Which gland atrophies as the person ages

Aging of thymus gland and immune system. DOI: Download PDF. Aging is an inevitable, progressive and irreversible process that is manifested with multiple organ dysfunction.

Reactive oxygen species ROS is considered the main etiological factor of aging. The thymus gland is the primary site of T cell production and it represents a key organ of the immune system. It is endodermal in origin and lies in the anterior mediastinum behind the sternum. Deterioration of the immune system with aging contributes to increased incidence of infection, autoimmunity, and cancer, thus increasing the rates of morbidity and mortality in elderly humans.

Aging is a multifactorial physiological condition that includes a progressive decline of organ function. It is accompanied with increased vulnerability to infections, immune disorders and neoplasms, and ultimately death. Imbalance between oxidants like free oxygen radicles reactive oxygen species, ROS and antioxidants is considered as an important etiology of aging.

Inside the mitochondria, oxidative stress liberates excessive ROS that induces more mitochondrial damage and more ROS, and the cycle repeats itself. Thymus is the primary cell donor for the lymphatic system, like the bone marrow which is the cell donor for the hemopoietic system.

It manufactures the immunocompetent T cells. Within the thymus the progenitor cells are created, then maturated and differentiated into mature T cells. The thymus gland is one of the contents of the anterior mediastinum as it lies behind the sternum but in front of the pericardium and heart. It is formed of two identical lobes; each lobe has a central medulla and a peripheral cortex.

It develops from the third endodermal pharyngeal branchial pouch. The thymus is the largest and most active in neonates and pre-adolescents, afterwards it gradually involutes and ultimately disappears to be replaced by fat in elderly when it weighs 5g. In congenital absence of thymus DiGeorge Syndrome there is deficiency of T cell immunity.

Thymic involution refers to the process of multiple sessions of age-related atrophy and redevelopment before the incidence of complete thymic degeneration. Several authors relate the early involution of the thymus to an innate aging program while others attribute its incidence in early puberty to a developmental program that decelerates the growth rate. Changes in thymus weight with age and during pregnancy were investigated in mice.

In female mice thymus weight was markedly reduced by pregnancy and involution started 50 days after birth. MicroRNAs miRNAs may be considered as potential biomarkers for the study of sex- and age-related differences in involution of the thymus. In these animals, there were age-related increases in the fibronectin content in the thymic capsule, the interlobular connective tissue, the perivascular tissue, and in the medulla and cortex.

Properly functioning thymus is the needed for reduction of morbidity and mortality rates in infections and transplantations. This led to the conclusion that maternal protein restriction during lactation slows aging of the immune system and prolongs the life span. The two glands form a functional complementary unit that maintains the immune and endocrine systems during aging.

The pineal gland is supposed to be responsible for involution of the thymus and control of its lifespan- determining function. Adult mice injected with embryonic thymic calf extracts ETCE , there was a fall in the level of cerebral and splenic unsaturated fatty acid peroxides. Histologically, thymus, liver and spleen of these injected animals resembled those of neonatal mice. In individuals treated with ETCE, presbyopia and climacteric symptoms disappeared.

Thymuses, obtained from old mice and grafted into thymectomized young adult mice, could partially restore the circulating FTS level. On the other hand, newborn thymuses could not sufficiently restore the serum FTS level when grafted in old thymectomized mice. Whether age-associated cataract in dogs could be cured or not, using thymus calf extract, remains a question for further studies.

On the contrary, the rate of protein synthesis diminished rapidly during involution, and continued to decrease at a slower rate during aging. The thymus is thought to be indulged in the pathogenesis of myasthenia gravis MG in patients with anti-acetylcholine receptor autoantibodies. Thymectomy is widely used as a treatment of EOMG. Curr Opin Immunol 22 — The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines.

Vaccine 30 —7. Anderson G, Jenkinson EJ. Lymphostromal interactions in thymic development and function. Nat Rev Immunol 1 — CrossRef Full Text. Regulatory mechanisms of thymus and T cell development. Dev Comp Immunol 39 — Thymic involution with ageing: obsolescence or good housekeeping? Immunol Today 17 — Insights into thymic aging and regeneration. Immunol Rev — Thymic involution and immune reconstitution. Trends Immunol 30 — An evolutionary perspective on the mechanisms of immunosenescence.

Telomere dysfunction, autoimmunity and aging. Aging Dis 2 — Pubmed Abstract Pubmed Full Text. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol 11 — Haynes L, Swain SL. Why aging T cells fail: implications for vaccination. Immunity 24 —6. Understanding immunosenescence to improve responses to vaccines.

Nat Rev Immunol 14 — Aw D, Palmer DB. The origin and implication of thymic involution. Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates. Ablation of thymic export causes accelerated decay of naive CD4 T cells in the periphery because of activation by environmental antigen. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans.

Immunity 36 — Aging Cell 5 — Tracing thymic output in older individuals. Clin Exp Immunol — Age-related deregulation of naive T cell homeostasis in elderly humans.

Age Dordr 33 — Sauce D, Appay V. Altered thymic activity in early life: how does it affect the immune system in young adults? Curr Opin Immunol 23 —8. Evidence of premature immune aging in patients thymectomized during early childhood.

J Clin Invest —8. Diminished response to tick-borne encephalitis vaccination in thymectomized children. Vaccine 26 — Maintenance of peripheral T cell responses during Mycobacterium tuberculosis infection. J Immunol —8. Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection. J Exp Med —9.

Thymopoietic and bone marrow response to murine Pneumocystis pneumonia. Infect Immun 79 — Changes in thymic function with age and during the treatment of HIV infection. Nature —5. Thymic involvement in recovery of immunity among HIV-infected adults on highly active antiretroviral therapy. J Antimicrob Chemother 52 —8. Thymic function failure and C-reactive protein levels are independent predictors of all-cause mortality in healthy elderly humans.

Age Dordr 35 —9. Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immunol 5 —9. Stem cells and the aging hematopoietic system.

Curr Opin Immunol 22 —6. Van Zant G, Liang Y. Concise review: hematopoietic stem cell aging, life span, and transplantation. Stem Cells Transl Med 9 —7. Reduction in the developmental potential of intrathymic T cell progenitors with age. J Immunol — But starting around the time of puberty, the thymus rapidly decreases in size and loses its capacity to produce enough new T cells. This loss is partially offset by the duplication of existing T cells, but the resulting population of cells becomes more and more biased toward memory T cells, which recognize pathogens from previous or ongoing infections.

As a result, broad-spectrum immunity against new pathogens and protective immune responses elicited by new vaccines diminish with age.

The development of interventions to slow the progression of thymus atrophy has been limited by the lack of knowledge about the underlying mechanisms. The prevailing theory suggests that sex hormones play a key role, but this explanation does not account for the accelerated speed at which the thymus diminishes in size in comparison to other tissues. Moreover, the body of scientific evidence clearly indicates that other factors must be involved in age-related thymus atrophy.

To address this question, Petrie and first author Ann Griffith, currently at the University of Texas Health Science Center at San Antonio, developed a computational approach for analyzing the activity of genes in two major thymic cell types--stromal cells and lymphoid cells--in mouse tissues, which are very similar to human thymic tissues in terms of function and the properties of atrophy. They found that stromal cells were deficient in an antioxidant enzyme called catalase, resulting in the accumulation of free radical and metabolic damage.

To test whether catalase deficiency plays a causal role in thymus atrophy, the researchers performed genetic experiments to enhance catalase levels in mice.

By 6 months of age, the size of the thymus of the genetically engineered mice was more than double that of normal mice. Once inside the cells, glucose is either metabolised immediately to release energy, or stored and converted into glycogen. Alongside race, genetic predisposition and a high body mass index, ageing is one of the many risk factors linked to the development of type 2 diabetes Knight and Nigam, Ageing human cells become less sensitive to the effects of insulin.

The most likely cause appears to be a reduction in the number of insulin receptors at the surface of cells. This gradual insulin resistance goes hand in hand with an increase in blood glucose concentrations. As shown in a study of 6, non-diabetic people Ko et al, , fasting blood glucose levels rise by around 0. Whether this rise is a normal age-related change or a sign of diabetes in its early stages is not always clear, but it is certainly seen in many older people with no other symptoms of diabetes.

With advancing age, the insulin-producing beta cells become less sensitive to the level of glucose in the blood, so higher blood glucose levels are needed to trigger insulin release. This can put excessive stress on the beta cells, leading to their exhaustion. Age-related depletion of the beta cell population in the pancreas also occurs as a result of increased programmed cell death apoptosis and a diminished ability of the pancreas to produce new cells.

Beta cell exhaustion and depletion result in a drop of insulin secretion of up to 0. Additionally, the clearance of insulin by the liver increases with age, so there is less insulin available to interact with cells and promote glucose uptake.

These age-related changes to insulin production, clearance and response contribute to the creation of a diabetogenic environment. This may partially explain why the risk of developing type 2 diabetes increases with age Brown, Many age-related changes to the endocrine system contribute to this accumulation of adipose tissue, including the somatopause, autoimmune hypothyroidism, insulin resistance, and reduced circulating sex hormones. This abdominal fat accumulation is linked to heart disease, high blood pressure and type 2 diabetes.

These conditions may occur in isolation or together in the form of metabolic syndrome Gong and Muzumdar, The two adrenal glands are located above the kidneys and each consists of two main regions: the adrenal medulla inner region and the adrenal cortex outermost layer. The adrenal medulla is the location of chomaffin cells, which secrete the catecholamines adrenaline epinephrine and noradrenaline norepinephrine. The effects of adrenaline and nor-adrenaline include:.

Ageing is associated with a decline in the secretion of adrenaline, but adrenaline plasma levels remain relatively constant as clearance by the kidneys is usually reduced.

There is some evidence that older men secrete less adrenaline in response to acute stress than younger men Seals and Esler, The adrenal cortex synthesises a variety of steroidal hormones from cholesterol, mainly aldosterone and cortisol. Aldosterone Aldosterone is a mineralocorticoid that regulates plasma levels of sodium and potassium, and plays an important role in water balance and blood pressure control.

Decreased aldosterone secretion may contribute to postural hypotension and the light-headedness that is often experienced by older people when they stand up. This is supported by research demonstrating significant reductions in serum aldosterone levels in older people when they are upright, as opposed to recumbent Hegstad et al, Since sodium attracts water into the cardiovascular system via osmosis, lower plasma sodium levels hyponatraemia can lead to reduced blood volume and blood pressure.

Several medications commonly prescribed to older people — such as opiates, non-steroidal anti-inflammatory drugs, diuretics and antidepressants — can exacerbate hyponatraemia Liamis et al, Blood volume and blood pressure may be further reduced by age-related increases in the secretion of atrial natriuretic hormone ANH , a powerful diuretic produced by the heart Miller, Cortisol Cortisol is a glucocorticoid and its release is triggered by biological stressors such as physical injury or starvation.

It is a natural anti-inflammatory and plays an important role in the breakdown of protein and fat. Research into how cortisol levels change with ageing is often contradictory. More recently, however, it has been shown that this is not necessarily true: in some people, cortisol secretion diminishes with age, in others levels remain relatively stable throughout life Wolf, There appears to be a link between increased cortisol levels, reduced bone density and increased risk of bone fracture.

There is also growing evidence that a higher cortisol concentration can contribute to the loss of cells from the hippocampus, resulting in hippocampal atrophy. This is often associated with a reduction in cognitive function in older people Chahal and Drake, Other studies have shown that age-related increases in cortisol may also be linked to memory loss and sleep disorders Chahal and Drake, ; Wolf et al,