Thymic function and survival at advance ages in nursing home residents from Southern Italy (original) (raw)
Tracing thymic output in older individuals
Clinical and Experimental Immunology, 2010
As a result of age-associated thymic atrophy, T cell production declines with age. Some studies suggest that production undergoes an exponential decline starting at birth, while others consider the decline to be in a biphasic manner with a rapid reduction in output occurring before middle age followed by a phase in which output declines at a regular, albeit much slower, rate. Both approaches provide estimations of the time of termination of thymic output, but on the basis of limited amounts of data. We have analysed blood from more than 200 individuals between the ages of 58 and 104 years to determine changes in thymic output using signal-joint T cell receptor excision circles (sjTREC)/T cells as our measure. To reduce any potential geographical or nutritional bias we have obtained samples from five different European countries. Our results reveal that while the absolute number of T cells per microlitre of blood does not change significantly across the age range we tested, the values of sjTREC per microlitre show wide variation and reveal an age-associated decline in thymic output. In addition we show gender differences, with notably higher thymic output in females than males at each decade. More importantly, we noted a significant decline in sjTREC/T cell levels in those more than 90 years of age in both males and females. Our results provide information about the potential end-point for thymic output and suggest that sjTREC analysis may be a biomarker of effective ageing.
AGE, 2013
Relationship between thymic function and elderly survival has been suspected, despite the fact that formal proof is elusive due to technical limitations of thymic function-related markers. The newly described sj/β-TREC ratio allows now, by overcoming these limitations, an accurate measurement of thymic output in elderly humans. Thus, the aim of this study was to determine the impact of thymic function and inflammatory markers on healthy elderly human survival. Healthy volunteers (n=151), aged over 65, were asked to participate (CARRERITAS cohort). Subjects were excluded if diagnosed of dementia or, during the last 6 months, had clinical data of infection, hospital admission, antitumor therapy, or any treatment that could influence the immune status. Thymic function (sj/β-TREC ratio), CD4:CD8 T cell ratio, C-reactive protein, interleukin-6, and neutrophilia were determined from basal samples. All basal variables and age were associated with 2-year allcause mortality. Multivariate analysis showed that only thymic function and C-reactive protein were independently associated with time to death. In conclusion, we show, for the first time, the direct role of thymic function in human survival. C-reactive protein raise is also a marker of mortality in the healthy elderly, in a thymic-independent way.
Journal of gerontology, 1981
T lymphocytes, T lymphocyte subpopulations and delayed hypersensitivity reactions to recall antigens were studied in 20 aged subjects clinically unaffected by disorders of the immune system. T-cells evaluated by the sheep rosette test and absolute T-cell number were within normal range. T-cell subsets were studied by the high affinity rosetting test and by the sheep rosette test after pre-incubation with theophylline; such methods have been shown by others to discriminate between T-cells with helper or suppressor activity. We did not observe an imbalance of such subpopulations. Skin reactivity to recall antigens (Candida and SK-SD) was depressed in several cases. Since a decline in serum levels of thymic hormones has been reported in the ageing and it is suggested that this could account for the T-dependent immunity defect, we treated these patients with a bovine thymic extract (thymostimulin, TP-1) 1 mg/kg/day for three consecutive days. Immunological tests were performed again aft...
The effect of age on thymic function
Frontiers in immunology, 2013
Age-related regression of the thymus is associated with a decline in naïve T cell output. This is thought to contribute to the reduction in T cell diversity seen in older individuals and linked with increased susceptibility to infection, autoimmune disease, and cancer. Thymic involution is one of the most dramatic and ubiquitous changes seen in the aging immune system, but the mechanisms which underlying this process are poorly understood. However, a picture is emerging, implicating the involvement of both extrinsic and intrinsic factors. In this review we assess the role of the thymic microenvironment as a potential target that regulates thymic involution, question whether thymocyte development in the aged thymus is functionally impaired, and explore the kinetics of thymic involution.
Age-dependent incidence, time course, and consequences of thymic renewal in adults
Journal of Clinical Investigation, 2005
Homeostatic regulation of T cells involves an ongoing balance of new T cell generation, peripheral expansion, and turnover. The recovery of T cells when this balance is disrupted provides insight into the mechanisms that govern homeostasis. In a long-term, single cohort study, we assessed the role of thymic function after autologous transplant in adults, correlating serial computed tomography imaging of thymic size with concurrent measurements of peripheral CD4 + T cell populations. We established the age-dependent incidence, time course, and duration of thymic enlargement in adults and demonstrated that these changes were correlated with peripheral recovery of naive CD45RA + CD62L + and signal-joint TCR rearrangement excision circle-bearing CD4 + populations with broad TCR diversity. Furthermore, we demonstrated that renewed thymopoiesis was critical for the restoration of peripheral CD4 + T cell populations. This recovery encompassed the recovery of normal CD4 + T cell numbers, a low ratio of effector to central memory cells, and a broad repertoire of TCR Vβ diversity among these memory cells. These data define the timeline and consequences of renewal of adult thymopoietic activity at levels able to quantitatively restore peripheral T cell populations. They further suggest that structural thymic regrowth serves as a basis for the regeneration of peripheral T cell populations.
Reevaluation of T Cell Receptor Excision Circles as a Measure of Human Recent Thymic Emigrants
The Journal of Immunology, 2002
The human thymus exports newly generated T cells to the periphery. As no markers have been identified for these recent thymic emigrants (RTE), it is presently impossible to measure human thymic output. T cell receptor excision circles (TREC) have been recently used to assess thymic output during both health and disease. Using a mathematical model, we quantify age-dependent changes both in the number of RTE generated per day and in TREC concentration during an 80-year lifespan. Through analyses, we demonstrate that RTE and peripheral T cell division have the same potential to affect TREC concentration at any age in healthy people. T cell death also influences TREC concentration, but to a lesser extent. During aging, our results indicate that thymic involution primarily induces an age-dependent decline in TREC concentrations within both CD4 ؉ and CD8 ؉ T cell populations. We further apply this model for studying TREC concentration during HIV-1 infection. Our analyses reveal that a decrease in thymic output is the major contributor to the decline in TREC concentration within CD4 ؉ T cells, whereas both increased peripheral T cell division and decreased thymic output induce the decline in TREC concentration within CD8 ؉ T cells. Therefore, we suggest that T cell turnover should be examined together with TREC concentration as a measure of RTE. If peripheral T cell division remains relatively unchanged, then TREC concentration indeed reflects thymic output.
Clinical and Experimental Immunology, 2001
Summary The thymus undergoes age-associated involution, with studies showing thymic size decreasing from birth at a rate of approximately 3% per year until middle age, and at a rate of 1% per year thereafter. The aim of this study was to determine the effect of thymic atrophy on T-lymphocyte production by the thymus, and to clarify the ongoing uncertainty regarding gender differences in thymic function. We quantified recent thymic emigrants (RTEs) in blood through the measurement of signal joint T-cell receptor rearrangement excision circles (sjTRECs), and showed that the decline in the number of RTEs in the blood with increasing age is gender-linked. Peripheral blood from females contained significantly higher levels of sjTRECs per CD3+ T cell than blood from males (P = 0·002), despite there being no significant gender difference in the absolute number of CD3+ T cells in the populations analysed (P > 0·10). Our findings suggest better thymic function in females compared with mal...
Thymic Aging May Be Associated with COVID-19 Pathophysiology in the Elderly
Cells, 2021
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient antiviral immune function and excessive self-damaging immune reaction, involving T cell immunity and associated with pre-existing basal inflammation in the elderly. Age-related changes to T cell immunosenescence is characterized by not only restricted T cell receptor (TCR) repertoire diversity, accumulation of exhausted and/or senescent memory T cells, but also by increased self-reactive T cell- and innate immune cell-induced chronic inflammation, and accumulated and functionally enhanced polyclonal regulatory T (Treg) cells. Many of these changes can be traced back to age-related thymic involution/degeneration. How these changes contribute to differenc...
Thymic involution and rising disease incidence with age
Proceedings of the National Academy of Sciences, 2018
Significance Understanding the risk factors of carcinogenesis is a major goal of biomedical research. Historically, the focus has been on the role of somatic mutations, and the reason for cancer typically occurring late in life is predominantly attributed to a gradual accumulation of such mutations. We challenge that view and propose that the decline of the immune system is the primary reason why cancer is an age-related disease. The immunological model featured here captures risk profiles for many cancer types and infectious diseases, suggesting that therapies reversing T cell exhaustion or restoring T cell production will be promising avenues of treatment.