scholarly journals Early Life Thymectomy Induces Glucose Intolerance in Middle-Aged Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 679-679
Author(s):  
David Buckley ◽  
Daniel Trott ◽  
Sunita Sharma
Keyword(s):  
T Cell ◽  
Glucose Intolerance ◽  
Repeated Measures ◽  
Early Life ◽  
Fasting Glucose ◽  
Cell Aging ◽  
Cell Phenotype ◽  
Middle Aged ◽  
Aged Mice ◽  
Age Related

Abstract Previously we have found that T cells contribute to age-related glucose intolerance. The purpose of this study was to test the hypothesis that early life thymectomy at 3wks of age induces T cell aging and subsequent impairments in glucose homeostasis in otherwise young animals. Male C57BL6 mice underwent thymectomy (thymex; n=7) or sham surgery (control; n=7) at 3wks of age. A glucose (2g/kg) tolerance test (GTT) was performed at 6 and 9mo via intraperitoneal injection. Following euthanasia at 9mo of age, splenic T cell phenotype was assessed by flow cytometry. Group differences were assessed by independent samples t-test or repeated measures ANOVA and Bonferroni post-hoc test. Data are presented as mean±SEM. At 6mo, the thymex animals had a significantly lower fasting glucose compared to controls (156.8±7.9mg/dl,174.1±5.8mg/dl, p=0.06). During the GTT, 6mo old thymex mice had a greater area under the curve (AUC) compared to controls (31893.8±612.3mg/dl, 28020.9±1112.9mg/dl, p=0.03). At 9mo, the thymex mice had greater fasting glucose compared to controls (215.6±11.6mg/dl, 176.3±7.9mg/dl, p=0.016), as well as a greater GTT AUC (61445.4±1949.2mg/dl, 41527.5±2530.3mg/dl, p=0.0001). The thymex group also had increased fasting and glucose stimulated insulin levels compared to controls (0=1.3±0.2ng/ml 0.3±0.1ng/ml, p=0.01; 15=1.7±0.2ng/ml,0.44±0.1ng/ml, p=0.0014). Thymex mice exhibited a blunted splenic CD4:CD8 ratio (0.5±0.2, 1.1±0.2, p=0.04) compared to controls and a trend toward a memory CD8+ T cell phenotype (23.1±11.6%, 7.1±2.6, p=0.08), both consistent with aging. This data indicates that early life thymectomy may accelerate T cell aging, resulting in impairments in glucose tolerance in otherwise young and middle aged mice.

scholarly journals Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice

2021 ◽  
Vol 118 (23) ◽  
pp. e2103730118
Author(s):  
Yuka Nakajima ◽  
Kenji Chamoto ◽  
Takuma Oura ◽  
Tasuku Honjo
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Critical Role ◽  
Cell Subset ◽  
Effector Memory ◽  
T Cell Subset ◽  
Aged Mice ◽  
Age Related

CD8+ T cells play a central role in antitumor immune responses that kill cancer cells directly. In aged individuals, CD8+ T cell immunity is strongly suppressed, which is associated with cancer and other age-related diseases. The mechanism underlying this age-related decrease in immune function remains largely unknown. This study investigated the role of T cell function in age-related unresponsiveness to PD-1 blockade cancer therapy. We found inefficient generation of CD44lowCD62Llow CD8+ T cell subset (P4) in draining lymph nodes of tumor-bearing aged mice. In vitro stimulation of naive CD8+ T cells first generated P4 cells, followed by effector/memory T cells. The P4 cells contained a unique set of genes related to enzymes involved in one-carbon (1C) metabolism, which is critical to antigen-specific T cell activation and mitochondrial function. Consistent with this finding, 1C-metabolism–related gene expression and mitochondrial respiration were down-regulated in aged CD8+ T cells compared with young CD8+ T cells. In aged OVA-specific T cell receptor (TCR) transgenic mice, ZAP-70 was not activated, even after inoculation with OVA-expressing tumor cells. The attenuation of TCR signaling appeared to be due to elevated expression of CD45RB phosphatase in aged CD8+ T cells. Surprisingly, strong stimulation by nonself cell injection into aged PD-1–deficient mice restored normal levels of CD45RB and ameliorated the emergence of P4 cells and 1C metabolic enzyme expression in CD8+ T cells, and antitumor activity. These findings indicate that impaired induction of the P4 subset may be responsible for the age-related resistance to PD-1 blockade, which can be rescued by strong TCR stimulation.

scholarly journals Identification of factors differentially associated with isolated impaired fasting glucose and isolated post-load impaired glucose tolerance: the Hong Kong Cardiovascular Risk Factor Study

2006 ◽  
Vol 155 (4) ◽  
pp. 623-632 ◽  
Author(s):  
G Neil Thomas ◽  
C Mary Schooling ◽  
Sarah M McGhee ◽  
Sai-Yin Ho ◽  
Bernard M Y Cheung ◽  
...  
Keyword(s):  
Hong Kong ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Glucose Intolerance ◽  
Impaired Fasting Glucose ◽  
Early Life ◽  
Fasting Glucose ◽  
Oral Glucose ◽  
Hip Circumference ◽  
Glucose Levels

Background: The use of fasting and post-prandial glucose levels in the classification of hyperglycaemic states often identifies distinct subjects, but the factors determining these intermediate-isolated glucose intolerant states are yet to be clearly elucidated in Chinese subjects. Methods: Representative subjects (n = 2769) were randomly recruited from the Hong Kong Chinese population and glycaemic status was determined using both fasting and 2h 75 g oral glucose tolerance test glucose levels. The relationship between the groups with isolated glucose intolerance and vascular risk factors was investigated using ANOVA and logistic regression analyses. Results: Using either criterion, diabetes was identified in 265 (9.6%) subjects and glucose intolerance in 568 (20.5%) subjects. Of those 568, isolated impaired glucose tolerance (IGT) using the post-load criterion was identified in 49.5% and isolated impaired fasting glucose (IFG) in 30.5%. Ageing and hyperinsulinaemia were common determinants of IGT and IFG; with small hip circumference a marker of poorer early life development and being born in China rather than Hong Kong, a possible low birth weight marker was also associated with IFG. Hypertension, hypertriglyceridaemia and poor education were also associated with IGT. When we looked for factors differentially associated with these glucose intolerant states, female sex, greater hip circumference, high triglyceride levels, low fasting insulin levels, and not being born in China were independently associated with isolated IGT compared with isolated IFG. Conclusion: Despite common antecedents to the glucose intolerant states, isolated IFG appeared to be particularly associated with early life development, and isolated IGT was more strongly associated with obesity-related determinants such as hypertriglyceridaemia.

Longitudinal Relationship of Early-Life Immunomodulatory T-cell Phenotype and Function with Development of Allergic Sensitization in an Urban Cohort

2010 ◽  
Vol 125 (2) ◽  
pp. AB126
Author(s):  
R.M. McLoughlin ◽  
A. Calatroni ◽  
C.M. Visness ◽  
P.K. Wallace ◽  
W.W. Cruikshank ◽  
...  
Keyword(s):  
T Cell ◽  
Early Life ◽  
Allergic Sensitization ◽  
Cell Phenotype ◽  
And Function ◽  
Relationship Of

Age-related increase of frequency of a new, phenotypically distinct subpopulation of human peripheral blood T cells expressing lowered levels of CD4

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 1100-1107 ◽  
Author(s):  
Ewa Bryl ◽  
Magdalena Gazda ◽  
Jerzy Foerster ◽  
Jacek M. Witkowski
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Human Peripheral Blood ◽  
The Elderly ◽  
Cell Subpopulation ◽  
Cell Phenotype ◽  
Receptor Complexes ◽  
Age Related

Aging is associated with modifications of T-cell phenotype and function, leading to impaired activation in response to both new and recall antigens. It is not known if T-cell activation results in elimination of a number of the CD4 molecules from the cell surface, as is the case with CD3/T-cell receptor complexes, or how aging influences the process. The T cells of young and elderly donors with reduced expression of CD4 were examined to see whether these cells exhibit other phenotypic features suggesting their active state. It was found that T lymphocytes expressing CD4 can be divided into 2 semidiscrete subpopulations: the major (CD4+) population, in which the level of expression of CD4 is constant and high, and a minor population (CD4lo), in which the expression of CD4 can be up to an order of magnitude lower than on the CD4+ cells. The proportion of CD4locells is age dependent and highly variable in the apparently healthy human population, with the expression of CD4 ranging from around 10% of all peripheral blood lymphocytes in the young to more than 30% in the elderly. Lowered expression of CD4 is correlated with a reduced expression of CD3, as well as with a decreased amount of CD28 and CD95Fas. Activation of CD4lo cells is suggested by their expression of CD25 and increased amounts of HLA-DR. Phenotypic characteristics of the CD4lo T-cell subpopulation suggest that it might be formed by (perhaps chronically) activated, temporarily apoptosis-resistant cells, possibly accumulating in the elderly.

Early-life stress induces cognitive disorder in middle-aged mice

2018 ◽  
Vol 64 ◽  
pp. 139-146 ◽  
Author(s):  
Hiroyuki Yajima ◽  
Asahi Haijima ◽  
Miski Aghnia Khairinisa ◽  
Noriaki Shimokawa ◽  
Izuki Amano ◽  
...  
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Early Life Stress ◽  
Cognitive Disorder ◽  
Middle Aged ◽  
Aged Mice

Age‐related alterations in human gut CD4 T cell phenotype, T helper cell frequencies, and functional responses to enteric bacteria

2019 ◽  
Vol 107 (1) ◽  
pp. 119-132 ◽  
Author(s):  
Stephanie M. Dillon ◽  
Jay Liu ◽  
Christine M. Purba ◽  
Allison J. Christians ◽  
Jon J. Kibbie ◽  
...  
Keyword(s):  
T Cell ◽  
Enteric Bacteria ◽  
T Helper Cell ◽  
Cd4 T Cell ◽  
Helper Cell ◽  
Cell Phenotype ◽  
T Helper ◽  
Functional Responses ◽  
Human Gut ◽  
Age Related

Abstract 123: Age-Related Diminishment of the Subventricular Zone Cytogenic Response and Its Contributions to Motor Recovery After Cortical Infarcts

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Michael R Williamson ◽  
Stephanie Le ◽  
Ronald L Franzen ◽  
Michael R Drew ◽  
Theresa A Jones
Keyword(s):  
Young Adult ◽  
Subventricular Zone ◽  
Motor Recovery ◽  
Lineage Tracing ◽  
Stem Cell Markers ◽  
Middle Aged ◽  
Reaching Task ◽  
Aged Mice ◽  
Adult Mice ◽  
Age Related

Stroke increases proliferation within the subventricular zone (SVZ) cytogenic niche and causes subsequent migration of newborn cells towards the site of injury. We investigated the functional consequences of age-related blunting of the SVZ cytogenic response to ischemia. We found that there was a marked reduction in proliferation and neural stem cell markers within the SVZ of middle aged (aged 12-16 months) versus young adult (aged 3-5 months) mice in the intact brain and after photothrombotic infarcts in motor cortex. Using an inducible, heritable lineage tracing system (Nestin-CreER T2 :: Ai14 mice) to quantify SVZ-derived neural precursor cells (NPCs) that migrated towards the infarct, we found that there was a considerable age-related reduction in the number of NPCs in peri-infarct cortex. These findings indicate a marked diminishment of SVZ NPC proliferation and migration after focal ischemia by middle age. Next, we assessed the contributions of the SVZ cytogenic response to recovery of skilled motor function. We used glial fibrillary acidic protein-thymidine kinase mice to conditionally ablate NPCs with ganciclovir administration. In young adult mice, NPC ablation significantly impaired recovery of motor performance on the single seed reaching task after motor cortical infarcts. By contrast, NPC ablation did not affect motor recovery in middle aged mice. Importantly, the magnitude of recovery was less in middle aged mice—regardless of NPC ablation—than in control young adult mice. Middle aged mice recovered similarly to young adult mice lacking NPCs. These results indicate that SVZ cytogenesis contributes to functional improvements after cortical infarcts and that the diminishment of the cytogenic response with age may be implicated in age-related worsening of outcome after stroke. Restoration of SVZ cytogenesis in aged animals might improve behavioral recovery.

scholarly journals Recombinant T-cell receptor ligand RTL1000 limits inflammation and decreases infarct size after experimental ischemic stroke in middle-aged mice

Neuroscience ◽  
2015 ◽  
Vol 288 ◽  
pp. 112-119 ◽  
Author(s):  
W. Zhu ◽  
A.L. Dotson ◽  
N.L. Libal ◽  
A.S. Lapato ◽  
S. Bodhankar ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
T Cell ◽  
Infarct Size ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Middle Aged ◽  
Receptor Ligand ◽  
Aged Mice

scholarly journals Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Alessandro Bitto ◽  
Takashi K Ito ◽  
Victor V Pineda ◽  
Nicolas J LeTexier ◽  
Heather Z Huang ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Optimal Dose ◽  
Increase Life Expectancy ◽  
Middle Aged ◽  
Short Term ◽  
Cancer Prevalence ◽  
Rapamycin Treatment ◽  
Hematopoietic Malignancies ◽  
Aged Mice ◽  
Age Related

The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. We also define a dose in female mice that does not extend lifespan, but is associated with a striking shift in cancer prevalence toward aggressive hematopoietic cancers and away from non-hematopoietic malignancies. These data suggest that a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome.

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