Aging is described as the accumulation of detrimental changes in cells of the body caused by both internal and external influence. All major systems of the body are directly or indirectly affected by aging, particularly the immune, endocrine and musculoskeletal systems. Immunosenescence is an alteration in the functioning of the immune system that leaves an individual more susceptible to disease, which increases the risk of morbidity and mortality. Senescence of the endocrine system affects three hormonal systems leading to menopause/andropause, adrenopause and somatopause.. In the musculoskeletal system, senescence leads to profound loss of muscle mass and strength, also referred to as sarcopenia, as well as decreased bone mineral density and bone tensile strength. Due to the advances in medicine the elderly population continues to rapidly increase. Therefore, it is important to investigate the cellular mechanism involved in normal and pathological aging, in order to promote longevity and increase quality of life. The purpose of this paper is to provide the general population the fundamental knowledge of the affects of aging on cellular mechanisms.
Aging causes a gradual involution of the thymus reducing its size to “only 5-15% of its maximal size” by 45 to 50 years of age. Most of the decline in immune system function is a direct result of degradation of the thymus. A complete cessation of thymic hormone production is evident by age 60. Along with diminished T cell proliferation and function, specific antibody responses decrease by up to 80%. Additionally, phagocytic function declines steadily with advancing age. Endocrine changes within the body generally occur gradually with age. For example, anterior pituitary secretion of hormones decline 14% with each decade of life and adrenal hormones peak in the mid-20s then gradually decline with age. The exception to this gradual decline rule is reproductive hormone secretion, particular female sex hormones which take a dramatic plunge after menopause. Bone density reaches peak an adult’s 20’s and remains stable for 2 decades. Calcium loss is 1% per year after 35 for women and men lose 10-15% by age 70. Muscle mass is lost at a rate of 4-6% per decade starting at age 40 in women and 60 in men. 80% of the population age 60 or older shows evidence of degeneration of thinning of articular cartilage. Connective tissue, such as fascia, ligament, and tendon changes are thought to start around the same time as changes in bone and muscle take place.
Aging is a multifactorial condition characterized by a decreased tolerance in the body's ability to respond to stress and maintain homeostasis, therefore resulting in tissue degeneration and malfunction. In the United States, the older population (those over the age of 65 years) has rapidly increased and will continue to do so. Currently there are 38.9 million people over the age of 65 in the United States equaling about 12.8% of the population. This estimate is expected to increased to 71.5 million (about 21%) by the year 2030. Recently the elderly population in the United States has been divided into three sub-categories. "Young old" are those people 65-74 years; "old" is 75-84; and "very old" is considered 85 years and over..
Table 1. Population by Age and Sex: 2008
|Under 55 years||229,014||76.6||115,014||78.3||113,999||74.9|
|55 to 59 years||18,371||6.1||8,929||6.1||9,442||6.2|
|60 to 64 years||14,931||5.0||7,150||4.9||7,781||5.1|
|65 to 69 years||11,165||3.7||5,238||3.6||5,928||3.9|
|70 to 74 years||8,423||2.8||3,740||2.5||4,683||3.1|
|75 to 79 years||7,353||2.5||3,200||2.2||4,154||2.7|
|80 to 84 years||5,559||1.9||2,106||1.4||3,453||2.3|
|85 years and over||4,289||1.4||1,479||1.0||2,810||1.8|
(Numbers in thousands. Civilian noninstitutionalized population1)
US Census Bureau. http://www.census.gov/population/socdemo/age/2008_older_table1.xls. Updated 3/26/2007. Accessed 2/24/2010.
|Table 2. Death rates by 10-year age groups: United States and each state, 2006|
|[Rates per 100,000 population in specified group. Rates are based on populations estimated as of July 1, 2006]|
|Age||45-54||55-64||65-74||75-84||85 and over|
CDC/NCHS. Death rates by 10-year age groups: United States and each state, 2006. http://www.cdc.gov/nchs/data/dvs/MortFinal2006_Worktable23r.pdf. Updated 2/17/2009. Accessed 2/24/2010.
The immune system is comprised of the adaptive and innate systems. Innate immunity is the body’s first line of defense and is focused on preventing the entry of pathogens. This system is composed of two nonspecific systems, the skin and its mucosal barriers, and a nonspecific inflammatory response. Acquired immunity is a more specific line of defense and is able to recognize and destroy foreign substances. Aging affects both the adaptive and innate systems, although modifications from aging are more detrimental to the adaptive system due to the sophistication and specificity of the system.
Innate Immune System
The innate immune system contains all the immune defenses that lack specificity and memory. This explains why the innate immune system responds in the same manner no matter how many times the antigen is encountered. Innate immunity is carried out by a variety of phagocytic cells such as neutrophils, monocytes, macrophages, and dendritic cells; inflammatory mediators such as basophils, mast cells and eosinophils; and natural killer cells. Together these cells allow the innate immune system to identify and destroy antigens. The innate immune system does not respond to every individual antigen, but rather has developed a strategy to focus on a few structures present in large groups of microorganisms. These structures are called pathogen recognition receptors and allow the innate immune system to differentiate between potentially harmful microorganisms and self-constituents. This allows the innate immune system to function more efficiently since it only has to recognize a few structures rather than each individual pathogen.
The innate immune system also comprises external defenses such as skin and mucous membranes. This is the first and best line of protection as it prevents pathogens from entering the body. Openings in the skin are susceptible to pathogen invasion, which is why most natural openings have developed their own methods of protection. Tears contain lyxozymes that kill bacteria, waxy secretions in the ear canal and nasal hair trap and prevent bacteria from advancing inside, stomach acid for ingested organisms, acidic urine and acidic vaginal secretions all help defend against pathogens at skin openings. Immunosenescence decreases the effectiveness of these defenses. The dermis becomes thinner, loses elasticity, has increased wrinkles, and has diminished vascularity. Bruising and age spots appear more frequently due to decreased tissue support for capillaries.  Aging also decreases the ability of the skin to detect touch, temperature and pressure through the reduction of specific peripheral receptors. Meissner's corpuscles (touch-texture receptors), pacinian's corpuscles (pressure-vibration receptors), and krause's corpuscles (temperature receptors), as well as peripheral nerve fibers have been shown to decease with age. All these age related changes lead to a decreased ability of the skin to ward off pathogens from entering the body.
When organisms do enter the body by means of the epithelial, respiratory, gastrointestinal or genitourinary systems, the innate immune system has secondary defenses to offer additional protection. These biochemical defenses include acid secretions, lysosomes, phagocytes and natural killer (NK cells). As previously mentioned, acid secretions can be found in the GI tract, urine and vaginal canal. Aging decreases the acidity of the secretions rendering the body more susceptible to infection. In addition, the bladder becomes less elastic which causes urine retention. The combination of urine retention and decreased acidity of secretions leaves the body more susceptible to infection.
Phagocytes are another important part of the secondary defenses of the innate immune system and are programmed to destroy microorganisms such as bacteria or fungi. The two main phagocytes are neutrophils and monocytes although there are five types of phagocytic leukocytes (neutrophils, eosinophils, basophils, monocytes, and lymphocytes). Neutrophils respond to infection and inflammation by directly destroying invading organisms via phagocytosis. Monocytes can be found circulating in the blood looking for sites of inflammation or infection. Once a suitable site has been located, monocytes mature into macrophages. Macrophages clear up the debris produced by the neutrophils as well as destroy any bacteria that were too large for the neutrophils. Macrophages also act as antigen-presenting cells (APCs) to introduce the pathogen to lymphocytes. During the introduction of the pathogen to the T4 lymphocyte, a chemical messenger interleukin-1 is released by the macrophage to help the T4 lymphocyte identify the antigen. Lymphocytes then stimulate the specific immune response.
Phagocytes are negatively affected by aging and their effectiveness within the innate immune system is greatly reduced. With monocytes there is a decrease in total numbers, surface expression (TLR4), upregulation (TLR-induced), signaling in macrophages, and phagocytosis. Toll-like receptors (TLR) are receptors for portions of pathogens and are expressed on a wide variety of cells in the immune system, including antigen-presenting cells. Activation of TLR is a crucial role in linking innate and adaptive immune responses as it results in proinflammatory cytokine responses and upregulation of interferon type I IFN. As monocytes decrease in number, effectiveness, and in expression of TLR, the link between the innate and adaptive immune systems is weakened.
Neutrophils are also affected by aging. Various functions carried out by neutrophils, including synthesis of reactive oxygen intermediates, phagocytic capacity, and intracellular killing efficiency are all shown to be negatively impacted by aging in elderly humans. To further understand the effects of aging on neutrophil functioning, murine studies have been conducted. Recent evidence suggests that neutrophils increase progressively as mice age, and that functions of the neutrophils were unaltered. This finding was duplicated by work from Murcaino et al, which found that higher numbers of neutrophils were recruited to the peritoneum of aged mice after injection of Candida albicans. Findings from these murine studies have shown well preserved neutrophils with limited, if any, reduction in effectiveness. This may indicate that neutrophil changes seen in human subjects are largely based on intrinsic and extrinsic factors not easily duplicated in mice populations.
Macrophage functioning is also affected by aging. Murine studies have found cytokine production to be decreased in macrophages in old vs. young mice. Signaling pathways are also affected by aging. The IFNy-mediated signal transducer and activator of transcription-1 (STAT-1a) activation pathway has found to be reduced in aged subjects. This could affect the ability to affect downstream targets of IFNy stimulation. Yoon et al, found a reduction in phosphorylation of the transcription factor STAT-1a, in macrophages of aged mice (18-24 months) when compared to young mice (2 months). The reduction in cytokine production and signaling pathways efficiency decrease the effectiveness of macrophages and the innate immune system.
Natural killer cells, commonly called cytotoxic T cells or CD8, are large granular lymphocytes that recognize and destroy tumor cells. Little is understood about the exact mechanism of how NK cells operate with the body to locate pathogens, but with NK cells available at the scene, a full-scale immune response can be avoided. Aging affects NK cells by increasing the total number of cells but decreasing the overall cytotoxicity. Impaired production of cytokines and chemokines leads to decreased NK cell activity and a reduction in NK cell driven adaptive immune responses in the elderly. NK cell activity seems to have a strong correlation with risk of infection and mortality. The presence of NK cells has also been shown to be a predictor of immune system functioning, and longevity.  Studies have shown that low NK activity in elderly individuals was associated with increased morbidity and mortality, and conversely high NK activity related to increased endocrine functioning and increased muscular mass in elderly subjects. While the exact mechanisms NK cells is not fully understood, it is evident that they are a major player in the immune system and are negatively affected by aging.
Acquired Immune System
Once a pathogen has conquered the innate immune system, the acquired immune response is required to protect the organism from infection. This system operates on immunity directed against a particular pathogen (specificity) and prepares the body for re-exposure to the same pathogen (memory). Cell-mediated immunity and humoral immunity work together to comprise the acquired immune response and its numerous sub-types of lymphocytes lymphocytes. In humoral immunity B lymphocytes (B cells) B cells are activated and produce antibodies to circulate in blood, lymph, and lymph nodes. Humoral immunity primarily protects against toxins, free bacteria, and viruses in body fluids and is a rapid response. Cell mediated immunity relies on the function of T lymphocytes (T cells) T cells which also circulate in the blood, lymph, and lymph nodes. Cell-mediated immunity protects against fungi, parasites, viruses, and bacteria within cells and is crucial to responding to "nonself" tissues and cells. B and T cells are antigen-specific with only a few lymphocytes for a given antigen.
Age-related decline in the acquired immune system function is thought to be largely the result of involution of the thymus.The thymus is a lymphoid organ located posterior to the sternum that is responsible for T cell development. Murine and human studies of thymic involution have revealed that the rate of thymus shrinking is greatest around the mid-life period for both mice and humans[22,23,21] and by 45-50 years the thymus has shrunk 85-95% from its maximum size. Due to thymus shrinking, a decrease in immunoresponsiveness results as a decline in thymic hormone production and a decreased ability of the thymus to support T cell differentiation.[24,50] This change puts aging populations at increased risk for infections and cancer. Researchers continue to explore the possibilities of reversal of thymic atrophy and its overall effects on the immune system in aging individuals. Studies conducted include, but are not limited to, reversal of thymic shrinking in aged rats after implantation of pituitary derived epithelial cells[25,26,22] and regeneration of the thymus after castration of aged rats.[27,28,21]
Although a fall in the output of new T cells from the thymus to the peripheral blood is apparent in aging individuals [29,21], studies comparing the total number of T cells between old and young populations has neglected to demonstrate any significant difference.[30,31,22] T cells have the ability to proliferate and differentiate into various effector cells when triggered by an antigen including: suppressor T cells, T helper cells, cytotoxic T cells, and plasma cells. However, T cells have a terminable replicative lifespan, therefore the majority of T cells comprising the "peripheral T cell pool" in older individuals may be an accumulation of T cells at or near their replicative limit.[32,33,22] Clonal selection is the antigen-driven cloning process by which B cells and T cells proliferate and differentiate into a large number of effector and memory cells. Clonal selection is imperative in order for the antigen to be eliminated. Moreover, the variance of the T cell receptor reserve is greatly reduced.[29,34] Consequently, immune dysfunction results due to the inability of the T cells to proliferate and differentiate in response to an antigen once they have reached their replicative limit. 
Murine studies have suggested that thymic atrophy is due to changes in the thymic microenvironment, resulting in decreased thymopoiesis linked to a diminished production of the cytokine interleukin 7 (IL-7) Interleukin 7 by thymic stromal cells.[21,35,36,37,29] In the thymus, IL-7 plays a crucial role in T cell development concerning T cell receptor beta (TCRbeta) chain rearrangement in T cell progenitors.[38,39,40,21,41] The TCRbeta chain regulates the transition from CD4-CD8- to CD4+CD8+thymocytes.
CD4+ and CD8+ T cells are well-known memory cells and are a principle component of the acquired immune system. CD4+ and CD8+ T cells proliferate into effector cells and then differentiate into long-lived memory cells specific for a particular antigen.[20,43] A decreased response by these T cells with aging leads to a decline in the acquired immune response, an increased susceptibility to re-infection, and a less effective response to vaccinations.[29,44] For example, studies have shown that elderly individuals were less likely to have a rise in antibodies after vaccinations, such as, an influenza vaccination.[44,45] Further, an increase in the population of CD8+CD28null T cells have been associated with aging suggesting oligoclonal growth of CD8+ T cells and deficiency of the CD28 receptor.[46,47] These CD8+CD28null Treg cells inhibit CD4+ T cell response adding to the decline in the acquired immune response.
In addition to decreased production of T cells, there is also a decline in production of B cells with aging due to a decrease in amount of hematopoietic bone marrow tissue. Furthermore, B cells in elderly individuals have a reduced ability to proliferate, are more difficult to activate, produce fewer and less efficient antibodies.
The endocrine system consists of glands and organs that produce and release hormones. The numerous types of hormones affect the body in different ways and help control body functions including tissue homeostasis, growth/development, reproduction, response to stress, and metabolism. There are four types of hormones: polypeptides, glycoproteins, amines, and steroids. Hormones are the chemical messengers that allow the endocrine system to interact and help regulate the body through extracellular communication. Communication depends on the solubility of the hormone. Those that are lipophilic (fat soluble) can pass through cell membranes of target cells independently, while those that are hydrophilic must act through second messenger systems. Raven Three of the most important hormone axis in the endocrine system that are affected by aging include growth hormone(GH) / insulin-like growth factor I (IGF-I), cortisol/dehydroepiandrosterone (DHEA), and testoterone/estradiol.
Somatopause is a term used to describe the change in GH/IGF-I axis which involves a decrease in production and sensitivity to GH and IGF-I. Typically, GH secretion declines 14% with each decade of life.Toogood In the developing human body, GH from the anterior pituitary gland stimulates production and release of IGF-I by the liver, which is then transported in the blood to stimulate growth of muscle and bone. There has been extensive animal studies done in regards to the GH/IGF-I control of aging. One of the best characterized pathways is the IGF-I like endocrine system that regulates C. elegan life-span. In this model, mutations that lessen the level of daf-2, which is responsible for encoding an IGF-I receptor homologue, results in a more active, youthful animals that lives twice as long. This shows that aging is hormonally controlled in C. elegans.Guarente Decreases in IGF-I signaling, GH deficiency, and GH resistance cause delayed aging and markedly extended lifespan in animal models, which is in sharp contrast to the effects of GH/IGF-I in humans. Declines in pituitary GH secretion is associated with loss of skeletal muscle mass, increased adiposity, and other detrimental effects of aging in elderly humans. The reason for the opposing actions of GH/IGF-I in different species is not presently understood.Bartke
Another animal model that is frequently used for examining GH/IGF-I is the mouse. IGF-I is a strong anabolic hormone that affects bone by stimulating proliferation, reducing bone marrow stromal cell (BMSC) apoptosis, and encouraging recruitment and migration of osteoblasts to the bone surface.Cao With aging, there is a decrease in the amount of circulating GH and consequently IGF-I which results in weaker bones with a low BMD.Cao, Lamberts In addition to lower circulating amounts of IGF-I, the responsiveness of the bone to this protein has been shown to decrease in animal models. This decrease in responsiveness can be attributed to a decrease in IGF-I signaling pathways with advanced cell age.Cao Binding of IGF-I to its receptors normally intiates signaling cascades involving phosphorylation of extracellular signal related kinase (ERK 1/2) and cyclin-dependent kinase (AKT). These two pathways both combine to promote osteoblast proliferation and survival.
Another hormone axis that changes with aging is the cortisol/DHEA axis. The hypothalums-pituitary-adrenal pathway plays an integral role in controlling immune function. Two adrenal hormones, DHEA and cortisol have opposing effects on immune system function with DHEA generally enhancing immunity and cortisol suppressing it.Buford DHEA is released from the adrenal cortex in response to adrenocorticotrophic hormone (ACTH). DHEA peaks in the mid-20s and then gradually declines with aging (termed adrenopause) and can reach as low as 5% of its original level.Buford Cortisol on the other hand remains relatively unchanged with aging, causing an imbalance in hormone levels and thus altered immune function. Glucocorticoids (GCs) such as cortisol also respond to ACTH and are released from the adrenal glands. One specific mechanism in which GCs suppress the immune system is through inhibition of an inhibitor. Nuclear factor kappa B, which is a transcription factor, inhibits the activation induced apoptotic response (programmed cell death) that becomes more prevalent with aging.Buford GCs inhibit this transcription factor which in turn decreases inhibition of apoptosis.
Menopause/Andropause refers to the decrease in production and circulation of estradiol(estrogen) in females and testosterone in males. Testosterone is a steroid hormone secreted by the Leydig cells. It can act upon many target organs resulting in development of secondary sexual characteristics and growth spurt at puberty. Estradiol is the female equivalent of testosterone and is secreted from granulosa cells. It too is a steroid that acts directly on many target organs to develop secondary sexual characteristics and also prepares the uterus for pregnancy month to month. In addition to playing a role in reproduciton and growth, both estrogen and testosterone demonstrate neuroprotective effects and have been theorized to play a role in reducing the effects of Alzheimer’s disease (AD) in the brain. AD is characterized by age-related protein deposits in the brain. Specifically, the protein beta-amyloid (Ab) collects in vulnerable brain regions and plays a central role in the progression of AD. In vitro, cells treated with testosterone demonstrated a decrease in Ab release.Gouras However, the effects of testosterone are not as potent as that of estrogen. B-estradiol (B-E) has been reported to have neuroprotective effects in 12 different types of neuronal cells against 14 different toxicities, including Ab. Estrogen acts on the nucleus of the cell by binding with the nuclear endoplasmic reticulum (ER). The nucleus is accessed through passive diffusion and once it binds to the ER, a series of activation steps are initiated resulting in the binding of the estrogen-ER complex to the estrogen responsive element (ERE). This unit mediates expression of neurotrophic factors in the brain, which contribute to neuroprotection. Further, estrogen offers an antioxidant effect at the cellular level in that it can stop oxidation induced by Ab exposure.Green As a result, the effects of AD are diminished in the presence of both estrogen and testosterone. Thus, a reduction in these hormones with normal aging leaves the brain more vulnerable to AD along with other pathologies. Estrogen levels take a dramatic plunge with menopause. The average age of menopause in American women is 51.van Noord
Aging is a risk factor for the loss of skeletal muscle mass and strength.Wentz The primary effects of aging on the musculoskeletal system include muscle atrophy, decreased muscle fiber number, decreased water content, increased collagen changes and decreased calcium retention.Goodman As a result of the primary effects, an aging individual experiences decreased strength, flexibility, endurance, elasticity, stiffness and cartilage deterioration.Goodman Age related loss of muscle mass (sarcopenia) is lost at a rate of 4-6% per decade starting at age 40 in women and 60 in men.Goodman Sarcopenia is defined as having a muscle mass index less than two standard deviations below the mean for a given age group.Dirks Sarcopenia is due to both a decrease in the number of muscle fibers and atrophy of the remaining fibers.Dirks Although the mechanisms of these losses are not completely known, it is primarily thought that mitochondrial dysfunction, through reactive oxygen species, triggers apoptotic cellular responses leading to skeletal muscle cell termination.
Sarcopenia represents a distinct risk factor in the aging population for loss of independence, physical disability and injuries. In order to fully understand these risk factors it is important to understand the cellular mechanisms leading to these effects. In normal skeletal muscle, a pairing known as excitation-contraction uncoupling is the primary means of producing a skeletal muscle contraction. The basic functional unit used to produce such a contraction is known as a sarcomere. Skeletal muscle contraction is initiated by action potentials that are generated within motor neurons and conducted along an axon towards the neuromuscular junction. Once the action potential reaches the terminal end plate, acetylcholine is released, increasing the sodium and potassium conductance at the end plate. This influx of sodium sends an electromechanical signal to the T-tubules towards the voltage-gated calcium channels which become activated. This activation releases calcium from its intracellular storage in the sarcoplasmic reticulum into the sarcoplasm. The available calcium in the sarcoplasm is bound to troponin C, which facilitates the formation of cross linkages between actin and myosin filaments, thus producing a forceful contraction. This process is dependent upon the person’s ability to efficiently produce energy known as adenosine triphosphate (ATP) within the mitochondria to drive muscle contraction.Delbono
There are two main processes our body uses to produce ATP. The first is the Kreb’s Cycle which occurs in the cytoplasm and produces only 4 ATP. The second is the electron transport chain (ETC), which is the most important process, occurs in the mitochondria and produces roughly 90% of the required ATP necessary for cellular function through a process called oxidative phosphorylation (OXPHOS). This process is initiated by burning hydrogen from fats and glucose from our diet, particularly glucose. The electron transport chain is carried out within the intracellular membrane of the mitochondria. It is responsible for stripping hydrogen (H+) from glucose by-product and pumping them into the inner membrane space in order to generate a pH gradient of H+ as potential energy. Due to this concentration gradient, the hydrogen can diffuse into the membrane down the gradient through the use of ATP synthase. This is an enzyme that is used to generate ATP from adenosine diphosphate (ADP).Wallace
Within the electron transport chain, electrons are shuttled along the chain through carriers, Ubiquinone (CoQ10) and cytochrome C. The terminal electron acceptor of the transport chain is Cytochomre C Oxidase (COX) which reduces oxygen from cytochrome C into water.Zee If these shuttle carries do not perform efficiently, oxygen is able to leak from the chain into the inner membrane which can lead to reactive oxygen species (ROS). Reactive oxygen species are also known as free radicals. These are usually oxygen, hydroxyl or nitrogen radicals that are missing an electron in their outer shell and find a completion electron from the mitochondrial membrane. If there is a surplus of free radicals within the cell, the mitochondrial membrane can become compromised triggering cellular apoptosis.Wallace
A progressive loss of muscle mass, flexibility, and changes in connective tissue and bone occur with normal aging. These changes become pathological when these changes result in disability. In muscle, aging results in the atrophy of the number of muscle fibers, decrease in the number of neurons and decreased strength. Connective tissue loses its elasticity, its ability to retain water and becomes fibrous. Within bone, there is decreased calcium, decreased Vitamin D levels, decreased red blood cell reserves and decreased bone mineral density (BMD).Lewis
Loss of muscle function appears to be due to an age-related acceleration loss of myocytes, or muscle cells. This loss is believed to be triggered via apoptosis and is thought to be the primary mechanism responsible for muscle loss. Apoptosis is a cell suicide program that is regulated and executed through signaling pathways responsible for acknowledging cellular dysfunction and salvaging or terminating the cell. Apoptosis is executed and leads to DNA fragmentation, proteolysis and formation of apoptotic bodies that are engulfed by macrophages of neighboring cells. Recent evidence suggests the following cellular events can lead to apoptosis: calcium dysregulation, increased chronic inflammatory markers and mitochondrial dysfunction.Marzetti
Under stress conditions, such as those experienced with aging, there is oxidative damage to the calcium ATPase pump in the endoplasmic reticulum which causes a release of cytochome C from the mitochondria. This can cause a decreased ability of the electron transport chain to appropriately shuttle electrons leading to increased ROS and triggering apoptosis. Chronic inflammation has been a contributing factor to muscle loss and impairment. Increased levels of the inflammatory markers, tumor necrosis factor-alpha(TNF-a), interleukin 6 (IL-6) and C reactive protein (CRP), are found to trigger myocyte apoptosis through a caspase cascade.Marzetti These inflammatory markers are secreted by adipose tissue which result in a low grade fever response from the cells which precipitate apoptosis. As people age their percentage of body fat composition increases, therefore increasing their susceptibility to an inflammatory response. With aging, there is an increase in abdominal fat in men and an increase in thigh girth in women. An increased percentage of fat in these areas leads to increased inflammatory markers like TNFa, IL-6 and CRP, therefore increasing myocyte apoptosis.Hughes
Mitochondrial dysfunction is considered a prime target for age related changes in skeletal muscle. A decline in mitochondrial oxidative function and an increase in mitochondrial DNA (mtDNA) mutations can lead to increases in ROS that can interfere with synthesis of proteins, enzymatic pathways and ATP production. In a recent study with rats, it was found that animals with increased mtDNA mutations yielded premature aging and decreased life expectancy.Marzetti In a 2003 cross sectional study comparing the gastrocnemius muscle in 344 rats, the author found that there was a 50% decrease in the production of ATP at 26 months compared to 12 months of age. With mitochondrial dysfunction, glycation end products (AGE) accumulate on proteins in the intracellular space, such as actin and myosin, and impair the excitation-contraction uncoupling mechanism. This leads to reduced motility speed of the cross linkages therefore affecting the overall muscle performance and strength.Dirks In most cells apoptosis of the nucleus means total cell death. However, since skeletal muscle is multinucleated, apoptosis of the nucleus does not mean death of the entire muscle fiber. This is the mechanism behind skeletal muscle fiber atrophy.Dirks
Another large component to mitochondrial function is the peroxisome proliferator activated receptor (PGC-1a), which is a key regulator in mitochondrial biogenesis. This activator has been found to be essential in determining mitochondrial function and muscle integrity. It is known that PGC-1a levels decrease with age and in a study conducted by Wenz et al. it was concluded that in aged mice infused with transgenic PGC-1a, elevated levels leads to the following effects: preservation of mitochondrial oxidative phosphorylation capacity, enhancement in anti-oxidant defense, prevention of oxidative damages, preservation of muscle integrity and the neuromuscular junction, as well as preventing muscle atrophy.Wenz Within this study the authors compared age matched controllled wild mice versus mice with elevated PGC-1a levels.
It was found that at 3 months of age both groups had the same level of cytochome c oxidase (COX) in the mitochondria. At 12 months, there was a decline in COX activity with the wild mice, but not with the PGC-1a mice. At 22 months, the wild type sample had only 60% of the COX activity observed in the younger animals and the PGC-1a mice had the same COX level as they did at 3 months of age.Wenz When analyzing the anti-oxidant response in this study, young and aged PGC-1a mice had a 2.5 to 3 fold increase in the superoxide dismutase 2 (SOD2) levels which is useful in the prevention of oxidative damage compared to wild type controls. The aged wild type control mice also showed a greater increase in inflammatory markers TNF-a and IL-6 compared to the PGC-1a mice indicating severe tissue damage in the control aged group. It was also seen that the control group showed increased collagen deposition indicating fibrous tissue whereas the PGC-1a mice had less collagen deposition inferring that PGC-1a levels are partly responsible for muscle fibrosis.Wenz There was also a significant increase in the apoptotic index in the wild type controls starting at 12 months of age compared to the experimental group. There was an increase in the DNA fragmentation level in both groups, but the PGC-1a animals had 50% lower levels than the wild type group. Less ubiquinone, CoQ10, was also seen in the control group compared to the PGC-1a group indicating less efficient electron transport chain, therefore decreased ATP production. Overall, this study concluded that increased PGC-1a expression leads to protection against decline in OXPHOS function, decreased degenerative processes and preserved muscle integrity.Wenz Although the exact mechanisms for skeletal muscle function decline are not completely known, research has focused on mitochondrial dysfunction, particularly levels of PGC-1a as prime targets for current and future research. Further studies on additional contributors to this decline are necessary in order to provide an all inclusive cause to skeletal muscle atrophy and decline in function.
With aging, there is a progressive loss of flexibility and changes in connective tissues that contribute to an increased incidence of joint problems. It is not clear whether this decreased flexibility occurs as a reaction to inactivity, degenerative disease changes or adhesion formation. One possible cause of this chain links connective tissue damage to fibrinogen. Fibrinogen is produced in the liver and converted to fibrin and circulated through the body as a clotting mechanism for injury. Normally, fibrinogen leaks from the blood vessels and into the intracellular space and adheres to cellular structures causing adhesions. With normal body movement these adhesions are broken down and macrophagic activity dissolves the unused fibrinogen. With aging, fewer fibrinogen and macrophages are available, therefore not allowing as much clotting factor to be in the systemic system. Due to decreased physical activity, there is less movement of the adhesions that are formed and they are not effectively dissolved which can cause accumulation in the muscle and cartilage causing increased stiffness of these structures.Lewis
Another theory being investigated is the relationship that with increased age, cartilage dehydrates and stiffens because of its inability to retain water, thus thinning out weight bearing surfaces. There is shown as decreased articular cartilage with age. The primary proteoglycan or glycoprotein found in articular cartilage is aggrecan. Normally aggrecan binds with hyaluronan to expand the collagen matrix of the cartilage and improve its tensile and compressive strength capacity. With age, there is a reduction in size and number of aggrecans which have been shown to lose their ability to hold water in the collagen matrix leading to dehydration. If articular cartilage loses its elasticity and flexibility, it has a reduced ability to dissipate forces across the joint.Lewis
Age related changes in bone result in decreased BMD and increased bone fragility, also known as osteoporosis.Ginaldi Although osteoporosis has been linked to endocrine, metabolic and mechanical factors, new evidence has emerged suggesting that inflammation plays a role in osteoblast and osteoclast activity.Ginaldi “Inflamm-ageing” is the term used to describe the chronic inflammatory state that is caused by ageing and results in the hyperproduction of pro-inflammatory cytokines.DeMartinis Cytokines that are elevated during senescense include TNF-a, IL-6, and Interleukin-1 (IL-1), which all stimulate osteoclast activity leading to osteoporosis.DeMartinis Evidence of this pro-inflammatory state is CRP, an inflammatory marker that is associated with lower BMD.Martinis Higher CPR serum levels are linked to higher bone turnover rate, which lowers bone mass.DeMartinis
Pro-inflammatory cytokines affect bone mass by regulating bone resorption via direct and indirect regulation.DeMartinis IL-6 promotes osteoclast differentiation and activation, which is stimulated by parathyroid hormone (PTH).Ginaldi IL-1, along with IL-6, cause bone resorption seen in both postmenopausal and idiopathic osteoporosis.Martinis TNF-a has also been shown to increase bone resorption, as well as decrease bone formation.DeMartinis IL-1 and TNF-a also activate the inducible NO synthesis (iNOS) pathway, which results in decreased osteoblast function and stimulates osteoblast apoptosis.Martinis Another pathway responsible for decreased BMD is through the immune system.DeMartinis Activation of T-cells results in the production of Receptor Activator for Nuclear Factor k B Ligand (RANK-L), which is key regulators in bone remodeling and is needed for the development and activation of osteoclasts.Ginaldi Normally, other T-cell derived cytokines such as Interleukin-12 (IL-12), Interleukin-18 (IL-18) and Interferon-y (IFN-y), along with the expression of Osteoprotegerin (OPG) interfere with RANK-L signaling, which inhibits osteoclastogensis and osteoclast function.DeMartinis With senescence, T-cells show decreased production of OPG, IL-12, IFN-y and IL-18, which results in osteoporosis.DeMartinis
Hormonal changes associated with aging have also been shown to play a role in osteoporosis.DeMartinis Estrogen and testosterone has been shown to inhibit IL-6 gene expression, which results in decreased bone resorption.DeMartinis Due to decreased estrogen levels in postmenopausal women, as well as decreased testosterone production in the aging male, IL-6 levels are increased in the bone microenvironment contributing to osteoporosis.DeMartinis “Inflamm-ageing” is a result of our immune system evolving to control pathogens over a life time.DeMartinis This pro-inflammatory state results in immune-related diseases or conditions, such as increased bone turnover resulting in osteoporosis.DeMartinis
With the number of aging individuals increasing, health care professionals need to be cognizant of the prevalence of depression among the elderly. Depression has even been termed the “common cold of the elderly.”Bottomley Incidence of depression in the community dwelling elderly varies depending on the source from 8%-16%.Blazer Just as in early-mid life, depression can be a severe cause of emotional suffering and a decrease in quality of life in older adults. Often times, it goes unnoticed or passed over in health care fields due to an ageist thought pattern. The elderly have added variables in late life that may contribute to depression including chronic conditions, personal/emotional losses, decreasing functional abilities, and cognitive impairments.
Etiology of late-life depression is a subject of much debate and research is ongoing. Vascular depression, which has been identified as a particular type, involves accumulation of vascular lesions in various areas of the brain including the frontal lobes, caudate, and the putamen. Researchers believe that lesions in these areas can cause depressive symptoms through decreased function/efficiency of neuronal pathways.Blazer
On the molecular level, most studies done of depression involve neurotransmitters (and their receptors) in the central nervous system: 5-hydroxytryptamine (5-HT), noradrenaline (NA), and dopamine (DA). A dysregulation of these monamines have been implicated as a probable contributor to depression. In the aging brain, metabolism of both 5-HT and NA is reduced leading to a decrease in the amount of each. In addition to decreased metabolism, there is also an increase in enzymes such as monoamine oxidase type B (MAO-B) that catalyze oxidative deamination of DA.Gareri
Depression in old age is not always the primary disorder. Often times, depression is secondary to diseases such as Parkinson’s and Alzheimer’s. Brain studies examining blood flow changes and glucose metabolic rates have shown that Parkinson’s, Alzheimer’s, Huntington’s, and primary depression are all associated with decrease activity and/or lesions in basal ganglia and orbitofrontal cortex. This implicates the cortical basal ganglia-thalamic neuronal loop as a possible pathophysiological source of depression.Gareri