Abstract
During aging, the thymus undergoes a marked involution that is responsible for profound changes in the T-cell compartment. To investigate the capacity of the thymus to produce new cells at the limit of human lifespan, we analyzed some basic mechanisms responsible for the renewal and maintenance of peripheral T lymphocytes in 44 centenarians. Thymic functionality was analyzed by the quantification of cells presenting the T-cell receptor rearrangement excision circles (TREC). A new method based upon real-time PCR was used, and we found that most centenarians (84%) had undetectable levels of TREC+ cells. Six-color cytofluorimetric analysis revealed that centenarians had an extremely low number of naïve T cells; central memory and effector memory T cells were greatly increased, while terminally differentiated cells were as numerous as in young (aged 20-45) or middle-aged (aged 58-62) donors. Interleukin (IL)-7 and IL-7 receptor alpha-chain (CD127) levels were the same at all ages, as shown by ELISA, flow cytometry and real-time PCR. However, IL-7 plasma levels were higher in centenarian females than males. The presence of TREC+ cells and of very few naïve T lymphocytes suggests that in centenarians such cells could either derive from residues of thymic lymphopoietic islets, or even represent long-living lymphocytes that have not yet encountered their antigen. IL-7 could be one of the components responsible, among others, for the higher probability of reaching extreme ages typical of females.
Highlights
Several studies have demonstrated that immunological aging, defined as immunosenescence, is not characterized by a simple deterioration of the immune system but is part of a continuum of developmental processes with complex reorganizational events, compensatory mechanisms and qualitative alterations in function
The thymus undergoes a marked involution that is responsible for profound changes in the T-cell compartment
Thymic functionality was analyzed by the quantification of cells presenting the T-cell receptor rearrangement excision circles (TREC)
Summary
Several studies have demonstrated that immunological aging, defined as immunosenescence, is not characterized by a simple deterioration of the immune system but is part of a continuum of developmental processes with complex reorganizational events, compensatory mechanisms and qualitative alterations in function. Immunological aging is characterized by profound modifications of the thymus gland (Cossarizza et al, 1996, 1997; Aspinall & Andrew, 2000; Haynes et al, 2000; Taub & Longo, 2005). Shortly after birth the thymus undergoes a life-long process of involution whereby the organ is replaced by adipose tissue, accompanied by the loss of its main immune function (i.e. the production of T cells). Such an involution results in a reduction in the number of constituent thymocytes with age, a consequent shrinking of the thymus and a decline in the output of naïve T cells, typical of the gland. Far advanced age is characterized by a profound reduction and consequent exhaustion of naïve T-cell population and by a progressive accumulation of memory/effector T cells (Sansoni et al, 1997; Fagnoni et al, 2000)
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