11: Clinical Problems of Aging

While an in-depth understanding of internal medicine serves as a foundation, proper care of older adults should be complemented by insight into the multidimensional effects of aging on disease manifestations, consequences, and response to treatment. In younger adults, individual diseases tend to have a more distinct pathophysiology with well-defined risk factors; the same diseases in older persons may have a less distinct pathophysiology and are often the result of failed homeostatic mechanisms. Causes and clinical manifestations are less specific and can vary widely between individuals. Therefore, the care of older patients demands an understanding of the effects of aging on human physiology and a broader perspective that incorporates geriatric syndromes, disability, social contexts, and goals of care. For example, care planning for the older patient should account for the substantial portion of the wide variability in life expectancy across individuals of the same age that can be predicted by simple and inexpensive measures such as walking speed. Estimation of the expected remaining years of life can guide recommendations about appropriate preventive and other long-term interventions and can shape discussions about treatment alternatives.

DEMOGRAPHY

(See also Chap. 93e) Population aging emerged as a worldwide phenomenon for the first time in history within the past century. Since aging influences many facets of life, governments and societies—as well as families and communities—now face new social and economic challenges that affect health care. Fig. 11-1 highlights recent and predicted changes in U.S. population structure. The overall number of children has remained relatively stable, but explosive growth has occurred among older populations. The percentage of growth is particularly dramatic among the oldest of the old. For example, the number of persons aged 80–89 years more than tripled between 1960 and 2010 and will increase over tenfold between 1960 and 2050. Women already outlive men by many years, and the sex discrepancy in longevity is projected to increase further in the future.

Population aging occurs at different rates in varying geographic regions of the world. Over the past century, Europe, Australia, and North America have had the populations with the greatest proportions of older persons, but the populations of Asia and South America are aging rapidly, and the population structure on these continents will resemble that of “older” countries by around 2050 (Fig. 11-2). Among older persons, the oldest old (those >80 years of age) are the fastest-growing segment of the population (Fig. 11-3), and the pace of population aging is projected to accelerate in most countries over the next 50 years. There is no evidence that the rate of population aging is decreasing.

POPULATION AGING AND HEALTH

Many chronic diseases increase in prevalence with age. It is not unusual for older persons to have multiple chronic diseases (Fig. 11-4), although some seem more susceptible than others to co-occurring problems. Functional problems that pose difficulties or require help in performing basic activities of daily living (ADLs) (Table 11-1) increase with age and are more common among women than among men. In recent decades, the age-specific prevalence of disability has declined, especially in the oldest old. Estimated rates are shown in Fig. 11-5 as the percentage of persons who reported severe difficulty or needed help in bathing, and data on other basic ADLs show similar trends. Although the age-specific prevalence of disability is decreasing, the magnitude of this decline is small compared to the overwhelming effect of population aging. Thus, the number of people with disability in the United States and other countries is rapidly expanding. Rates of cognitive impairments, such as memory problems, also increase with aging (Fig. 11-6). Chronic disease and disability lead to increased use of health care resources. Health care expenditures increase with age, increase more with disability, and are highest in the last year of life. However, new medical technologies and expensive medications are greater influences on health care costs than population aging itself. General practitioners and internists with little specific training in geriatric medicine provide the bulk of care for older persons.

SYSTEMIC EFFECTS OF AGING

Systemic consequences of aging are widespread but can be clustered into four main domains or processes (Fig. 11-7): (1) body composition; (2) balance between energy availability and energy demand; (3) signaling networks that maintain homeostasis; and (4) neurodegeneration. Each domain can be assessed with routine clinical tests, although more detailed research techniques are also available (Table 11-2).

Body Composition

Profound changes in body composition may be the most evident and inescapable effect of aging (Fig. 11-8). Over the life span, body weight tends to increase through childhood, puberty, and adulthood until late middle age. Weight tends to decline in men between ages 65 and 70 years and in women somewhat later. Lean body mass, composed predominantly of muscle and visceral organs, decreases steadily after the third decade. In muscle, this atrophy is greater in fast-twitch than in slow-twitch fibers. The origin of this change is unknown, but several lines of evidence suggest that progressive loss of motor neurons probably plays an important role. Fat mass tends to increase in middle age and then declines in late life, reflecting the trajectory of weight change. Waist circumference continues to increase across the life span, a pattern suggesting that visceral fat, which is responsible for most of the pathologic consequences of obesity, continues to accumulate. In some individuals, fat also accumulates inside muscle, affecting muscle quality and function. With age, fibroconnective tissue tends to increase in many organ systems. In muscle, fibroconnective tissue buildup also affects muscle quality and function. In combination, the loss of muscle mass and quality result in reduced muscle strength, which ultimately affects functional capacity and mobility. Muscle strength declines with aging; this decrease not only affects functional status but also is a strong independent predictor of mortality (Fig. 11-9). Progressive demineralization and architectural modification occur in bone, resulting in a decline of bone strength. Loss of bone strength increases the risk of fracture. Sex differences in the effects of aging on bone mass are due to differences in peak bone mass and the effects of gonadal hormones on bone. Overall, compared with men, women tend to lose bone mass at a younger age and more quickly reach the threshold of low bone strength that increases fracture risk.

All of these changes in body composition can be attributed to disruptions in the links between synthesis, degradation, and repair that normally serve to remodel tissues. Such changes in body composition are influenced not only by aging and illness but also by lifestyle factors such as physical activity and diet. Body composition can be approximated in clinical practice on the basis of weight, height, body mass index (BMI; weight in kilograms divided by height in meters squared), and waist circumference or, more precisely, with dual-energy x-ray absorptiometry, CT, or MRI. In healthy men and women in their twenties, lean body mass is, on average, 85% of body weight, with roughly 50% of lean mass represented by skeletal muscle. With aging, both the percentage of lean mass and the percentage represented by muscle decline rapidly, and these changes have important health and functional consequences.

Balance Between Energy Availability and Energy Demand

Release of phosphate from ATP provides every living cell with the energy required for life. However, the storage of ATP is only enough for 6 sec; therefore, ATP is constantly resynthesized. Although ATP can be resynthesized by anaerobic glycolysis, most of the energy used in the body is generated through aerobic metabolism. Therefore, energy consumption is usually estimated indirectly by oxygen consumption (indirect calorimetry). There is currently no method to measure true “fitness,” which is the maximal energy that can be produced by an organism over extended periods. Thus, fitness is estimated indirectly from peak oxygen consumption (MVo_{2 peak}), often during a maximal treadmill test. Longitudinal studies have demonstrated that MVo_{2 peak} declines progressively with aging (Fig. 11-10), and the rate of decline is accelerated in persons who are sedentary and in those affected by chronic diseases.

A large portion of energy is consumed as the “resting metabolic rate” (RMR)—i.e., the amount of energy expended at rest in a neutral temperature environment and in a postabsorptive state. In healthy men and women, RMR declines with aging, and such decline is only partially explained by the parallel decline in the highly metabolically active tissues that make up lean body mass (Fig. 11-11). However, persons with unstable homeostasis due to illness require additional energy for compensatory mechanisms. Indeed, observational studies have demonstrated (1) that older persons with poor health status and substantial morbidity have a higher RMR than healthier individuals of the same age and sex and (2) that a high RMR is an independent risk factor for mortality and may contribute to the weight loss that often accompanies severe illness. Finally, for reasons that are not yet completely clear but certainly involve changes in the biomechanical characteristics of movement, older age, pathology, and physical impairment increase the energy cost of motor activities such as walking. Overall, older individuals with multiple chronic conditions have low available energy levels and require more energy both at rest and during physical activity. Thus, sick older people may consume all their available energy performing the most basic ADLs, and consequent fatigue and restriction may lead to a sedentary existence. Energy status can be assessed clinically by simply asking patients about their perceived level of fatigue during daily activities such as walking or dressing. Energy capacity can be assessed more precisely by exercise tolerance during a walking test or a treadmill test coupled with spirometry.

The main signaling pathways that control homeostasis involve hormones, inflammatory mediators, and antioxidants; all are profoundly affected by aging. Sex hormone levels, such as testosterone in men (Fig. 11-12) and estrogen in women, decrease with age, while other hormone systems may change more subtly (Table 11-3). Most aging individuals, even those who remain healthy and fully functional, tend to develop a mild proinflammatory state characterized by high levels of proinflammatory markers, including interleukin 6 (IL-6) and C-reactive protein (CRP) (Fig. 11-13). Aging is also thought to be associated with increased oxidative stress damage, either because the production of reactive oxygen species increases or because antioxidant buffers are less effective. Since hormones, inflammatory markers, and antioxidants are integrated into complex signaling networks, levels of individual biomarkers may well reflect adaptation within homeostatic feedback loops rather than true causative factors. Thus, the therapeutic strategy of single-molecule replacement may be ineffective or even counterproductive. The presence of such signaling networks and feedback loops may help explain why single-hormone “replacement therapy” for problems of aging has demonstrated little benefit. The focus of research in this area is now on multiple-hormone dysregulation. For example, taken one at a time, levels of testosterone, dehydroepiandrosterone (DHEA), and insulin-like growth factor 1 (IGF-1) do not predict mortality, but in combination they are highly predictive of longevity. This combination effect is especially strong in the setting of congestive heart failure. Similarly, several micronutrients, such as vitamins (especially vitamin D), minerals (selenium and magnesium), and antioxidants (vitamins D and E), also regulate aspects of metabolism. Low levels of these micronutrients have been associated with accelerated aging and a high risk of adverse outcomes. However, except for vitamin D, no clear evidence suggests that supplementation has positive effects on health. Unfortunately, no standard criteria exist that allow the detection and quantification of homeostatic dysregulation as a general phenomenon.

Neurodegeneration

It was long generally believed that neurons stop reproducing shortly after birth and that their number declines throughout life. However, results from animal models and even some studies in humans suggest that neurogenesis in the hippocampus continues at low levels throughout life. Brain atrophy occurs with aging after the age of 60 years. Atrophy proceeds at varying rates in different parts of the brain (Fig. 11-14) and is often accompanied by an inflammatory response and microglial activation. Age-associated brain atrophy may contribute to age-related declines in cognitive and motor function. Atrophy may also be a factor in some brain diseases that can occur with aging, such as mild cognitive impairment, in which persons have mild but detectable impairments on tests of cognition but no severe disability in daily activities. In mild cognitive impairment, atrophy has been found mostly in the prefrontal cortex and hippocampus, but these findings are not specific and their diagnostic utility is unclear (Fig. 11-15). Other neurophysiologic changes in the brain frequently occur with aging and may contribute to cognitive decline. Functional imaging studies have shown that some older people have diminished coordination between the brain regions responsible for higher-order cognitive functions and that such diminished coordination is correlated with poor cognitive performance. In young healthy individuals, the brain activity associated with executive cognitive functions (e.g., problem-solving, decision-making) is very well localized; in contrast, in healthy older individuals, the pattern of cortical activation is more diffuse. Brain pathology has typically been associated with specific diseases; amyloid plaques and neurofibrillary tangles are considered the pathologic hallmarks of Alzheimer’s disease. However, these pathologic markers have been found at autopsy in many older individuals who had normal cognition, as assessed by extensive testing in the year before death.

Taken together, trends in brain changes with aging suggest that some neurophysiologic manifestations are compensatory adaptations rather than primary contributors to age-related declines. Because the brain is capable of reorganization and compensation, extensive neurodegeneration may not be clinically evident. Therefore, early detection requires careful testing. Clinically, cortical and subcortical changes are reflected in the high prevalence of “soft,” nonspecific neurologic signs, often reflected in slow and unstable gait, poor balance, and slow reaction times. These movement changes can be elicited more overtly with “dual tasks,” in which a cognitive and a motor task are performed simultaneously. In a simple version of a dual task, when an older adult has to stop walking in order to talk, an increased risk of falls can be predicted. Poor dual-task performance has been interpreted as a marker of reduced overall capacity for central processing, so that simultaneous processing is more constrained. Beyond the brain, the spinal cord also experiences changes after the age of 60 years, including reduced numbers of motor neurons and damage to myelin. The motor neurons that survive compensate by increased branching complexity and by service to larger motor units. As motor units become larger, they decline in number at a rate of ∼1% per year, starting after the third decade. These larger motor units contribute to reductions in fine-motor control and manual dexterity. Age-related changes also occur in the autonomic nervous system, affecting cardiovascular and splanchnic function.

Systemic Changes Coexisting with and Affecting One Another

The Phenotype of Aging: the Final Common Pathway of Systemic Interaction

While age-related system changes have been described individually, in reality, these changes develop in parallel and affect one another through many feed-forward and feedback loops. Some systemic interactions are well understood, while others are under investigation. For example, body composition interacts with energy balance and signaling. Higher lean body mass increases energy consumption and improves insulin sensitivity and carbohydrate metabolism. Higher fat mass, especially visceral fat mass, is the culprit in the metabolic syndrome and is associated with low testosterone levels, high sex hormone–binding globulin levels, and increased levels of proinflammatory markers such as CRP and IL-6. Altered signaling can affect neurodegeneration; insulin resistance and adipokines such as leptin and adiponectin are associated with declines in cognitive function. Combined with loss of motor neurons and dysfunction of the motor unit, a state of inflammation and reduced levels of testosterone and IGF-1 have been linked to accelerated decline of muscle mass and strength. Normal intersystem coordination is also affected by aging. The hypothalamus normally functions as a central regulator of metabolism and energy use and coordinates physiologic responses of the entire organism through hormonal signaling; aging-related changes in the hypothalamus alter this control. The central nervous system (CNS) also controls adaptive sympathetic/parasympathetic activity, so that age-related CNS degeneration may have implications for autonomic function.

The phenotype that results from the aging process is characterized by increased susceptibility to diseases, high risk of multiple coexisting diseases, impaired response to stress (including limited ability to heal or recover after an acute disease), emergence of “geriatric syndromes” (characterized by stereotyped clinical manifestations but multifactorial causes), altered response to treatment, high risk of disability, and loss of personal autonomy with all its psychological and social consequences. In addition, these key aging processes may interfere with the typical pathophysiology of specific diseases, thereby altering expected clinical manifestations and confounding diagnosis. Clinically, patients may present with obvious problems within only one of these domains, but, since systems interact, all four main domains should be evaluated and considered potential therapeutic targets. When patients present with obvious problems in multiple main systems affected by aging, they tend toward extreme degrees of susceptibility and loss of resilience, a condition that is globally referred to as frailty.

Biologic Underpinnings of the Domains of the Aging Phenotype

The changes that occur with aging encompass multiple physiologic systems. Although they are often described in isolation, they are likely attributable to the progressive dysfunction of a unique mechanism that affects some fundamental housekeeping mechanism of cellular physiology. An important goal of future research is to connect the aging phenotype in humans to theories of aging that have largely been developed from studies in cell or animal models. If the main theories of aging could be operationalized into assessments that are feasible in humans, it would be possible to test the hypothesis that some of these processes are correlated with all the domains of the aging phenotype, above and beyond chronologic age. Review of the biologic theories (hallmarks) of aging provides an excellent template for a working hypothesis that, at least theoretically, could be tested in longitudinal studies. Candidate mechanisms of mammalian aging include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.

Frailty

Frailty has been described as a physiologic syndrome that is characterized by decreased reserve and diminished resistance to stressors, that results from cumulative decline across multiple physiologic systems, and that causes vulnerability to adverse outcomes and a high risk of death. A proposed “phenotype” definition characterized by weight loss, fatigue, impaired grip strength, diminished physical activity, and slow gait has shown good internal consistency and strong predictive validity and has been used in many clinical and epidemiologic studies. An alternative approach, the Frailty Index, assesses cumulative physiologic and functional burden. When combined with a structured clinical assessment (the Comprehensive Geriatric Assessment), the Frailty Index can be applied in clinical settings and has low rates of missing data; it predicts survival in community-dwelling older people as well as survival, length of stay and discharge location in acute-care settings. Regardless of the definition, an extensive body of literature shows that older persons who are considered frail by any definition have overt changes in the same four main processes: body composition, homeostatic dysregulation, energetic failure, and neurodegeneration—the characteristics of the aging phenotype. A classic clinical case would be an older woman with sarcopenic obesity characterized by increased body fat and decreased muscle (body composition changes); extremely low exercise tolerance and extreme fatigue (energetic failure); high insulin levels, low IGF-1 levels, inadequate intake of calories, and low levels of vitamins D and E and carotenoids (signal dysregulation); and memory problems, slow gait, and unstable balance (neurodegeneration). This woman is likely to exhibit all the manifestations of frailty, including a high risk of multiple diseases, disability, urinary incontinence, falls, delirium, depression, and other geriatric syndromes. It is expected that the biologic process underlying a particular “aging theory” would be more advanced in this woman than would be expected on the basis of chronologic age.

A goal of future research in geriatric medicine that has strong potential for clinical translation is to demonstrate that the hypothetical patient described above is biologically older, according to some robust biomarkers of biologic aging, than would be estimated from chronologic age alone. Conceptualizing frailty through the four main underlying processes is a step in this direction that stems from accumulated evidence and recognizes the heterogeneity and dynamic nature of the aging phenotype. Aging is universal but proceeds at highly variable rates, with wide heterogeneity in the emergence of the aging phenotype. Thus, the question is not whether an older patient is frail, but rather whether the severity of frailty is beyond the threshold of clinical and behavioral relevance. Understanding frailty through the lens of four interacting underlying processes also provides an interface with diseases that, like aging itself, affect the aging phenotype. For example, congestive heart failure is associated with low energy availability, multiple hormonal derangements, and a proinflammatory state, thereby contributing to frailty severity. Parkinson’s disease provides an example of neurodegeneration that, in an advanced state, affects body composition, energy metabolism, and homeostatic signaling, resulting in a syndrome that closely resembles frailty. Diabetes is especially important to aging and frailty because it harms body composition, energy metabolism, homeostatic dysregulation, and neuronal integrity. Accordingly, a number of studies have found that type 2 diabetes is a strong risk factor for frailty and for many of its consequences. Since disease and aging interact, careful and appropriate treatment of disease is critical to prevent or reduce frailty.

While the pathophysiology of frailty is still being elucidated, its consequences have been well characterized in prospective studies. Four main consequences are important for clinical practice: (1) ineffective or incomplete homeostatic response to stress, (2) multiple coexisting diseases (multi- or comorbidity) and polypharmacy, (3) physical disability, and (4) the so-called geriatric syndromes. We will briefly address each one of these consequences.

Low Resistance to Stress

Frailty can be considered a progressive loss of reserve in multiple physiologic functions. At an early stage and in the absence of stress, mildly frail older individuals may appear to be normal. However, they have reduced ability to cope with challenges, such as acute diseases, traumas, surgical procedures, or chemotherapy. Acute illness involving a hospital stay is associated with undernutrition and inactivity, which sometimes may be of such magnitude that the residual muscle mass fails to meet the minimal requirement for walking. Even when nutrition is reinstated, energy reserves may be insufficient to adequately rebuild muscle mass. Older persons have a reduced ability to tolerate infections, in part because they are less able than younger people to build a dynamic inflammatory response to vaccination or infectious exposure; thus, infections are more likely to become severe and systemic and to resolve more slowly. In the context of tolerance to stress, assessing aspects of frailty can help estimate the individual’s ability to withstand the rigors of aggressive treatments and to respond to interventions aimed at infection as well as the caregiver’s ability to anticipate and prevent complications of hospitalization and generally to estimate prognosis. Accordingly, treatment plans may be adjusted to improve tolerance and safety; bed rest and hospitalization should be used sparingly; and infections should be prevented, anticipated, and managed assertively.

Comorbidity and Polypharmacy

Older age is associated with high rates of many chronic diseases (Fig. 11-4). Thus, not unexpectedly, the percentage of individuals affected by multiple medical conditions (co- or multimorbidity) also increases with age. In frail older individuals, comorbidity occurs at higher rates than would be expected from the combined probability of the component conditions. It is likely that frailty and comorbidity affect each other, so that multiple diseases contribute to frailty and frailty increases susceptibility to diseases.

Clinically, patients with multiple conditions present unique diagnostic and treatment challenges. Standard diagnostic criteria may not be informative because there are additional confusing signs and symptoms. A classic example is the coexistence of deficiencies in iron and vitamin B₁₂, creating an apparently normocytic anemia. The risk/benefit ratio for many medical and surgical treatment options may be reduced in the face of other diseases. Drug treatment planning is made more complex because comorbid diseases may affect the absorption, volume of distribution, protein binding, and, especially, elimination of many drugs, leading to fluctuation in therapeutic levels and increased risk of under- or overdosing. Drug excretion is affected by renal and hepatic changes with aging that may not be detectable with the usual clinical tests. Formulas for estimating glomerular filtration rate in older patients are available, whereas the estimation of changes in hepatic excretion remains a challenge.

Patients with many diseases are usually prescribed multiple drugs, especially when they are cared for by multiple specialists who do not communicate. The risk of adverse drug reactions, drug–drug interactions, and poor compliance increases geometrically with the number of drugs prescribed and with the severity of frailty. Some general rules to minimize the chances of adverse drug events are as follows: (1) Always ask patients to bring in all medications, including prescription drugs, over-the-counter products, vitamin supplements, and herbal preparations (the “brown bag test”). (2) Screen for unnecessary drugs; those without a clear indication should be discontinued. (3) Simplify the regimen in terms of number of agents and schedules, try to avoid frequent changes, and use single-daily-dose regimens whenever possible. (4) Avoid drugs that are expensive or not covered by insurance whenever possible. (5) Minimize the number of drugs to those that are absolutely essential, and always check for possible interactions. (6) Make sure that the patient or an available caregiver understands the administered regimen, and provide legible written instructions. (7) Schedule periodic medication reviews.

Disability and Impaired Recovery from Acute-Onset Disability

The prevalence of disability in self-care and home management increases steeply with aging and tends to be higher among women than among men (Fig. 11-5). Physical and cognitive function in older persons reflects overall health status and predicts health care utilization, institutionalization, and mortality more accurately than any other known biomedical measure. Thus, assessment of function and disability and prediction of the risk of disability are cornerstones of geriatric medicine. Frailty, regardless of the criteria used for its definition, is a robust and powerful risk factor for disability. Because of this strong relationship, measures of physical function and mobility have been proposed as standard criteria for frailty. However, disability occurs late in the frailty process, after reserve and compensation are exhausted. Early in the development of frailty, body composition changes, reductions in fitness, homeostatic deregulation, and neurodegeneration can begin without affecting daily function. As opposed to disability in younger persons, in which the rule is to look for a clear dominant cause, disability in frail older persons is almost always multifactorial. Multiple disrupted aging processes are usually involved, even when the precipitating cause seems unique. Excess fat mass, poor muscle strength, reduced lean body mass, poor fitness, reduced energy efficiency, poor nutritional intake, low circulating levels of antioxidant micronutrients, high levels of proinflammatory markers, objective signs of neurologic dysfunction, and cognitive impairment all contribute to disability. The multifactorial nature of disability in frail older persons reduces the capacity for compensation and interferes with functional recovery. For example, a small lacunar stroke that causes problems with balance in a young hypertensive individual can be overcome by standing and walking with the feet further apart, a strategy that requires brain adaptation, strong muscles, and a high energy capacity. The same small lacunar stroke may cause catastrophic disability in an older person already affected by neurodegeneration and weakness, who is less able to compensate. As a consequence, interventions aimed at preventing and reducing disability in older persons should have a dual focus on both the precipitating cause and the systems needed for compensation. In the case of the lacunar stroke, interventions to promote mobility function might include stroke prevention, balance rehabilitation, and strength training.

As a rule of thumb, the assessment of contributing causes and the design of intervention strategies for disability in older persons should always consider the four main aging processes that contribute to frailty. One of the most popular approaches to disability measurement is a modification of the International Classification of Impairments, Disabilities and Handicaps (World Health Organization, 1980) proposed by the Institute of Medicine (1992). This classification infers a causal pathway in four steps: pathology (diseases), impairment (the physical manifestation of diseases), functional limitation (global functions such as walking, grasping, climbing stairs), and disability (ability to fulfill social roles in the environment). In practice, the assessment of functional limitation and disability is performed either by (1) self-reported questionnaire concerning the degree of ability to perform basic self-care or more complex ADLs or by (2) performance-based measures of physical function that assess specific domains, such as balance, gait, manual dexterity, coordination, flexibility, and endurance. A concise list of standard tools that can be used to assess physical function in older persons is provided in Table 11-4. In 2001, the WHO officially endorsed a new classification system, the International Classification of Functioning, Disability and Health, known more commonly as the ICF. In the ICF, health measures are classified from bodily, individual, and societal perspectives by means of two lists: a list of body functions and structure and a list of domains of activity and participation. Since an individual’s functioning and disability occur in a context, the ICF also includes a list of environmental factors. A detailed list of codes that allow the classification of body functions, activities, and participation is being developed. The ICF system is widely implemented in Europe and is gaining popularity in the United States. Whatever classification system is used, the health care provider should try to identify factors that can be modified to minimize disability. Many of these factors are discussed in this chapter. Important issues related to aging that are not addressed in this chapter but are covered elsewhere include dementia (Chap. 35) and other cognitive disorders including aphasia, memory loss, and other focal cerebral disorders (Chap. 36).

Geriatric Syndromes

The term geriatric syndrome encompasses clinical conditions that are frequently encountered in older persons; have a deleterious effect on function and quality of life; have a multifactorial pathophysiology, often involving systems unrelated to the apparent chief symptom; and are manifested by stereotypical clinical presentations. The list of geriatric syndromes includes incontinence, delirium, falls, pressure ulcers, sleep disorders, problems with eating or feeding, pain, and depressed mood. In addition, dementia and physical disability are sometimes considered to be geriatric syndromes. The term syndrome is somewhat misleading in this context since it is most commonly used to describe a pattern of symptoms and signs that have a single underlying cause. The term geriatric syndromes, by contrast, refers to “multifactorial health conditions that occur when the accumulated effects of impairments in multiple systems render an older person vulnerable to situational challenges.” According to this definition, geriatric syndromes reflect the complex interactions between an individual’s vulnerabilities and exposure to stressors or challenges. This definition aligns well with the concept that geriatric syndromes should be considered as phenotypic consequences of frailty and that a limited number of shared risk factors contribute to their etiology. Indeed, in various combinations and frequencies, virtually all geriatric syndromes are characterized by body composition changes, energy gaps, signaling disequilibria, and neurodegeneration. For example, detrusor (bladder) underactivity is a multifactorial geriatric condition that contributes to urinary retention in the frail elderly. It is characterized by detrusor muscle loss, fibrosis, and axonal degeneration. A proinflammatory state and a lack of estrogen signaling cause bladder muscle loss and detrusor underactivity, while a chronic urinary tract infection may cause detrusor hyperactivity; all of these factors may contribute to urinary incontinence.

Because of limited space, only delirium, falls, chronic pain, incontinence, and anorexia are addressed here. Interested readers are referred to textbooks on geriatric medicine for a discussion of other geriatric syndromes.

Delirium

(See also Chap. 34) Delirium is an acute disorder of disturbed attention that fluctuates with time. It affects 15–55% of hospitalized older patients. Delirium has previously been considered to be transient and reversible and a normal consequence of surgery, chronic disease, or infections in older people. Delirium may be associated with a substantially increased risk for dementia and is an independent risk factor for morbidity, prolonged hospitalization, and death. These associations are particularly strong in the oldest old. Fig. 11-16 shows an algorithm for assessment and management of delirium in hospitalized older patients. The clinical presentation of delirium is heterogeneous, but frequent features are (1) a rapid decline in the level of consciousness, with difficulty focusing, shifting, or sustaining attention; (2) cognitive change (rumbling incoherent speech, memory gaps, disorientation, hallucinations) not explained by dementia; and (3) a medical history suggestive of preexisting cognitive impairment, frailty, and comorbidity. The strongest predisposing factors for delirium are dementia, any other condition associated with chronic or transient neurologic dysfunction (neurologic diseases, dehydration, alcohol consumption, psychoactive drugs), and sensory (visual and hearing) deprivation; these associations suggest that delirium is a condition of brain function susceptibility (neurodegeneration or transient neuronal impairment) that precludes the avoidance of decompensation in the face of a stressful event. Many stressful conditions have been implicated as precipitating factors, including surgery; anesthesia; persistent pain; treatment with opiates, narcotics, or anticholinergics; sleep deprivation, immobilization; hypoxia; malnutrition; and metabolic and electrolyte derangements. Both the occurrence and the severity of delirium can be reduced by anticipatory screening and preventive strategies targeting the precipitating causes. The Confusion Assessment Method is a simple, validated tool for screening in the hospital setting. The three pillars of treatment are (1) immediate identification and treatment of precipitating factors, (2) withdrawal of drugs that may have promoted the onset of delirium, and (3) supportive care, including management of hypoxia, hydration and nutrition, mobilization, and environmental modifications. Whether patients who are cared for in special delirium units have better outcomes than those who are not is still in question. Physical restraints should be avoided because they tend to increase agitation and injury. Whenever possible, drug treatment should be avoided because it may prolong or aggravate delirium in some cases. The treatment of choice is low-dose haloperidol. It remains difficult to reduce delirium in patients with acute illness or other stressful conditions. Interventions based on dietary supplementation or careful use of pain medications and sedatives in pre- and postoperative older patients have been only partially successful.

Falls and Balance Disorders

Unstable gait and falls are serious concerns in the older adult because they lead not only to injury but also to restricted activity, increased health care utilization, and even death. Like all geriatric syndromes, problems with balance and falls tend to be multifactorial and are strongly connected with the disrupted aging systems that contribute to frailty. Poor muscle strength, neural damage in the basal ganglia and cerebellum, diabetes, and peripheral neuropathy are all recognized risk factors for falls. Therefore, evaluation and management require a structured multisystem approach that spans the entire frailty spectrum and beyond. Accordingly, interventions to prevent or reduce instability and falls usually require a mix of medical, rehabilitative, and environmental modification approaches. Guidelines for the evaluation and management of falls, released by the American Geriatrics Society, recommend asking all older adults about falls and perceived gait instability (Fig. 11-17). Patients with a positive history of multiple falls as well as persons who have sustained one or more injurious falls should undergo an evaluation of gait and balance as well as a targeted history and physical examination to detect sensory, nervous system, brain, cardiovascular, and musculoskeletal contributors. Interventions depend on the factors identified but often include medication adjustment, physical therapy, and home modifications. Meta-analyses of strategies to reduce the risk of falls have found that multifactorial risk assessment and management as well as individually targeted therapeutic exercise are effective. Supplementation with vitamin D at 800 IU daily may also help reduce falls, especially in older persons with low vitamin D levels.

Persistent Pain

Pain from multiple sources is the most common symptom reported by older adults in primary care settings and is also common in acute-care, long-term-care, and palliative-care settings. Acute pain and cancer pain are beyond the scope of this chapter. Persistent pain results in restricted activity, depression, sleep disorders, and social isolation and increases the risk of adverse events due to medication. The most common causes of persistent pain are musculoskeletal problems, but neuropathic pain and ischemic pain occur frequently, and multiple concurrent causes are often found. Alterations in mechanical and structural elements of the skeleton commonly lead to secondary problems in other parts of the body, especially soft tissue or myofascial components. A structured history should elicit information about the quality, severity, and temporal patterns of pain. Physical examination should focus on the back and joints, on trigger points and periarticular areas, and on possible evidence of radicular neurologic patterns and peripheral vascular disease. Pharmacologic management should follow standard progressions, as recommended by the World Health Organization (Chap. 18), and adverse effects on the CNS, which are especially likely in this population, must be monitored. For persistent pain, regular analgesic schedules are appropriate and should be combined with nonpharmacologic approaches such as splints, physical exercise, heat, and other modalities. A variety of adjuvant analgesics such as antidepressants and anticonvulsants may be used; again, however, effects on reaction time and alertness may be dose limiting, especially in older persons with cognitive impairment. Joint or soft tissue injections may be helpful. Education of the patient and mutually agreed-upon goal setting are important since pain usually is not fully eliminated but rather is controlled to a tolerable level that maximizes function while minimizing adverse effects.

Urinary Incontinence

Urinary incontinence—the involuntary leakage of urine—is highly prevalent among older persons (especially women) and has a profound negative impact on quality of life. Approximately 50% of American women will experience some form of urinary incontinence over a lifetime. Increasing age, white race, childbirth, obesity, and medical comorbidity are all risk factors for urinary incontinence. The three main clinical forms of urinary incontinence are as follows: (1) Stress incontinence is the failure of the sphincteric mechanism to remain closed when there is a sudden increase in intraabdominal pressure, such as a cough or sneeze. In women this condition is due to insufficient strength of the pelvic floor muscles, while in men it is almost exclusively secondary to prostate surgery. (2) Urge incontinence is the loss of urine accompanied by a sudden sensation of need to urinate and inability to control it and is due to detrusor muscle overactivity (lack of inhibition) caused by loss of neurologic control or local irritation. (3) Overflow incontinence is characterized by urinary dribbling, either constantly or for some period after urination. This condition is due to impaired detrusor contractility (due usually to denervation, for example, in diabetes) or bladder outlet obstruction (prostate hypertrophy in men and cystocele in women). Thus, it is not surprising that the pathogenesis of urinary incontinence is connected to the disrupted aging systems that contribute to frailty, body composition changes (atrophy of the bladder and pelvic floor muscle), and neurodegeneration (both central and peripheral nervous systems). Frailty is a strong risk factor for urinary incontinence. Indeed, older women are more likely to have mixed (urge + stress) incontinence than any pure form (Fig. 11-18). In analogy with the other geriatric syndromes, urinary incontinence derives from a predisposing condition superimposed on a stressful precipitating factor. Accordingly, treatment of urinary incontinence should address both. The first line of treatment is bladder training associated with pelvic muscle exercise (Kegel exercises) that sometimes should be associated with electrical stimulation. Women with possible vaginal or uterine prolapse should be referred to a specialist. Urinary tract infections should be investigated and eventually treated. A long list of medications can precipitate urinary incontinence, including diuretics, antidepressants, sedative hypnotics, adrenergic agonists or blockers, anticholinergics, and calcium channel blockers. Whenever possible, these medications should be discontinued. Until recently, it was believed that oral or local estrogen treatment alleviated the symptoms of urinary incontinence in postmenopausal women, but this notion is now controversial. Antimuscarinic drugs such as tolterodine, darifenacin, and fesoterodine are modestly effective for mixed-etiology incontinence, but all of these drugs can affect cognition and so must be used with caution and with monitoring of cognitive status. In some cases, surgical treatment should be considered. Chronic catheterization has many adverse effects and should be limited to chronic urinary retention that cannot be managed in any other way. Bacteriuria always occurs and should be treated only if it is symptomatic. Bacterial communities isolated from the urine of women with urinary incontinence appear to differ with the type of incontinence; this observation suggests that the bladder microbiota may play a role in urinary incontinence. If so, this microbial population would be a potential target for treatment.

Undernutrition and Anorexia

There is strong evidence that the healthy mammalian life span is greatly affected by changes in the activity of central nutrient-sensing mechanisms, especially those that involve the rapamycin (mTOR) network. Polymorphic variations in the gene that encodes mTOR in humans are associated with longevity; this association suggests that the role of nutrient signaling in healthy aging may be conserved in humans. Normal aging is associated with a decline in food intake that is more marked in men than in women. To some extent, food intake is reduced because energy demand declines as a result of the combination of a lower level of physical activity, a decline in lean body mass, and slowed rates of protein turnover. Other contributors to decreased food intake include losses of taste sensation, reduced stomach compliance, higher circulating levels of cholecystokinin, and, in men, low testosterone levels associated with increased leptin. When food intake decreases to a level below the reduced energy demand, the result is energy malnutrition.

Malnutrition in older persons should be considered a geriatric syndrome because it is the result of intrinsic susceptibility due to aging, complicated by multiple superimposed precipitating causes. Many older individuals tend to consume a monotonous diet that lacks sufficient fresh food, fruits, and vegetables, so that intake of important micronutrients is inadequate. Undernutrition in older people is associated with multiple adverse health consequences, including impaired muscle function, decreased bone mass, immune dysfunction, anemia, reduced cognitive function, poor wound healing, delayed recovery from surgery, and increased risk of falls, disability, and death. Despite these serious potential consequences, undernutrition often remains unrecognized until it is well advanced because weight loss tends to be ignored by both patients and physicians. Muscle wasting is a frequent feature of weight loss and malnutrition that is often associated with loss of subcutaneous fat. The main causes of weight loss are anorexia, cachexia, sarcopenia, malabsorption, hypermetabolism, and dehydration, almost always in various combinations. Many of these causes can be detected and corrected. Cancer accounts for only 10–15% of cases of weight loss and anorexia in older people. Other important causes include a recent move to a long-term-care setting, acute illness (often with inflammation), hospitalization with bed rest for as little as 1–2 days, depression, drugs that cause anorexia and nausea (e.g., digoxin and antibiotics), swallowing problems, oral infections, dental problems, gastrointestinal pathology, thyroid and other hormonal problems, poverty, and isolation, with reduced access to food. Weight loss may also result from dehydration, possibly related to excess sweating, diarrhea, vomiting, or reduced fluid intake. Early identification is paramount and requires careful weight monitoring. Patients or caregivers should be taught to record weight regularly at home, the patient should be weighed at each clinical encounter, and a record of serial weights should be maintained in the medical record. If malnutrition is suspected, formal assessment should begin with a standardized screening instrument such as the Mini Nutritional Assessment, the Malnutrition Universal Screening Tool, or the Simplified Nutritional Appetite Questionnaire. The Mini Nutritional Assessment includes questions on appetite, timing of eating, frequency of meals, and taste. Its sensitivity and specificity are >75% for future weight loss of ≥5% of body weight in older people. Many nutritional supplements are available, and their use should be initiated early to prevent more severe weight loss and its consequences. When an older patient has malnutrition, the diet should be liberalized and dietary restrictions should be lifted as much as possible. Nutritional supplements should be given between meals to avoid interference with food intake at mealtime. Limited evidence supports the use of any pharmacologic intervention to treat weight loss. The two antianorexic drugs most often prescribed in older persons are megesterol and dronabinol. Both can increase weight; however, the gain is mostly fat, not muscle, and both drugs have serious side effects. Dronabinol is an excellent drug for use in the palliative-care setting. There is little evidence that intentional weight loss in overweight older people prolongs life. Weight loss after the age of 70 should probably be limited to persons with extreme obesity and should always be medically supervised.

Common diseases in older adults may have unexpected and atypical clinical features. Most age-related changes in clinical presentation, evolution, and response to treatment are due to interaction of disease pathophysiology with age-related system dysregulation. Some diseases, such as Parkinson’s disease (PD) and diabetes, directly affect aging systems and therefore have a devastating impact on frailty and its consequences.

Parkinson’s Disease

(See also Chap. 449) Most cases of PD begin after the age of 60 years, and the incidence increases up to the age of ∼80 years. Brain aging and PD have long been thought to be related. The nigrostriatal system deteriorates with aging, and many older persons tend to develop a mild form of movement disorder characterized by bradykinesia and stooped posture that mimics mild PD. It is interesting that, in PD, older age at presentation is associated with a more severe and rapid decline in gait, balance, posture, and cognition. These age-related motor and cognitive manifestations of PD tend to be poorly responsive to levodopa or dopamine agonist treatments, especially in the oldest old. In contrast, age at presentation does not correlate with the severity and progression of other classic PD symptoms, such as tremor, rigidity, and bradykinesia, nor does it affect the response of these symptoms to levodopa. The pattern of PD features in older persons suggests that late-life PD may reflect a failure of the normal cellular compensatory mechanisms in vulnerable brain regions and that this vulnerability is increased by age-related neurodegeneration, making PD symptoms particularly resistant to levodopa treatment. In addition to motor symptoms, older PD patients tend to have reduced muscle mass (sarcopenia), eating disorders, and poor levels of fitness. Accordingly, PD is a powerful risk factor for frailty and its consequences, including disability, comorbidity, falls, incontinence, chronic pain, and delirium. Use of levodopa and dopaminergic agonists by older PD patients requires complex dosing schedules; therefore, slow-release preparations are preferred. Both dopaminergic and anticholinergic agents increase the risk of confusion and hallucinations. Use of anticholinergic agents should generally be avoided. For dopaminergic agents, cognitive side effects can be dose limiting.

Diabetes

(See also Chaps. 417, 418, and 419) Both the incidence and the prevalence of diabetes mellitus increase with aging. Among persons ≥65 years old, the prevalence is ∼12% (with higher figures among African Americans and Hispanics), reflecting the effects of population aging and the obesity epidemic. Diabetes affects all four main aging systems that contribute to frailty. Obesity, especially visceral obesity, is a strong risk factor for insulin resistance, the metabolic syndrome, and diabetes. Diabetes is associated with both reduced muscle mass and accelerated rates of muscle wasting. Diabetic patients have an elevated RMR and a poor degree of fitness. Diabetes is associated with multiple hormone dysregulation, a proinflammatory state, and excess oxidative stress. Finally, diabetes-induced neurodegeneration involves both the central and peripheral nervous systems. Given these characteristics, it is not surprising that patients with diabetes mellitus are more likely to be frail and at high risk of developing physical disability, depression, delirium, cognitive impairment, urinary incontinence, injurious falls, and persistent pain. Thus, the assessment of older diabetic patients should always include screening and risk factor evaluation for these conditions.

In young and adult patients, the main treatment goal has been strict glycemic control aimed at bringing the hemoglobin A1c level to within normal values (i.e., ≤6%). However, the risk/benefit ratio is optimized by the use of less aggressive glycemic targets. In fact, in the context of a randomized clinical trial, strict glycemic control was associated with a higher mortality rate. Thus, a more reasonable goal for hemoglobin A1c is 7% or slightly below. Treatment goals are altered further in frail older adults who have a high risk of complications of hypoglycemia and a life expectancy of <5 years. In these cases, an even less stringent target (e.g., 7–8%) should be considered, with A1c monitored every 6 or 12 months. Hypoglycemia is particularly difficult to identify in older diabetic patients because autonomic and nervous system symptoms occur at a lower blood sugar level than in younger diabetics, although the metabolic reactions and neurologic injury effects are similar in the two age groups. The autonomic symptoms of hypoglycemia are often masked by beta blockers. Frail older adults are at even higher risk for serious hypoglycemia than are healthier, higher-functioning older adults. In older patients with type 2 diabetes, a history of severe hypoglycemic episodes is associated with higher mortality risk, more severe microvascular complications, and greater risk of dementia. Thus, patients with suspected or documented episodes of hypoglycemia, especially those who are frail or disabled, need more liberal glucose-control goals, careful education about hypoglycemia, and close follow-up by the health care provider, possibly in the presence of a caregiver. Chlorpropamide has a prolonged half-life, particularly in older adults, and should be avoided because it is associated with a high risk of hypoglycemia. Metformin should be used with caution and only in patients free of severe renal insufficiency. Renal insufficiency should be assessed by a calculated glomerular filtration rate or, in very old patients who have reduced muscle mass, by a direct measure of creatinine clearance from a 24-h urine collection. Lifestyle changes in diet and exercise and a little weight loss can prevent or delay diabetes in high-risk individuals and are substantially more effective than metformin treatment. The risk of type 2 diabetes decreased by 58% in a study of diet and exercise, and this effect was similar at all ages and in all ethnic groups. The risk reduction with standard care plus metformin was 31%.

Effects of Altered Pathophysiology and Multimorbidity on Clinical Decision-Making

The fact that older people are more likely to have atypical manifestations of disease and multiple coexisting conditions has serious consequences for the availability of high-quality evidence for medical practice and clinical decision-making. Randomized clinical trials—the basis for high-quality evidence—have tended to exclude older persons with atypical manifestations of disease, multimorbidity, or functional limitations. Across a wide range of conditions, the average age of a clinical trial participant is 20 years younger than the average age of the population with the condition. Clinical practice guidelines and care-quality metrics are focused on one condition at a time and tend not to consider the impact of comorbid conditions on the safety and feasibility of each set of recommendations. These disease-centric recommendations tend to result in fragmented care. Therefore, clinical decision-making with regard to an older person with multiple chronic conditions must be based on the weighing of several influential factors, including the patient’s priorities and preferences, potential beneficial and harmful interactions among the several conditions and their treatments, life expectancy, and practical issues such as transportation, or ability to cooperate with the test or treatment.

Organization of Health Care for Older Adults

The complex underlying physiology of aging leads to multiple coexisting medical problems and functional consequences that are often chronic, with recurrent exacerbations and remissions. Combined with the social consequences of aging (e.g., widowhood or lack of an available caregiver), these medical and functional factors mandate that older adults must sometimes use nonmedical services to meet functional needs. The end result of these medical, functional, and social factors is that older adults use many health care and social support services in a variety of settings. Thus, it is incumbent on the internist, whether a generalist or specialist, to be familiar with the scope of settings and services that are used by their patients.

For many settings, Medicare reimbursement requires a medical order based on specific indications, so the hospitalist or referring physician must be familiar with eligibility requirements. Table 11-5 summarizes the types of services and payment sources for common settings of care. Older adults who have experienced new disability during a hospitalization are eligible for rehabilitation services. Inpatient rehabilitation requires at least 3 h per day of active rehabilitative activity and is limited to specific diagnoses. More and more rehabilitative services are provided in postacute settings, where the required intensity of service is less stringent. Postacute settings are also used for complex nursing services such as provision and supervision of long-term parenteral medication use or wound care. Under current policy, Medicare covers postacute care only if there is an eligible medical, nursing, or rehabilitation service. Otherwise, nursing home care is not covered by Medicare and must be paid for with personal assets until all resources have been consumed, at which time Medicaid coverage becomes available.

Medicaid is a state–federal partnership whose greatest single expenditure is nursing home care. Thus, the need for chronic daily assistance with personal care in a nursing home consumes a large part of most state Medicaid budgets as well as personal assets. Accordingly, alternatives to chronic nursing-home care are of great interest to states, patients, and families. Some states have developed Medicaid-funded day-care programs, sometimes based on the Program for All-Inclusive Care of the Elderly (PACE) model. In this situation, older adults who are eligible for both Medicare and Medicaid and who are otherwise eligible for chronic nursing-home care can receive coordinated medical and functional services in conjunction with a day-care program.

For most older adults, a caregiver must be available to provide assistance on weeknights and weekends. Under current policy, home health services do not provide chronic functional assistance in the home but rather are targeted at episodes of care supplied by medical or rehabilitative services for older adults who are considered home bound. Some community agencies, whether private or public, can provide homemaker and home aide services to assist the home-bound older adult with functional needs, but there may be income requirements or expensive private payment may be needed.

Within the past decade, there has been tremendous growth in a broad spectrum of assisted-living settings. Such settings do not offer the degree of 24-h nursing supervision or personal aide care that is provided in traditional nursing homes, although distinctions are becoming blurred. Most assisted-living settings provide meals, medication supervision, and homemaking services, but they often require that residents be capable of transporting themselves to a congregate meal site. Moreover, most of these settings accept only private payment from residents and their families and thus are hard to access for older adults with limited resources. Some states are exploring coverage for lower-cost residential-care services such as family care homes.

Models of Care Coordination

The complexity and fragmentation of care for older adults results in both increased costs and increased risk of iatrogenic complications such as missed diagnoses, adverse medication events, further worsening of function, and even death. These serious consequences have led to a strong interest in care coordination through teams of providers, with the goals to reduce unnecessary costs and to prevent adverse events. Table 11-6 lists examples of evidence-based models of care coordination that were recommended in a 2009 Institute of Medicine report. While not mentioned as a specific type of team care, modern information technology offers substantial promise in providing consistent, readily available information across settings and providers. All such team programs are targeted at prevention and management of chronic and complex problems. Evidence from clinical trials or quasi-experimental studies supports the benefit of each model, and for some models data are sufficient to support meta-analyses. The evidence for benefit is not always consistent between studies or types of care but includes some support for improved quality of care, quality of life, function, survival, and health care costs and use. Some models of care are disease-specific and focus on common chronic conditions such as diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, and stroke. One challenge in the use of these models is that a majority of older adults will have multiple simultaneous conditions and thus will need services from multiple programs that may not communicate among themselves.

Most models of care are difficult to implement in today’s health care system because nonphysician services are not reimbursed, nor is physician effort that is not incorporated into “face-to-face” time. Thus, several models have been developed largely by the Department of Veterans Affairs Health Care System, Medicare Managed Care providers, and other sponsoring agencies. Medicare has developed a series of demonstration projects that can expand the evidence base and serve policy makers. More recently, there has been an effort to promote coordinated care through Accountable Care Organizations and patient-centered “medical homes.” However, the processes and outcomes of such care must evolve from disease-specific indicators to more general markers, such as optimizing functional status, focusing on outcomes that are important to patients, and minimizing inappropriate care.

In older adults, prevention tests and interventions are less consistently recommended for all asymptomatic patients. The guidelines fail to address the influence of health status and life expectancy on recommendations, although the benefits of prevention are clearly affected by life expectancy. For example, in most types of cancer, screening provides no benefit in patients with a life expectancy of ≤5 years. More research is needed to build an appropriate evidence base for age- and life expectancy–adapted preventive services. Health behavior modification, especially increasing physical activity and improving nutrition, probably has the greatest potential to promote healthy aging.

Screening Tests

• Osteoporosis: Bone mineral density (BMD) should be measured at least once after the age of 65 years. There is little evidence that regular monitoring of BMD improves the prediction of fractures. Because of limitations in the precision of dual-energy x-ray absorptiometry, the minimal interval between evaluations should be 2–3 years.

• Hypertension: Blood pressure should be determined at least once a year or more often in patients with hypertension.

• Diabetes: Serum glucose and hemoglobin A1c should be checked every 3 years or more often in patients who are obese or hypertensive.

• Lipid disorders: A lipid panel should be done every 5 years or more often in patients with diabetes or any cardiovascular disease.

• Colorectal cancer: A fecal occult blood test and a sigmoidoscopy or colonoscopy should be done on a regular schedule up to the age of 75 years. No consensus guidelines exist for these tests >75 years of age.

• Breast cancer: Mammography should be done every 2 years between the ages of 50 and 74 years. No consensus guidelines exist for mammography after the age of 75 years.

• Cervical cancer: A Pap smear should be done every 3 years up to the age of 65 years.

Preventive Interventions

• Influenza: Immunize annually.

• Shingles: Administer herpes zoster vaccine once after the age of 50 years.

• Pneumonia: Administer pneumococcal vaccine once at the age of 65 years.

• Myocardial infarction: Prescribe daily aspirin for patients with prevalent cardiovascular disease or with a poor cardiovascular risk profile.

• Osteoporosis: Prescribe calcium at 1200 mg daily and vitamin D at ≥800 IU daily.

Exercise

Rates of regular physical activity decrease with age and are lowest in older persons. This situation is unfortunate because increased physical activity has clear benefits in older adults, improving physical function, muscle strength, mood, sleep, and metabolic risk profile. Some studies suggest that exercise can improve cognition and prevent dementia, but this association is still controversial. Exercise programs, both aerobic and strength training, are feasible and beneficial even in very old and frail individuals. Regular, moderate-intensity exercise can reduce the rate of age-associated decline in physical function. The Centers for Disease Control and Prevention recommends that older persons should spend at least 150 min per week in moderate-intensity aerobic activity (e.g., brisk walking) and should engage in muscle-strengthening activities that work all major muscle groups (legs, hips, back, abdomen, chest, shoulders, and arms) at least 2 days a week. In the absence of contraindications, more intense and prolonged physical activity provides greater benefits. Frail and sedentary persons may need supervision, at least at the start of the exercise program, to avoid falls and exercise-related injuries.

Nutrition

Older persons are particularly vulnerable to malnutrition, and many problems that affect older patients can be addressed by dietary modification. As mentioned above, nutrient sensing is the major factor associated with differential longevity in several animal models, including mammals. Treatment with rapamycin, the only pharmacologic intervention that has been associated with longevity, affects nutrient sensing. Nevertheless, there are almost no evidence-based guidelines for individualizing dietary modifications based on differing health outcomes in the elderly. Even when guidelines exist, older people tend to be poorly compliant with dietary recommendations. Basic principles of a healthy diet that are also valid for older persons are as follows:

• Encourage the consumption of fruits and vegetables; they are rich in micronutrients, mineral, and fibers. Whole grains are also a good source of fiber. Keep in mind that some of these foods are costly and thus less accessible to low-income persons.

• Emphasize that good hydration is essential. Fluid intake should be at least 1000 mL daily.

• Encourage the use of fat-free and low-fat dairy products, legumes, poultry, and lean meats. Encourage consumption of fish at least once a week, since there is strong epidemiologic evidence that fish consumption is associated with a lowered risk of Alzheimer’s disease.

• Match intake of energy (calories) to overall energy needs in order to maintain a healthy weight and BMI (20–27). Recommend moderate (5–10%) caloric restriction only when the BMI is >27.

• Limit consumption of foods with high caloric density, high sugar content, and high salt content.

• Limit the intake of foods with a high content of saturated fatty acids and cholesterol.

• Limit alcohol consumption (one drink per day or less).

• Introduce vitamin D–fortified foods and/or vitamin D supplements into the diet. Older persons who have little exposure to UVB radiation are at risk of vitamin D insufficiency.

• Make sure that the diet includes adequate food-related intake of magnesium, vitamin A, and vitamin B₁₂.

• Monitor daily protein intake, which, in healthy older persons, should be in the range of 1.0–1.2 g/kg of body weight. Higher daily protein intake (i.e., ≥1.2–1.5 g/kg) is advised for those who are exercising or are affected by chronic diseases, especially if these conditions are associated with chronic inflammation. Older people with severe kidney disease (i.e., an estimated glomerular filtration rate of <30 mL/min per 1.73 m²) who are not on dialysis should limit protein intake.

• For constipation, increase dietary fiber intake to 10–25 g/d and fluid intake to 1500 mL/d. A bulk laxative (methylcellulose or psyllium) can be added.

Novel Interventions to Modify Aging Processes

Aging is a complex process with multiple manifestations at the molecular, cellular, organ, and whole-organism level. The nature of the aging process is still not fully understood, but aging and its effects may be modulated by appropriate interventions. Dietary and genetic alterations can increase healthy life span and prevent the development of dysregulated systems and the aging phenotype in laboratory model organisms. The mechanisms responsible for life span expansion are “food” sensors typically activated in situations of food shortage, such as IGF/insulin and the TOR (target of rapamycin) pathways. Accordingly, a reduction in food intake without malnutrition extends the life span by 10–50% in diverse organisms, from yeasts to rhesus monkeys. Mechanisms that mediate the effects of caloric restriction are under intensive study because they are potential targets for interventions aimed at counteracting the emergence of the aging phenotype and its deleterious effects in humans. For example, resveratrol, a natural compound found in grape skin that mimics some of the effects of dietary restriction, increases longevity and improves health in mice fed a high-fat diet but has little effect on mice fed a standard diet. Other compounds that potentially mimic caloric restriction are being developed and tested. A high prevalence of IGF-1 receptor gene mutation has been found in Ashkenazi Jewish centenarians and in other long-lived individuals, suggesting that the downregulation of IGF-1 signaling may promote human longevity. A 20-year period of 30% dietary restriction applied to adult rhesus monkeys was associated with reduced cardiovascular and cancer morbidity, reduced signs of aging, and greater longevity, although a second such study did not find increased longevity. In humans, dietary restriction is effective against obesity and reduces insulin resistance, inflammation, blood pressure, CRP level, and intima-media thickness of the carotid arteries. However, the beneficial effects of dietary restriction in humans are still controversial, and some potential negative effects have not been sufficiently studied. An interesting effect of caloric restriction in humans is mitochondrial biogenesis. Mitochondrial dysfunction has emerged as a potentially important underlying contributor to aging. Reduced expression of mitochondrial genes is a strongly conserved feature of aging across different species. Mitochondria are the machinery for chemical energy production, and brain and muscle are particularly susceptible to defective mitochondrial function. Thus, declining mitochondrial function may be a direct cause of at least three of the main dysregulated systems contributing to the phenotype of aging.

This chapter has touched on some of the fundamental aspects of human aging, focusing mostly on those that are relevant to the care of older patients. Many aspects of geriatric medicine have not been addressed because of space limitations. Valuable topics not considered include details of comprehensive geriatric assessment, depression and anxiety, hypertension, orthostatic hypotension, dementia, vision and hearing impairment, osteoporosis, palliative care, prostate disorders, foot problems, and women’s health. Some of these topics are treated extensively elsewhere in this text, sometimes with comments on age-specific issues.

The universal process of aging is becoming better understood. There appear to be shared underlying cellular and molecular processes that induce widespread dysregulation in key systems. This dysregulation contributes to clinical manifestations of a frailty phenotype and can be used to understand how to evaluate and manage the older patient.

We would like to thank our colleagues who provided criticisms and suggestions for improvement of this chapter. We are particularly indebted to Dr. John Morley for his valuable suggestions regarding the section on undernutrition and anorexia.