is impaired and myelotoxicity from chemotherapy is often increased. Advancing age leads to a
procoagulant state, with increased platelet responsiveness and levels of clotting factors. (See
'Hematopoietic system' above.)

● Reflux esophagitis, due to altered contractions and sphincter tone, is common with age and may affect
nutrition. Helicobacter pylori infection is common, and sensitivity to gastric irritants such as nonsteroidal
antiinflammatory drugs (NSAIDs) is increased. Colonic changes include motility changes resulting in
constipation, decreased visceral response to bowel perforation or ischemia, colon diverticuli, and increased
risk for colon cancer. (See 'Gastrointestinal tract' above.)

● Renal mass and function decline, with decrease in creatinine clearance and ability to maximally dilute urine
or excrete an acid load. The older kidney is more prone to nephrotoxicity related to medications or
intravenous contrast. (See 'The renal system' above.)

● It is difficult to isolate the impact of age alone on the cardiovascular system, since age increases risk for
hypertension, coronary artery disease, and a more sedentary lifestyle. There is an age-related decrease in
maximum heart rate, as well as the compensatory response of left ventricular ejection fraction (LVEF) to
exercise. The annulus of both the aortic and mitral valve thicken, with development of valvular calcific
deposits. (See 'Cardiovascular system' above.)

● About one-third of surface area per volume of lung tissue is lost over the lifespan, with increase in anatomic
dead space increases and decrease in functional reserves. Age increases the alveolar-arterial (A-a) oxygen
gradient, more marked in the supine than sitting position. Cough is less vigorous in the older person and
mucociliary clearance is slower. (See 'Respiratory system' above.)

● Aging changes in the genitourinary system increase the older person's risk of urinary incontinence, urinary
 tract infection, erectile dysfunction, and dyspareunia. (See 'Genitourinary system' above.)

● With aging, muscle mass decreases in relation to body weight, leading to impaired motility and balance, as
well as age-related increased insulin resistance and changes in the volume of distribution for water soluble
drugs. Aging increases the probability of fracture and slows the rate of fracture repair. Increasing
weightbearing may increase bone mineral and prevent age-related bone loss. (See 'Musculoskeletal system'
above.)

● The normal aging of the skin leads to atrophy, decreased elasticity, and impaired metabolic and reparative
responses. Photoaging, not physiologic aging, produces 90 percent of the cosmetically undesirable changes
in skin. (See 'Skin' above.)

● Presbyopia is due to age-related changes in the lens and iris. Age-related changes in the auditory system
produce decrements in high-frequency hearing acuity and impaired speech recognition in noisy
environments. Loss of taste in older patients is in large part due to decreased olfaction rather than taste
itself. Decreased taste and smell sensation may result in decreased enjoyment of food and result in
nutritional deficiencies. (See 'Sensory system' above.)

● Decrements in immune functions with aging are among the most critical changes, contributing to the
increased frequency of infections, malignancies, and autoimmune disorders. Immunosenescence is
associated with loss of regulation of inflammatory processes. Older adults display cytokine profiles that are
consistent with a chronic, low-level inflammatory state, sometimes referred to as "inflammaging." (See
"Immune function in older adults".)

ACKNOWLEDGMENT — We wish to acknowledge the input of Nicolin Neal, MD in the preparation of sections in
this topic content.

Use of UpToDate is subject to the Subscription and License Agreement.

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Topic 14605 Version 25.0
GRAPHICS

Homeostenosis

Based on information from: Taffet GE. Physiology of aging. In: Cassel CK, Leipzig RM, Cohen HJ, et al
[eds]. Geriatric Medicine: An Evidence-Based Approach, 4th ed. New York, Springer, 2003.

Graphic 58907 Version 9.0

Renal changes with aging

Anatomic
Decrease in renal mass, mostly from cortex

Increased renal fat and fibrosis

Sclerosis of cortical nephrons with longest loops of Henle

Functional
Decreased renal blood flow

Impaired vasodilation in response to dopamine

Decreased creatinine clearance

Impaired sodium excretion and conservation

Decreased potassium excretion and conservation

Decreased concentrating and diluting capacity

Impaired excretion of acid loads

Decreased serum renin and aldosterone

Altered intrarenal nitric oxide actions

Increased dependence on renal prostaglandins to maintain intrarenal perfusion

Decreased vitamin D activation

Increased vulnerability to dye, ischemia, or other insults

Impaired recovery after insults

Data from: Taffet GE. Physiology of aging. In: Geriatric Medicine: An Evidence-Based Approach, Cassel CK, Leipzig RM,
Cohen HJ, et al (Eds), 4th ed, Springer, New York 2003.

Graphic 68244 Version 1.0

Pulmonary function with age

TLC: total lung capacity; VC: vital capacity; IC: inspiratory capacity; ERV: expiratory reserve volume;
RV: residual volume; FRC: functional residual capacity.

Modified and reproduced with permission from: Janssens JP, Pache JC, Nicod LP. Physiological
changes in respiratory function associated with ageing. Eur Respir J 1999; 13:197. Copyright © 1999
European Respiratory Society. All rights reserved.

Graphic 67608 Version 6.0

Life expectancy by age

Ages in years

70 75 80 85 90 95

Women - years of expected life

Top 25th percentile 21.3 17 13 9.6 6.8 4.8

50th percentile 15.7 11.9 8.6 5.9 3.9 2.7

Lowest 25th percentile 9.5 6.8 4.6 2.9 1.8 1.1

Men - years of expected life

Top 25th percentile 18 14.2 10.8 7.9 5.8 4.3

50th percentile 12.4 9.3 6.7 4.7 3.2 2.3

Lowest 25th percentile 6.7 4.9 3.3 2.2 1.5 1

Data from: Walter LC, Covinsky KE. Cancer screening in elderly patients: a framework for individualized decision
making. JAMA 2001; 285:2750.

Graphic 53094 Version 2.0

Contributor Disclosures
George E Taffet, MD Grant/Research/Clinical Trial Support: Indus Instruments [activity and cardiac function];
Kiromics, Inc [atherosclerosis]. Kenneth E Schmader, MD Grant/Research/Clinical Trial Support: Merck
[Herpes zoster (Zoster vaccine)]; GlaxoSmithKline [Herpes zoster (Zoster vaccine)]. Lisa Kunins, MD Nothing to
disclose

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