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Overview and Description

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, defined as diseases for which aging is a risk factor (e.g., stroke, cancer, osteoporosis, heart disease). It is important for physiatrists to integrate their understanding of normative biologic aging into the treatment of superimposed diseases of aging. Second, knowledge about healthy aging is vital for physiatrists in order to assist their older patients in adopting lifestyle practices to maximize wellness and prevent 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 (e.g., 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.

Advances in aging research have led to the proposal and revision of the “hallmarks of aging”, a concept which has been widely accepted in the scientific community since its introduction in 2013.5 The hallmarks, revised in 2023, now represent the findings of nearly 600 studies of the cellular and molecular processes contributing to aging. The first group of processes are those that accumulate with time and only fuel the aging process. These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, and disabled macroautophagy. The second group are composed of stress responses that have a nuanced affect, often beneficial to the cell at low levels but damaging at high levels. These processes are deregulated nutrient sensing, cellular senescence, and mitochondrial dysfunction. The final group comes into play once the cell can no longer compensate for damage. These processes affect tissue homeostasis and function and include stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis.6

The hallmarks of aging are functionally quite closely related.  However, it has been shown that age-related diseases associated with one hallmark tend to share genomic characteristics and occur in conjunction with other diseases associated with the same hallmark.7 This supports the distinguishing of these interconnected processes in our understanding of and approach to aging.

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.4 The immune system theory contends that aging is related to the body’s decreased response to pathogens and to altered modulation of inflammation.4,8 Caloric restriction (CR) is a treatment that has brought to light other possible mechanisms of aging.4,9 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).9

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.


Sarcopenia is the age-related decline of skeletal muscle mass combined with progressive decline in muscle strength and function. Risk factors include age, a sedentary lifestyle and low BMI with prevalence reaching up to 29% in the community. Hallmarks of sarcopenia are muscle atrophy and muscle weakness, mainly driven by the size and number decline of type II muscle fibers with intramuscular and intermuscular fat infiltration 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. Resistance training has been shown to be the most effective way of mitigating sarcopenia in an easily accessible, non-pharmacologic manner. Regular resistance training consistently improves body composition, drives muscular hypertrophy and improves appendicular skeletal muscle function. Incorporating a high protein diet (rich in the amino acid leucine), adequate vitamin D intake and polyunsaturated fatty acids have shown efficacy in maintaining muscle mass and function.  


Maximum bone size and strength is termed peak bone mass and is influenced by both genetic factors and lifestyle factors such as resistance training and diet. Peak bone mass is achieved typically between ages 25-30. Risk factors for increased bone loss include, smoking, sedentary lifestyle, calcium and vitamin D deficiency and long-standing glucocorticoid use. Bone mineral density (BMD) begins to decline in around age 40 in both men and women with accelerated loss in women during the three to five years following menopause 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. Weightlifting exercises are particularly effective in inducing tensional stimuli to bones which produces an osteogenic response. Exercises with heavy axial loading such as deadlifts and squats have been particularly effective in improving bone density parameters in the lumbar spine, femoral neck and pelvis.


Articular cartilage undergoes various changes during the aging process. There is a decrease in water content and proteolytic fragmentation of collagen by collagenases leading to a decrease in tensile strength.   Additionally, alterations in the 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 years of age. Flexibility exercise may assist in improving such limitations. Loss of collagen in the intervertebral discs contributes to disc height loss, with possible collapse and compression of spinal structures. This is driven mainly by the increased autophagy and senescence of specialized cells responsible for maintaining the hyper-hydrated extra-cellular matrix of the nucleus pulposus leading to a substantial decrease in weight bearing capacity.   Although osteoarthritis is extremely common in older persons, it is considered a disease of aging rather than a condition of normative aging.

Nervous system16,17,18,19,20  

Other topics in the Knowledge NOW geriatric content address this topic in detail. From an anatomic standpoint, brain aging is characterized by brain volume loss, cortical thinning, and ventricular enlargement. Risk factors for accelerated age-related changes include, hypertension, Type II diabetes, small vessel disease and hyperlipidemia. Age related changes in cognition affect multiple realms of memory and intelligence.  Crystallized intelligence refers to skills and knowledge that is overlearned and familiar. Crystallized intelligence typically stays stable through normal aging and may even improve slightly in the sixth and seventh decades of life. Fluid intelligence is the ability to problem solve and learn new skills; it comprises of executive function, memory and processing speed all of which typically peak in the third decade of life and slowly decline thereafter.  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.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 aging is driven by several mechanisms and is a cause of substantial mortality and morbidity in patients over the age of 65.  With normal aging, the aorta and systemic vasculature stiffen due to an increased deposition of collagen and concurrent breakdown of elastin. This increased stiffness causes an isolated rise in systolic blood pressure leading to left ventricular hypertrophy and increased myocardial oxygen demand. Systemic hypertension also disrupts myocardial vasculature leading to further perfusion deficits. A. 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.10 Declines in maximal oxygen consumption may reach 9% per Submaximal oxygen consumption and a substantial decrease in maximal heart rate. 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.10 Aerobic exercise training may partially mitigate aging-related changes in blood pressure and maximal oxygen consumption. Zone II or low intensity steady state cardio (LISS) exercise has unique benefits in improving cardiac parameters, improving body composition and lowering blood pressure. It is done at 70-80% of maximal heart rate and at lower impact state making it an effective and accessible intervention to employ in an aging population.


Lung aging is a highly complex process and is influenced by the mismatch between accumulated damage and cellular repair processes. There is a decrease in stem cell reserves, accumulated oxidative damage and a decrease in mitochondrial function, all of which contribute to an inability to maintain baseline homeostasis. 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 provides a positive training effect on maximal oxygen consumption.


Many hormone levels decrease by approximately 1% per year after about age 30 years. Thyroid axis activity decreases with age resulting in an increase in TSH and decrease in T3. There is controversy as to whether these changes are detrimental or beneficial. Regardless, these changes likely lead to over treatment of older adults necessitating establishment of age-specific hormone reference ranges. 

Declining growth hormone levels are associated with decreased muscle and bone mass, increased adipose tissue, and altered immune function. GH replacement therapy has been shown to have positive effects in hormone deficient patients. However, given that there is some evidence to suggest GH receptor inhibition may serve as a protective factor against age-dependent cognitive decline, more research is needed to justify its use in treatment of older adults. 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 estrogen and testosterone, findings have not led to firm recommendations.

Immune system8,28

The thymus gland shrinks, and bone marrow produces fewer T cell and B cell lymphocytes.  T cell lymphocytes are less responsive to antigens and overall response to vaccinations is slower and less robust. Activation of inflammation may be heightened chronically. Antibodies bind to antigens less strongly and there is an increased number of autoantibodies. In fact, these changes are so reliable that immune age can be measured through age associated patterns in antibody production. Moreover, new data suggests that an immune age greater than chronological patient age, or accelerated immune aging, is associated with autoimmunity, autoinflammatory disease, and acute disease flares.


The esophagus changes anatomically with muscular hypertrophy of the upper 1/3 accompanied by decreased peristaltic response. The lower esophageal sphincter develops impaired relaxation during swallowing which can predispose people to dysphagia. Additionally, sensation of distension and clearance of refluxed food or acid become impaired. The stomach becomes more sensitive to gastric irritants and heals more slowly.

The small and large intestine both begin to atrophy with age. Colonic hypomotility increases transit time and over time can contribute to constipation and diverticula, neither of which are normative processes of aging.   Liver mass and perfusion decrease but function remains mostly intact aside from slowed metabolic clearance of CYP450 drugs.


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. Cystatin C, rather than creatinine alone, can be used to more accurately measure kidney function in older adults generally defined as age 60 or older. Moreover, multiple studies now support Cystatin C as a marker for trajectory of the ageing process, physical performance, and functional decline as a whole. This suggests potential for significant utility in rehabilitation evaluation and management.  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.


Sensitivity of the cornea decreases by 50% making injuries more difficult to identify. Lacrimal gland function decreases, but inefficient drainage due to punctum positioning increases causing both dry and watery eyes. Decreased aqueous and vitreous humor can present as flashes of light. Increased rigidity of the lens and weakening of the ciliary muscle causes presbyopia or impaired near vision. Changes to the lens also increase scattering of light, increasing sensitivity to glare and causing difficulty with activities like night driving. There is also decreased contrast and color discrimination and slower adjustment to transitions from dim to bright light.


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. Hearing loss can result in decreased cognitive sensory input and impact memory formation. This can mimic early dementia which is important to distinguish. Hearing loss can also result in progressive social isolation and impact mood and depression.


The rate of skin cell turnover decreases by 50% leading to thinning of the epidermis. This presents visually as wrinkling, loss of elasticity, and altered pigmentation. The number and function of sweat glands decrease and sebaceous glands become less productive. Thus, 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.36 A quiet environment may facilitate optimal verbal communication. Aging vision can be addressed with environments that incorporate good lighting that avoid glare.35 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.

Older patients are particularly invested in preserving their independence and quality of life (QOL). Austin et al. Found 200 patients enrolled in a 24 week aerobic and resistance training regimen reported significant increases in QOL along with improved physiological parameters.39 As previously mentioned, older patients can indeed manifest training responses to endurance and resistance exercise.10 Such 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.10 Physiatrists are uniquely positioned to help educate elderly patients on the immense health benefits of exercise and resistance training. There are simple ways to incorporate exercise in even the most sedentary individuals and physiatrists should make an active effort to provide patients with home exercise programs and resources for basic resistance training. Time should be spent to empathize with patients and inform them that the benefits of exercise can be reaped without the need of expensive equipment and be initiated with a simple routine such as rigorous walking.40 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

Although there is no FDA approved pharmacologic that addresses longevity and the effects of aging, rapamycin shows initial promise by modulating the mTOR network. The mTOR network is an evolutionary, conserved signaling hub that integrates environmental and intracellular growth signals to carry out a multitude of cellular responses ranging from proliferation, growth, apoptosis and inflammation. Rapamycin binds and inhibits the mTOR1 complex and is the only pharmacologic agent shown to increase lifespan and improve physiological parameters of aging. This offers a mechanistic target for future research and understanding this target might provide novel approaches to improve longevity and aging in humans.41

It is becoming increasingly important to recognize the role exercise and resistance training plays in ameliorating the various forces of aging as evidenced by the various clinical correlates highlighted in this chapter. It is vital to recognize the emerging evidence to incorporate creatine monohydrate supplementation in elderly patients as a synergistic addition to exercise. Creatine monohydrate is one of the most studied supplements and has a long-proven track record of improving muscular strength, performance, size and energy output. Briefly, creatine is a naturally occurring, nitrogenous compound that allows for increased ATP regeneration in skeletal muscle during high demand activities via donation of phosphate groups. Its safety and efficacy in younger populations has been well researched and documented. However, there is emerging evidence to suggest its utility in improving performance parameters in elderly patients. It can mitigate the effects of sarcopenia when paired with resistance training, improve cardiopulmonary fitness and might possibly improve cognitive abilities as well. The brain is a disproportionately energy expensive organ and creatine supplementation increase brain phosphocreatine content. There is emerging evidence to suggest this ability to expedite ATP regeneration through the rapid immobilization of phosphate groups in the brain might improve multiple realms of cognition, symptoms of depression and tasks requiring short term memory. There is also preliminary evidence to suggest it may slow the progression of neurodegenerative disorders (RCTS with longer follow-ups and defined end outcome measures needed).

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;42,43 causal relationships have yet to be clarified.’

Gaps in Knowledge

Please refer to the previously discussed Theories of Aging section.


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Original Version of the Topic

LeAnn Snow, MD. Age-associated changes and biology of aging. 9/20/2014

Previous Revision(s) of the Topic

LeAnn Snow, MD. Age-associated changes and biology of aging. 1/6/2020

Author Disclosure

Tracy Friedlander, MD
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Arvind Senthil Kumar, MD
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Soumya Mishra, BS
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