Age-Associated Changes and Biology of Aging

The study of aging is highly pertinent to the practice of physical medicine and rehabilitation for several reasons. First, physiatrists commonly treat persons with diseases of aging (eg, stroke, cancer, osteoporosis, heart disease). It is important for physiatrists to integrate understanding of normative biologic aging into the treatment of superimposed diseases of aging. Second, knowledge about healthy aging is vital for physiatrists because they assist their older patients in adopting healthy practices for maximizing wellness and preventing disease. This knowledge is also useful in the management of geriatric syndromes commonly seen in medical rehabilitation.

Basic concepts in biologic aging

Biologic aging is defined as a combination of processes that are intrinsic to the organism, universal, deleterious, progressive, and cumulative. These processes decrease the individual’s ability to withstand stress and other threats to survival.¹ Therefore, biologic aging occurs in all members of a species, regardless of environmental or cultural differences. Obligatory processes of human aging may be influenced, however, by environmental factors and nonobligatory factors (eg, an individual’s choice not to smoke).² Normative biologic aging is distinct from diseases of aging because diseases of aging are not universal or obligatory.

Chronologic age is not necessarily a good estimate of biologic age. Additionally, aging occurs nonuniformly between organ systems and cell types within an individual and between individuals of a population. With increasing age of a population, there is also increased variability in the characteristics of that population.³

Theories of aging

Despite its universal occurrence, the mechanisms of aging are not fully understood.⁴There are many theories of aging that have been proposed and studied, but none of them alone are able to fully explain the multitude of observations obtained from aging organisms.^1,4Because many theories are based in animal research, they may not have fully congruent application to human aging. However, animal research is important because it has contributed substantially to our understanding of aging biology, including in humans.

Many theories of aging include the premise that aging is associated with decreased ability of the organism to maintain the balance between cellular damage and repair.^1,3,4This loss of homeostasis leads to deterioration of resources in cells, tissues, and organs, and therefore, causes functional decline. Damage may involve deoxyribonucleic acid, proteins, and/or lipids, all of which are vital to cellular function. Damage may be caused by intrinsic factors, such as spontaneous genetic mutations, free radical effects (oxidative stress), or formation of abnormally cross-linked proteins via irreversible binding to sugars (glycation). Extrinsic factors may also play a part (eg, ultraviolet radiation or environmental toxins). The body has finely tuned mechanisms for recognizing such damage and repairing it. In aging, these repair mechanisms are less efficient, with resultant progressive accumulation of aberrantly functioning molecules.

Common physiological responses to cellular stressors may also be involved in aging; such responses include apoptosis, senescence, and repair.³ Apoptosis refers to programmed cell death, which is also a part of human growth and development. Senescence refers to cessation of cell division, which may occur after a specified number of mitotic events (Hayflick limit, telomere shortening theory). Although no longer dividing, senescent cells may secrete cytokines that foster an inflammatory environment. Repair mechanisms involve lysosomes, proteasomes (protein degradation), and autophagy (intracellular destruction of organelles, especially mitochondria).

There are several other theories that incorporate a more systemic approach to aging. The neuroendocrine theory emphasizes the altered stress responses of the aging hypothalamic-pituitary axis.⁴The immune system theory contends that aging is related to the body’s decreased response to pathogens and to altered modulation of inflammation.^4,5Caloric restriction (CR) is a treatment that has brought to light other possible mechanisms of aging.^4,6 CR entails decreasing an organism’s caloric intake by ~25% while maintaining fully balanced nutrition. CR has been shown to increase the lifespan in many species, from single cells to mice and nonhuman primates. The longevity-promoting effects of CR may be mediated through metabolic pathways or through modulation of oxidative stress. Effects of CR in nonhuman primates include lower body weight, increased insulin sensitivity, less adiposity, and healthy serum lipid levels. Although it is not feasible to routinely employ CR for humans, researchers are evaluating possible pharmaceutical use of CR-mimetic compounds (e.g. sirtuins and metformin).⁶

Relevance to clinical practice

Biologic aging changes in humans: a brief summary

The changes subsequently noted are those of normative aging and may decrease physical functioning to a degree but not to the extent found in disease.

Muscle ^7,8 

• The primary condition of aging muscle is sarcopenia. Hallmarks of sarcopenia are muscle atrophy and muscle weakness. Muscle mass may decrease by as much as 1-2% per year after age 50 years; muscle strength may decrease by as much as 1.5% per year after age 50 years, and accelerate to as much as 3% per year after age 60 years. However, severity and age of onset are highly variable across individuals. Muscle tissue may be replaced by connective tissue or fat. Sarcopenia is due, in part, to loss of large, fast-conducting motor neurons in the spinal cord resulting in loss of fast twitch, high force-producing type II myofibers. Resistance exercise can potentially mitigate these changes but cannot fully alleviate them.

Bone^7,9    

• Bone mineral density (BMD) begins to decline in both men and women during middle age. The decline is more prominent in trabecular bone than cortical bone. This bone loss is the result of increased osteoclast activity, with greater bone resorption than formation. The extent of BMD loss is variable between individuals, but can decrease by approximately 0.5% /year after 40 years of age. Postmenopausal bone loss is an accelerated form of aging-related decline in BMD, and may reach a rate of 2-3% per year. Aging bones may be more susceptible to fracture.  Good nutrition, weight bearing exercise and resistance exercise are non-pharmacological measures that may partially lessen the degree of bone loss in healthy older adults.

Joints^7,9     

• Articular cartilage thins because of decreased water content, leading to increased susceptibility to tissue fatigue. Increased connective tissue stiffness from collagen protein cross-linking contributes to increased stiffness of joint structures. Joint active range of motion may decrease; reductions as much as 20-30% have been reported for hip flexion and ankle flexion after 70 yrs of age. Flexibility exercise may assist in improving such limitations. Although osteoarthritis is extremely common in older persons, it is considered a disease of aging rather than a condition of normative aging.

Nervous system^10,11 

• Other topics in the Knowledge NOW geriatric content address this topic in detail. In brief, speed of cognitive processing may decrease, but problem-solving skills remain intact if not tested in a timed setting. Capacity for new learning remains essentially intact. Speed of movement decreases, and postural sway may increase. Decreased drive for physical activity is also observed with aging and is thought to be mediated through the central nervous system; however, the mechanism is not well understood.¹² Sleep is characterized by earlier rising and less total sleep time. Poor sleep may significantly influence performance on cognitive testing, so sleep status should be noted in conjunction with cognition assessment.

Cardiovascular^7,13

• Arterial walls become thickened because of fibrosis and increased collagen cross-linking. This thickening, along with declines in endothelial function, leads to mildly increased systolic blood pressure. Mild stiffening of the heart valves occurs, as does thickening of the left ventricular wall. The numbers of myocytes and pacemaker cells decline. There is no change in heart rate, stroke volume, or ejection fraction at rest. However, exercise responses in aging include lower maximal oxygen consumption and lower maximal heart rate.⁷ Declines in maximal oxygen consumption may reach 9% per Submaximal oxygen consumption and heart rate are less affected, but still are decreased. The aging cardiovascular system can respond to aerobic exercise with positive training adaptations, much the same as in younger individuals, but generally at a slower rate.⁷ Aerobic exercise training may partially mitigate aging-related changes in blood pressure and maximal oxygen consumption.

Lungs¹⁴  

• Decreased elasticity of connective tissue results in decreased alveolar expansion and lessened chest wall excursion. Alveolar surface area may decrease by up to 20%, resulting in less surface area for gas exchange. Weakness of intercostal muscle may occur as a result of sarcopenia. Forced expiration volumes decrease, and there may be small areas of ventilation-perfusion mismatch. In response to these changes, the energy cost of breathing may also increase by up to 120% compared to younger adults. As noted above, aerobic exercise provide a positive training effect on maximal oxygen consumption.

Endocrine^15,16

• Many hormone levels decrease by approximately 1% per year after about age 30 years. Decreased glucose tolerance occurs, and growth hormone (GH) levels decline. Lower GH levels are associated with decreased muscle, bone mass, and altered immune function. Little change is found in thyroid hormone levels. The well-known effects of estrogen depletion in menopause include hot flashes, vaginal atrophy, and bone loss. In men, free testosterone may decrease, resulting in decreases in bone and muscle mass. Secretion of the stress hormone cortisol is increased in aging and can contribute to bone mineral loss and insulin resistance. Although hormone replacement in aging has been studied for growth hormone, estrogen and testosterone, findings have not lead to firm recommendations.

Immune system⁵

• The thymus gland shrinks, and bone marrow produces fewer T cell and B cell lymphocytes. T cell lymphocytes are less responsive to novel antigens, and antibodies may bind to antigens less strongly. Responses to vaccinations are slower and less robust. Activation of inflammation may be heightened chronically. The number of autoantibodies is increased, but the clinical significance of this finding is not clear. Due to these age-related changes in immune function, vaccinations are particularly important for older adults.

Gastrointestinal¹⁷

• Much of gastrointestinal function remains unaffected by aging. Constipation is not a normative change of aging; use of multiple medications and effects of disease contribute more to constipation than aging alone. The liver can be less efficient at metabolizing medications.

Genitourinary¹⁸

• Decreased glomerular filtration rate may occur in the kidneys along with decreased ability to manage fluids and electrolytes. Nephron number and size decrease; renal blood flow can decrease by up to 10% per decade. Bladder fibrosis may lead to small bladder capacity and increased voiding frequency. Partial urethral obstruction from prostate enlargement may contribute to frequent voiding of small volumes. Sphincter and pelvic floor muscles are subject to sarcopenia. Urinary incontinence may be associated with some of these changes, but it is difficult to differentiate effects of aging alone from effects of disease.

Vision¹⁹

• Decreased lens accommodation for near vision leads to presbyopia. There is decreased contrast and color discrimination and slower adjustment to transitions from dim to bright light.

Hearing^10,20

• High-frequency hearing loss may occur and is related to loss of hair cells in the cochlea. Hearing thresholds with pure tone testing may increase by approximately 2 decibels per year. Important speech sounds (s, z, t) may be more difficult to distinguish. Vestibular reflexes may also be slowed.  Excessive environmental noise exposure can add further compromise to age-related hearing changes; therefore minimizing such exposure is vital.

Integument²¹

• Loss of hair pigment and wrinkling of the skin are common. The number and function of sweat glands decrease, and sebaceous glands become less productive. Therefore, drying of the skin and alteration in thermoregulation can occur. Changes of aging skin can be lessened by protection from sun exposure, and by avoiding cigarette smoking.

Pertinence to patient care

When working with older persons, accommodations should be made to facilitate optimal function, comfort, and safety. Slower auditory and verbal processing can be addressed by allowing extra time for an older person to process verbally- presented information, or to learn new tasks. In verbal communication, the speaker should face the listener directly and make sure the lips are visible to the listener.²⁰A quiet environment may facilitate optimal verbal communication. Aging vision can be addressed with environments that incorporate good lighting that avoid glare.¹⁹ Due to altered sweating responses in older persons, and in order to avoid heat or cold injury, attention should be paid to ambient temperature and use of clothing appropriate for the weather.

As previously mentioned, older persons can indeed manifest training responses to endurance and resistance exercise.⁷Such adaptations will likely take longer to develop than in younger persons. Thus exercise programs should be designed to start at lower levels, and to advance more gradually than in younger adults.⁷ Conversely, the consequences of disuse, illness, immobilization, and bed rest may be more severe in an older person because of superimposition of such conditions on the normative changes of aging.

Emerging concepts

Emerging concepts in the study of biologic aging include the effects of noncoding DNA modifications on aging (epigenetics), and the effects of aging on stem cell function. Another emerging concept is the effect of gut microbiota on aging. Changes in gut microbiota have been associated with biological age, and with altered immune system function, sarcopenia, and frailty;^22,23 causal relationships have yet to be clarified.

Gaps in knowledge

Please refer to the previously discussed Theories of Aging section.

Original Version of the Topic

LeAnn Snow, MD. Age-associated changes and biology of aging. 09/20/2014