Aging

Demographics of Aging

Longevity has generally increased during human history, with periods of decline during periods of war, famine, and disease, most recently due to the worldwide coronavirus pandemic. In 2016, longevity ranged from 53 years for the Central African Republic to 84.2 years for Japan. In general, women outlive men. (http://gamapserver.who.int/gho/interactive_charts/mbd/life_expectancy/atlas.html accessed May 5, 2023)

How Did Aging Evolve?

Why isn't aging a negative evolutionary pressure? The greatest effects of aging occur after the reproductive period is over and thus should not have an evolutionary impact, unless...grandparents play a role in childrearing...and collective knowledge and experience has an impact upon survival of humans in groups. Neolithic man had a lifespan of 20 to 25 years. In the last 2000 years the average lifespan hardly exceeded 40 years. Beginning in the 19th century, advances in sanitation, nutrition, and disease prevention began to steadily improve longevity until, in the 21st century, greater prevalence of diseases from excesses (dietary excess, sedentary lifestyle, abuse of drugs) have diminished some of these gains. (Denduluri and Ershler, 2004)

Aging and Health

Aging is NOT a disease, but the changes that occur with aging make aged persons more susceptible to disease.

The theoretical maximum lifespan is 120 years and is not increasing. The ideal maximum lifespan is currently about 85 years. Mostly within the past century, about 80% of the causes of premature deaths have been eliminated, mostly infectious diseases. Changes in lifestyle, such as diet and exercise, may further decrease or postpone chronic illness. Acute illness (infections) can often be prevented (vaccination) or controlled (antibiotics); surgically amenable diseases such as appendicitis are easily treated. Chronic illnesses (heart disease, cancer, stroke) now account for most deaths in developed nations.

The ideal strategy for improving longevity while maintaining quality of life is to compress the incidence of death into a narrow range in old age. This would give persons a long, healthy life and limit major illness to only a few months or years later in life. Expensive medical treatments do not necessarily increase longevity. Policy makers in the future must determine how best to utilize resources (preventive medicine vs acute care vs chronic care)

Theories of Aging

• Cellular Changes: One theory holds that changes at the cellular level are decisive in the aging process. Cell organelles wear out over time. There is cumulative free radical damage to DNA and to proteins with oxidative stress (perhaps due to lack of antioxidants). There is protein degradation through cross-linking of amino acids (same as formaldehyde) and glycosylation (as in cataracts). At the molecular level there is instability of chemical compounds, including proteins undergoing enzymatic and non-enzymatic post-translational modifications diminishing homeostasis and maintenance of structure. We can see that cellular debris in the form of intracellular lipochrome collects (as in brown atrophy of the heart) with aging. (Dyakin et al, 2021) (Polidori and Mecocci, 2022)

• Genetics: Another theory suggests that aging is determined by genetic programming and malfunction. This may be due to a limited number of cellular divisions that can take place. For example, fibroblasts can divide about 50 times, then stop. Other cells may act similarly; the number of divisions is not increased by the time that passes between divisions. There can be errors in DNA replication and repair, with accumulation of mutations or transcription errors. An enzyme called telomerase, which counteracts the tendency of the ends of chromosomes to shorten with each cellular division, may have decreased activity so that the telomeric ends of chromosomes shorten, and the ability of chromosomes to replicate is lost. The process of programmed cell death (apoptosis) may be part of a sequence of cell maturation. Since the risk for cancer in humans increases with age, a possible evolutionary outcome is limiting lifespan to avoid cancer. (Lansdorp, 2022)

• Loss of Homeostasis: Another theory of aging is based upon the observation that there is loss of "organ reserve" capacity, which is normally 4 to 10 times that needed to sustain life. For example, you can live with just half of one normal kidney. Organ reserve diminishes linearly with time after age 30. There is also loss of cellular "complexity" as evidenced by reduced branching of neuronal dendrites, by reduced maximal heart rate, and by loss of pulsatile hormonal release. This decreases the body's ability to react quickly to changes in the environment, or keep body functions in tight control. The result is an inability of the body to cope with--or adapt to--stress or changes in the environment, trauma, or disease states, even if minor. (Dyakin, 2021) (Sahabi et al, 2022)

• Environmental Stress: Stress-induced increases in glucocorticoids over time dampen the feedback response of neuronal steroid receptors in the brain, leading to hypersecretion of corticosteroids. Increased corticosteroid production contributes to immune suppression, osteoporosis, and impaired cognition; T-lymphocyte function also declines. (Dyakin, 2021) (Sahabi et al, 2022)

• Epigenetic Changes: There are portions of DNA called CpG sites that can undergo methylation by a variety of influences external to the genome (epigenetic) and such methylation can alter gene expression. Our genome has millions of CpG dinucleotides where a cytosine precedes a guanine in the DNA strand. These cytosines can be modified by adding a methyl group, called DNA methylation. Regulation of methylation can modify gene transcription. Such genes may be influencers (promoters) of other genes. Epigenetic changes from methylation may represent a clock to impact chronologic age. (Li et al, 2022)

• Neuroendocrine Dysfunction: Aging may be related to changes in hormonal output. The hypothalamic-pituitary-adrenal axis regulates much of development and involution of the reproductive functions. Production of dehydroepiandroterone (DHEA), growth hormone, and secondary sex steroids decrease with age. (Sahabi et al, 2022)

• Nutrition: The one sure way to increase the lifespan of laboratory animals (rodents) is to restrict caloric intake. Observations regarding this phenomenon include: increased free radical production with high caloric intake and decreased cellular mutation rate with decreased caloric intake. (Arafa et al, 2022)

Cellular Senescence

Senescence may involve a dynamic, multistep process affecting cells. This process may occur acutely or chronically. Normal cells with the ability to replicate, such as hepatocytes, may be quiescent and re-enter the cell cycle with proper signaling and growth conditions. Terminally differentiated cells such as neurons cannot re-enter the cell cycle, but remain under physiologic control. During embryogenesis, cells that were part of intermediate steps in development may undergo controlled apoptosis. Stem cells continue replication, but may become exhausted with excessive proliferation, though they are still potentially capable of continued replication.

Acute cellular senescence is a tightly controlled process typical for tissue repair. At the site of injury, connective tissue cells capable of mitotic division enter the cell cycle and proliferate. When healing has occurred, many cells involved in the initial repair response, such as myofibroblasts, undergo apoptosis.

Chronic cellular senescence may involve more complex mechanisms. Activation of the CDKN2A gene locus results in the increased production of the p16INK4a protein, best known as a tumor suppressor protein that inhibits certain cyclin-dependent kinases that initiate the phosphorylation of the retinoblastoma tumor suppressor protein, RB and control the cell cycle. This p16INK4a protein can arrest cells in the G1 phase of the cell cycle. leading to irreversible growth arrest. Affected cells are in a state of permanent growth arrest called cellular senescence. This state may be induced by a variety of stressors. The CDKN2A gene ordinarly becomes activated only at times of cellular damage or stress. Expression of the p16INK4a protein is low in young, healthy organisms but increases with aging. (He and Sharpless, 2017)

Senescence may play a useful role in some conditions. Production of p16INK4a protein following injury with a wound aids in a pro-inflammatory response, but then diminishes with healing. Pro-neoplastic conditions may induce cellular senescence to prevent neoplastic transformation. Atherosclerosis in arteries may be reduced by cellular senescence of plaque macrophages.

The growth arrested, senescent cells are more likely to produce pro-inflammatory cytokines. Senescent cells can suppress apoptosis and clearance of damaged cells and other senescent cells. Diminished immune function with T-lymphocytes producing more p16INK4a protein with aging reduces clearance of senescent cells and reduces T-cell diversity. The accumulation of senescent cells can diminish the ability to respond to cell damage. (He and Sharpless, 2017).

Progeroid Syndromes

The Hutchinson-Gilford Progeria Syndrome, or progeria, is a disease model of aging. This very rare disease is seen in children. The morphologic features of aging are manifested in early childhood, including advanced atherosclerosis. The entire lifespan is compressed into little more than a decade, with average lifespan of just 11 to 13 years. There a mutation in the LMNA gene that produces lamin A protein, which is the structural scaffolding that holds the nucleus of a cell together. Defective Lamin A protein makes the nucleus unstable. (Coppedé, 2022)

Werner Syndrome is also characterized by accelerated cell senescence, but is also known as 'adult progeria' because onset is not until the teen years, with an average lifespan of 47 years. This is a rare autosomal recessive disease characterized by early cataract formation, hair loss, atrophy of the skin, osteoporosis, T-cell immunodeficiency, diabetes mellitus, and advanced atherosclerosis. There is a mutated WRN gene that codes for a DNA helicase important in telomere maintenance and DNA repair and replication. WRN mutations result in the production of truncated proteins lacking the nuclear localization signal. This caretaker gene participates in DNA replication, DNA recombination, telomere maintenance, apoptosis, and DNA repair. Affected cells have increased chromosomal aberrations and premature senescence in culture, as well as accelerated telomere shortening and defects in DNA replication. (Coppedé, 2013)

Organ System Function in Aging

The decreases in organ function observed as persons age could be due to any or all of the following:

• Physiologic deterioration

• Disease processes (something to be prevented or treated by a health care worker)

• Environment (pollution, trauma, sun exposure)

• Lifestyle (diet, drug use, work habits) changes that an individual can make

Here is the graphical analysis of aging:

Thus, functional capacity declines with age. Your maximal heart rate or breathing rate is not as high. You cannot run as fast. Your organ reserve capacity is diminished, but organ failure is NOT a consequence of aging. There is enough function remaining to survive. Physiologic homeostatic controls are not as tight, so heart rate, blood pressure, water excretion, etc are more variable.

Findings in organ systems in aging are described below. It is often difficult to separate disease processes more likely to be seen in older persons from changes that are strictly age-related.

Central Nervous System

Brain function diminishes with aging. There is a gradual loss of neurons in the cerebral cortex. Neurons cannot divide and cannot be replaced. There can be cumulative effects of cardiovascular and cerebrovascular disease. "Strokes" can be due to infarction or hemorrhage. Infarction can occur with thromboemboli, usually from a diseased heart, or from cerebral arterial atherosclerosis. Hemorrhages most typically occur with vascular changes from hypertension.

Past the age of 50 to 60, there is an increased risk for development of Alzheimer's disease (AD). AD is the most common cause for dementia. This disease is due to some genetic factors and mostly unknown factors, but the end result is well-described: increased cortical senile plaques and neurofibrillary tangles along with neuronal loss and gliosis.

Eye

The crystalline lens of the eye becomes less distensible with aging. This decreases the ability of the eye to accomodate vision for near objects. The process is called presbyopia, and it typically becomes noticed when persons reach their 40's. The "cure" is the wearing of glasses with lenses for close focusing--bifocals or trifocals.

Older persons are more likely to develop opacification of the crystalline lens known as a cataract. Such opacification leads to decreased vision.

Ear

With aging comes some degree of hearing loss. This is termed presbycusis. The etiologies include:

• Loss of cochlear structure: the delicate hair cells can be damaged from exposure to loud noises. The ability to hear high-pitched sounds goes first.

• Otosclerosis: the small ossicles fuse together, reducing conduction of sound through bone.

• Nerve dysfunction: the acoustic (8th) nerve may not work as well.

Cardiovascular System

There are physiologic changes that occur with aging. The maximal heart rate and cardiac output decrease. The compensatory mechanisms to support circulation are delayed or deficient, leading to a greater risk for syncope.

There is greater atherosclerosis with advancing years.

Cardiac valvular calcification is more likely to occur in persons past the age of 50. The mitral valve annulus can become calcified, though this is usually not a cause for heart failure. However, calcification of valvular leaflets, typically involving the aortic valve, can produce valvular stenosis. This is called "senile calcific aortic stenosis".

There can be cardiac amyloid deposition with aging, most often on endocardial surfaces.

Urinary Tract

The glomerular filtration rate (GFR) decreases with aging. However, renal reserve is so great that renal failure is not an outcome in aging without the presence of a specific underlying renal disease.

There are more urinary tract infections in elderly women. Women can also experience urinary incontinence with uterine descensus as the ligaments and connective tissues of the pelvis weaken with aging.

Respiratory Tract

Though emphysema is not an aging phenomenon, the environmental insults incurred by the lung over a lifetime lead to mild loss of alveoli, mostly in upper lobes.<.P>

The dusts with carbonaceous pigments breathed in over one's life collect as anthracotic pigment in the lungs and hilar lymph nodes. Small amounts of anthracotic pigment do not produce significant lung disease, but large amounts with environmental exposures may lead to fibrogenesis and restrictive lung disease.

Musculoskeletal System

The muscle fibers are gradually replaced by fat and fibrous tissue, beginning at age 20, at a rate of about 1% of remaining fibers per year. This explains why athletes in power sports have short careers but why persons pursuing skill sports can still keep competing over the age of 60. In some sports that combine muscle strength with skill and tactics, athletes may see continued careers and even improved performance into the late 20's or early 30's.

Hyaline cartilage wears out over time, resulting in osteoarthritis and chronic pain, mostly of larger weight-bearing joints first.

Bone mass decreases as one gets older, particularly past age 40 and particularly in postmenopausal women. Building up bone mass with diet and exercise as a child and young adult provides a large reserve against loss. An abnormal, accelerated form of bone loss is called osteoporosis.

Genital Tract

In women, there is a programmed event of aging known as menopause, which typically occurs in the mid-40's to mid-50's. Menopause leads to atrophy of ovaries, uterus, and breasts. The epithelium of the vagina and vulva also become thinner.

In men, there is decreased spermatogenesis with aging, but not necessarily infertility, and it is possible for a very old man to father a child. Prostatic hyperplasia increases with aging. Risk for prostate carcinoma increases with aging.

Skin

There is loss of skin elasticity with aging, mainly due to thinning of the dermis and loss of elastic tissue fibers (which are not replaced). This produces sagging, wrinkled skin. This process can be accelerated by solar damage from ultraviolet light.

The squamous epithelium of the epidermis becomes thinner and more easily traumatized. This is apparent to anyone who has had experience performing phlebotomy or putting in intravenous access lines in an elderly person.

"Age spots" on the skin of older Caucasians, particularly on the dorsum of the hand, are areas of lentigo senilis. These "senile lentigenes" are usually about 0.5 to 2 cm in size and have light brown pigmentation.

Hematopoietic and Lymphoid Systems

The bone marrow mass decreases with aging. The bulk of hematopoiesis is limited to the ribs, sternum, and vertebrae in the elderly. Though this does not lead to cytopenias in healthy persons, the marrow reserve capacity is reduced when fighting infections or responding to blood loss.

Lymphoid tissues decrease in size with aging, but their functional capacity remains. With infection, it is harder to mount a rapid or large response in an older person. On physical examination, lymph nodes are hard to palpate in adults; thus, any palpable node (particularly a non-tender node) in an adult suggests the possibility of a malignant process. (Sadighi, 2018)

Major Health Problems in the Elderly

The table below delineates some of the major problems that are likely to be seen in elderly patients 65 years of age or more. 80% have at least one, and 68% 2 or more of these conditions.

(https://www.ncoa.org/article/the-top-10-most-common-chronic-conditions-in-older-adults)

Neoplasia and Aging

Both incidence and prevalence of cancer increases with age. Over 56% of all cancers are diagnosed in persons 65 years of age or more. Over the age of 75 years lung, prostate, breast, and colon cancers become more frequent. This may be related to the accumulation of more mutational "hits" in oncogenes and tumor suppressor genes that render them ineffective in growth control mechanisms.

The table below indicates incidence of the top 4 cancers diagnosed in persons 65 years of age and older. (https://www.cancer.org)

Problems in Medical Care for the Elderly

• Resistance to infection decreases

• Tolerance to drugs and toxins is diminished, pharmacodynamics altered (partly from diminished renal and hepatic drug clearance and metabolism functions)

• Healing or recovery from injury or illness is prolonged

• Response to therapy is diminished or prolonged

• "Polypharmacy" is the use of multiple drugs and it increases the risk for a greater number of adverse drug reactions and drug interactions, as well as decreased compliance that lessens the effectiveness of the drugs that are taken.

Prevention of Aging

Choose your parents. The degree of longevity tends to run in families.

Dietary factors have been suggested as one means to increase longevity. Use of antioxidants such as vitamin E or vitamin C has been touted as a means to combat cellular aging and prolong life, but they have yet to be proven effective. This is hard to prove, since so many factors are involved. Special vitamin and mineral supplements (including trace elements such as zinc and selenium) are probably not as important as just an overall good diet. Fiber in the diet has a positive benefit. Intermittent fasting has a positive effect upon health. Avoid foods with added sugar, salt, and fat. (de Cabo and Mattson, 2019)

Continued physical activity is helpful to prolong life and improve the quality of life. Thus, continue to get adequate exercise (use it or lose it).

Maintain mental activity. Persons who remain mentally active, particularly in a social environment, maintain mental function longer.

Choose a good lifestyle. Avoid behaviors that are detrimental to health. Overeating, smoking, and alcoholism are the most common lifestyle choices leading to diseases that increase morbidity and mortality.

References

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