Aging, Physiological Function and Chronic Disease

Most chronic conditions associated with aging are the result in the diminished ability of cells and tissues in the body to maintain homeostasis, particularly when placed under stress.

Hence, it can be difficult to disentangle normal process of aging from pathological disease

processes. Advancing age is a primary risk factor for a number of chronic conditions, including but not limited to: hypertension, cardiovascular disease, sarcopenia, osteoarthritis, osteoporosis, metabolic syndrome and type 2 diabetes, and cancer.^38-40 In the following sections, aging-related changes in physiological function and their role in the development of the aforementioned conditions are outlined.

2.1.4.1 Cardiovascular Health and Disease

Overall cardiovascular (CV) performance is determined by the integrated function of the arterial and cardiac systems.⁴¹ Progressive changes in CV structure and function occur as a normal part of aging, even in apparently healthy individuals. Age-induced CV changes are often adaptations resulting from changes in other systems in the body. For instance, the overall

function of the CV system is significantly affected by altered functioning of the autonomic nervous system.⁴² Furthermore, certain age-related CV changes differ between men and women, such as alterations in cardiac contractile proteins brought about by reductions in circulating testosterone levels.^42-44 Important changes associated with an aging CV system include increased arterial stiffness, impaired endothelial function, cardiac hypertrophy, altered left ventricular (LV) diastolic function, and diminished LV systolic reserve capacity (Figure 2.4).^41,42,45

Age-related vascular changes

Arteriosclerosis – the thickening and stiffening of the large arteries – is caused by

collagen and calcium deposition and the loss of elastic fibers in the arterial walls.⁴⁴ Although age is the most important contributing factor to arteriosclerosis, the degree to which vascular changes occur can be accelerated by other clinical factors, including hypertension, diabetes mellitus, dyslipidemia and vascular inflammation.⁴⁶ It is thought that these contributing factors act

through a common pathway of increased oxidative stress and vascular inflammation, leading to adverse vascular remodeling and accelerated arterial ageing.⁴⁶

Figure 2.4 Age-related changes in the cardiovascular system.

Adapted from Webb & Inscho, 2009.⁴²

The functional decline in arteriosclerosis is characterized by endothelial dysfunction with significant decreases in nitric oxide and 2-receptor dependent vasodilation, both of which promote vasoconstriction.^42,46 The loss of arterial distensibility resulting from endothelial dysfunction will lead to increases in systolic blood pressure and pulse pressure, which in turn leads to further reductions in arterial compliance.^42,46 In addition to hypertension, arteriosclerosis is implicated in many other CV conditions, including hypercholesterolemia and coronary and peripheral atherosclerosis.⁴⁴ These intermediate conditions may, over time, lead to more complex renal and cerebrovascular issues.

Age-related changes in cardiac structure & function

Increased left ventricular (LV) wall thickness, altered diastolic filling, impaired LV ejection and reduced HR reserve capacity are the most significant age-dependent changes in cardiac function occurring in healthy persons.^45,47 These changes do not necessarily result in clinical heart disease; however, they are likely contributing factors to the increased prevalence of left ventricular hypertrophy, chronic heart failure and atrial fibrillation seen with increasing age.^45,47

Age-related increases in arterial stiffness and the resultant increase in systolic blood pressure leads to progressive increases in LV wall thickness, even in normotensive

individuals.^42,47 Since the change in wall thickness is more pronounced at the interventricular septum than the free wall, the LV becomes less elliptical and more spherically shaped; the consequence of which is a decrease in contractile efficiency and reduced LV systolic reserve.⁴⁴

Changes in diastolic function of the left ventricle are also evident across the lifespan.

Early diastolic filling of the LV peaks during young adulthood and progressively slows with age where at 80 years of age, the rate is approximately 50% of its peak value.⁴² Adequate ventricular filling is maintained through a compensatory increase in atrial contraction which results in augmented LV filling in late diastole thereby sustaining stroke volume and sufficient ejection fraction.^41,42 The delay in LV filling is likely the result of reduced LV compliance due to fibrotic changes to the myocardium and prolonged myocardial contraction resulting from the impairment of calcium accumulation by the sarcoplasmic reticulum.⁴⁴ The increased contribution of the atria to maintain adequate diastolic filling leads to hypertrophy which, over time, may lead to a reduction in cardiac function.⁴¹

Age-related changes in cardiovascular regulation

With aging, autonomic cardiovascular control at rest is relatively well maintained;

however, age-related changes to sympathetic and parasympathetic tone may reduce the ability of the CV system to respond to acute physiological challenges.⁴⁸ Although aging is associated with sustained increases in resting sympathetic nerve activity, sensitivity of catecholamine receptors in the heart and blood vessels are reduced, resulting in diminished vasodilation, heart rate, and cardiac output responses.⁴⁸ These changes result in a decline of approximately 5 ml∙kg^-1∙min^-1 per decade in maximal aerobic capacity throughout adulthood.^45,49

Less understood are changes related to parasympathetic tone and heart rate that are seen with increasing age.⁴¹ Although resting heart rate does not dramatically change with age, the maximum heart rate achievable declines by approximately 30% between 20 and 85 years of age.^42,47 Heart rate variability (variation in the beat-to-beat interval) also declines with age; this is thought to reflect the autonomic dysregulation (specifically, diminished vagal tone) commonly found in older adults.⁴² After the age of 60 years, there is also a marked decrease in the number of pacemaker cells of the sino-atrial node; by 75 years of age the number of cells is 90% less than the number found in a young adult.⁴⁵ In addition, cardiac fibrosis and hypertrophy associated with aging will result in the slower propagation of electric impulse throughout the heart.^41,45

Cardiovascular Aging and Cardiovascular Disease

It is very difficult, if not impossible, to clearly distinguish components of normal

cardiovascular aging from pathological disease processes. In fact, age-associated changes in CV structure and function are the foundation on which cardiovascular diseases (CVDs)

develop.^42,45,50 The relationship between cardiovascular aging and the development of CVD is shown in Figure 2.5.

Figure 2.5 Relationship between cardiovascular aging and the development of cardiovascular disease (Adapted from Lakatta, 2002).⁵¹

Advanced age is an important independent risk factor in the development of several CVDs and risk conditions, including hypertension, ischemic heart disease (IHD), atrial

fibrillation (AF), congestive heart failure and cerebrovascular disease (stroke).^42,50 Among those 65 years of age and older, CVD is a leading cause of death, resulting in 40% of all deaths in this age group.⁴¹ Ischemic heart disease, in particular, is a significant cause of morbidity and

mortality in older adults, with approximately 80% of all deaths from IHD occurring among those aged 65 years and older.⁵⁰ New pharmaceuticals and medical advances along with decreased

CLINICAL PRACTICE THRESHOLD

PREVENTION or PRE-CLINICAL STAGEDISEASE INCREASING AGE

HEART FAILURE

rates of tobacco use have contributed to a decline in the mortality rate due to CVD of

approximately 3% per year since 1960.⁵² However, the costs associated with CVD, both in terms of economic costs and costs to quality of life, continue to be substantial. In 2005, costs related to healthcare (direct costs), lost productivity, disability and premature mortality (indirect costs) due to CVD were estimated to be $21 billion, making it the second-costliest disease in Canada.⁵²

2.1.4.2 Musculoskeletal health and disease

Musculoskeletal health is a key determinant of functional capacity, independent living and quality of life.^40,53 The adequate functioning of the musculoskeletal system provides support and structure to the body, force and strength to move the body, and stability and flexibility in movement. Musculoskeletal aging is a complex process involving atrophy and loss of function in several different tissues – muscle, bone, tendon, ligaments, articular cartilage, and intervertebral disk – along with diminished neuromuscular integrity.⁵⁴ As with the cardiovascular system, it is often difficult to differentiate between the effects of aging, disuse and disease; however, age-related declines in these tissues can have profound effects on the functioning of the

musculoskeletal system, contributing to several chronic conditions that are prevalent among older adults, including sarcopenia, osteoarthritis and osteoporosis.^55,56

Among people aged 65 years and older, musculoskeletal conditions are the most common cause of chronic disability, a situation that is attributable both to the high prevalence of these conditions and the central role of the musculoskeletal system in physical function.⁵⁶ At an estimated cost of $22.3 billion annually, musculoskeletal diseases are the most costly condition in Canada. While the direct costs of musculoskeletal diseases and injury are significant, indirect costs associated with lost productivity, due to disability and/or premature death, account for 75%

of the total economic burden.⁵⁷

Sarcopenia

Skeletal muscle is fundamentally important to all aspects of daily life. Most people take for granted that they will have adequate strength to meet the challenges presented by the countless daily activities such as arising out of a chair, dressing, and bathing that we all encounter each and every day. When a person’s ability to perform these activities is

compromised, maintaining one’s independence becomes very difficult, often necessitating a move to institutionalized care.⁵⁸ This, in turn, can have severe consequences, including social isolation and diminished quality of life.⁵⁹

Sarcopenia, defined as the age-related decline of skeletal muscle mass, strength, and function, is thought to affect over 20% of Canadian older adults aged 60 to 70 years and close to 50% of those aged 75 years and older.^60,61 The loss of muscle mass associated with aging has been thought to be the primary contributor to the gradual decrease (10 – 15% per decade) in muscular strength typically seen with aging. However, longitudinal studies reveal that changes in muscle mass explain only 5% of changes in muscle strength, suggesting that other factors, in addition to muscle mass, contribute to muscle weakness.⁶² These other age-dependent changes in muscle tissue are outlined in Table 2.1. While these sarcopenic changes begin around the age of 30 years, they are rarely functionally significant in healthy individuals until approximately 60 years of age.³²

Table 2.1 Age-related anatomical changes in muscle.

1. Decreased muscle mass and cross-sectional area 2. Infiltration of fat and connective tissue

3. Decrease in type II fiber size with no change in type I fiber size 4. Decrease in type I and type II fiber number

5. Accumulation of internal nuclei, ring fibers, and ragged fibers 6. Disarrangement of myofilaments and Z-lines

7. Proliferation of the sarcoplasmic reticulum and t-tubular system 8. Accumulation of lipofuscin and nemaline rod structures 9. Decreased number and size of motor units.

Adapted from Kamel, 2003; Muscaritoli et al, 2010 ^63,64

The cause of sarcopenia is multi-factorial in nature, with age-related molecular and hormonal changes, neurological decline, increased inflammation, insulin resistance, chronic diseases, sub-optimal nutrition and declines in physical activity among the factors thought to contribute to the accelerated loss of muscle mass and function (See Figure 2.6).60,61,65,66

Sarcopenia is a feature of several other chronic conditions including disease-related cachexia (e.g. in cancer or end-stage renal disease), osteoarthritis, and sarcopenic obesity.⁶⁵

Figure 2.6 Mechanisms of sarcopenia. Adapted from Cruz-Jentoft et al, 2010.⁶⁵

While there is currently no broadly accepted clinical definition of sarcopenia, a recently proposed system classifies and stages sarcopenia based upon the causal factors involved and the functional severity of the condition.^64,65 Primary sarcopenia is associated with aging itself, with no other evident cause identified while in secondary sarcopenia, one or more causes besides aging are present. Once classified, staging criteria are applied to describe the functional severity of the condition. These are outlined in Table 2.2.⁶⁵

SARCOPENIA

Table 2.2 Conceptual stages of sarcopenia

Stage Muscle mass Muscle strength Performance

Pre-sarcopenia ↓ – –

Sarcopenia ↓ ↓ or ↓

Severe sarcopenia ↓ ↓ ↓

Adapted from: Cruz-Jentoft et al, 2010.⁶⁵

The strength and functional declines associated with sarcopenia are serious and life-altering, with significant individual and societal impacts. Loss of strength and mobility deficits are associated with impaired balance, an increased risk of falls and bone fractures, significantly increased risk of disability, and frailty.^59,61,66 The risk of disability is 1.5 to 4.6 times higher in older persons with sarcopenia than in older persons with normal muscle.⁶⁷ In 2000,

approximately $18.5 billion, or 1.5% of total direct healthcare costs in the United States were attributable to sarcopenia.⁶⁸

Osteoarthritis

Osteoarthritis (OA) is the most common joint disorder in the world and is the most frequent source of pain and disability among older adults.^55,69,70 It is characterized by slow and progressive degradation and loss of articular cartilage in synovial joints with concomitant hypertrophy of the underlying bone and thickening of the joint capsule.^54,69,71 Structural changes to the joint are evident as early as the 3^rd decade of life and most people have osteoarthritic changes in at least one joint by the age of 70 years.⁷¹ Osteoarthritis is most commonly seen in the hip and knee joints along with the joints of the hands, feet and spine. Before 50 years of age, the prevalence of osteoarthritis is higher in men than in women across most joints while after the age of 50, women are more often affected with hand, foot, and knee osteoarthritis than men.^70,72

While OA is considered a ‘classic’ age-related disorder, the literature currently

conceptualizes the relationship between aging and OA be that of increased joint vulnerability and disease susceptibility, rather than one of a causal nature.⁷⁰ Genetic factors, anatomical structure, obesity and joint injuries are also contributing factors to the development of symptomatic

OA.^55,70,71 The relationship between musculoskeletal aging and the development of OA is shown in Figure 2.7.

Figure 2.7 Relationship between musculoskeletal aging and the development of osteoarthritis.

Adapted from Anderson & Loeser, 2010.⁵⁵

As a leading cause of disability in Canada, osteoarthritis presents a significant economic burden, which is expected to grow exponentially over the next 30 years. The annual direct and indirect costs of arthritis (both osteoarthritis and rheumatoid arthritis) are in excess of $6

billion.⁷³ Recent estimates suggest that the total economic cost of arthritis exceeds $33 billion annually and this is projected to grow to more than $894 billion by 2030.⁷⁴

Osteopenia/Osteoporosis

Osteoporosis is characterized by low bone mass along with changes to the bone micro-architecture that together, increase bone fragility and susceptibility to fracture.^69,75 Age-related deterioration in bone composition, structure and function leads to a predisposition to

osteoporosis, particularly in women. The loss of bone mass (osteopenia), and an associated reduction in bone strength occurs when the normal processes of bone remodeling become unbalanced in favor of bone resorption.^76,77 Aging, along with several intrinsic and extrinsic factors all impact the rate of decline in bone loss and are outlined in Table 2.3.⁷⁶

Table 2.3 Intrinsic and extrinsic factors affecting bone mass.⁷⁶

Intrinsic Factors Extrinsic Factors

 Age

 Genetics

 Peak bone mass accrual in youth

 Cellular changes

 Hormonal, biochemical, & vascular status

 Nutrition

 Physical activity

 Comorbidity

 Drugs

Age-related bone loss is a complex process, resulting from multiple cellular level changes affecting trabecular bone, cortical bone and bone marrow.^77,78 The onset and triggers of age-related bone loss (outside that age-related to menopause) remain poorly understood.⁷⁶ Bone remodeling is a lifelong continuous cycle between osteoblasts (new bone deposition) and osteoclasts (bone resorption). After reaching peak bone mass and size early in the third decade, the rate of bone turnover slows, and bone mineral density begins to decline by approximately

0.5% per year, even though serum levels of estrogens are still within the normal range.⁷⁸ In women, the menopausal transition is associated with a period of accelerated bone loss (2% to 3%

per year) that may persist for up to 10 years post-menopause.^76,79 The overall consequences of the shift in remodeling favoring resorption are thinning of cortical and trabecular bone, increased cortical porosity, and loss of trabecular connectivity, all of which reduce bone quality and bone strength.⁷⁶ The mechanisms involved in this process are summarized in Table 2.4.

Table 2.4 Mechanisms of age-related bone loss⁷⁶

Mechanism Result

Secondary hyperparathyroidism

 Vitamin D deficiency impairs calcium absorption, stimulating increased parathyroid secretion

 Chronic negative calcium balance due to age-related reductions in dietary intake

 Impaired renal function

 Use of diuretics

 Estrogen deficiency

 Decreased osteoblastogenesis (vitamin D)

 Increased osteoclastic activity leading to cortical bone loss

Sex steroid deficiency Women

 Decreased serum estradiol levels at menopause Men

 Decreased serum testosterone

 Decreased serum estradiol levels^*

 Increased osteoclast formation and osteoclastic activity

Increased adipogenesis in bone marrow

 Age-related changes in recruitment of

mesenchymal stem cells, release of key growth factors, activation of transcription factors, oxygen tension and blood supply in the bone marrow

 Differentiation of stem cells into adipocytes at the expense of osteoblasts

* Estrogen deficiency is more strongly correlated with bone loss than testosterone loss in aging men

Osteoporosis is a silent disease, often undiagnosed and asymptomatic until an incident fracture occurs, typically as a result of low-energy trauma.^69,80 Osteoporotic (or fragility)

fractures are significantly more common in women than men, accounting for 80% of all fractures in women over the age of 50 years.^69,81 The vertebrae, femoral neck (hip) and distal radius are

highly susceptible to fracture in older adults with osteoporosis. Vertebral and hip fractures, in particular, present a significant issue for older adults. Vertebral compression fractures can lead to height loss, kyphosis and significant pain, with the potential to impair pulmonary or

gastrointestinal function and/or severely limit a person’s ability to carry out activities of daily living such as bathing, dressing, or walking independently.⁵⁶ Hip fractures are associated with significant long-term morbidity, with fewer than 50% of older adults experiencing a full, functional recovery and approximately 25% residing in long-term care facilities for a year or more following a hip fracture.^69,82 Recent Canadian studies have shown that both hip and

vertebral fractures are associated with increased mortality (adjusted hazard ratios of 2.7 – 3.2) in the first (hip) and second (vertebral) year following fracture.^83,84 Morin et al (2011) found that in certain age groups (women aged 50-69; men aged 60-69), the relative risk of death remained elevated beyond five years. These findings suggest that hip and vertebral fractures may have long lasting effects that signal or induce a progressive decline in health, eventually leading to death.^83,84

In 2009, approximately 19% of Canadian women and 3.5% of Canadian men aged 50 years and older were diagnosed with osteoporosis while at age 70 years and older, 31% and 6.5%

of women and men, respectively reported having been diagnosed.²⁵ The direct and indirect costs of osteoporosis are substantial, totaling more than $2.3 billion as of 2010. If the proportion of people assumed to be living in long-term care facilities due to osteoporosis is factored in, the cost rises to $3.9 billion.⁸⁵

2.1.4.3 Metabolic function and health

Beginning around age 25–35 years, there is a slow and progressive decline in the levels of most hormones, brought about by decreased hormone synthesis along with a loss of hormone receptors.⁸⁶ Circadian rhythmicity is also altered in a slow but progressive manner, often

resulting in disturbances to the sleep-wake cycle.^87,88 Consequently, overall endocrine function declines and homeostatic regulation across all physiological systems is diminished.⁸⁹ With regards to metabolic function, the key age-dependent changes include physiological declines in sex hormones (estrogens and androgens), growth hormone (GH), and insulin-like growth factor-1 (IGF-factor-1), insulin resistance and changes in body composition.⁸⁹

At mid-life, around age 35-40 years, circulating testosterone levels in men begin to decline by 1%-3% per year, while in women, estrogen levels decrease by an average of 80%

during the first year of menopause.⁹⁰ Serum androgen levels in women and estrogen levels in men also decrease with age, although their biological roles in these instances are less

understood.⁹⁰ The declines in estrogens and androgens experienced by women during the

understood.⁹⁰ The declines in estrogens and androgens experienced by women during the

In document Cross-sectional and longitudinal relationships between physical activity and health services utilization in community-dwelling older adults (Page 35-55)