T lymphocyte depletion ameliorates age-related metabolic impairments in mice

Trott, Daniel W.; Islam, Torikul; Buckley, David; Donato, Anthony J.; Dutson, Tavia; Sorensen, Eric S.; Cai, Jinjin; Gogulamudi, Venkateswara R; Phuong, Tam T. T.; Lesniewski, Lisa A.

doi:10.1007/s11357-021-00368-4

Cited by 16 publications

(19 citation statements)

References 42 publications

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“…Likewise, it has been demonstrated that the age‐related impairments in glucose metabolism are associated with adipose tissue T‐cell infiltration (Bapat et al, 2015 ; Khan et al, 2020 ; Stout et al, 2017 ). Moreover, interventions attenuating adipose tissue T‐cell infiltration improve metabolic function in old mice, further supporting a critical role of adipose tissue immune cells in metabolic function in old age (Bapat et al, 2015 ; Feuerer et al, 2009 ; Trott et al, 2021 ). However, the interactions between senescent cells and immune cells, and particularly, if clearing senescent cells can attenuate the abundance of immune cells in the adipose tissue remains unknown.…”

Section: Introductionmentioning

confidence: 84%

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age

et al. 2023

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Aging results in an elevated burden of senescent cells, senescence‐associated secretory phenotype (SASP), and tissue infiltration of immune cells contributing to chronic low‐grade inflammation and a host of age‐related diseases. Recent evidence suggests that the clearance of senescent cells alleviates chronic inflammation and its associated dysfunction and diseases. However, the effect of this intervention on metabolic function in old age remains poorly understood. Here, we demonstrate that dasatinib and quercetin (D&Q) have senolytic effects, reducing age‐related increase in senescence‐associated β‐galactosidase, expression of p16 and p21 gene and P16 protein in perigonadal white adipose tissue (pgWAT; all p ≤ 0.04). This treatment also suppressed age‐related increase in the expression of a subset of pro‐inflammatory SASP genes ( mcp1, tnf‐α, il‐1α, il‐1β, il‐6, cxcl2, and cxcl10 ), crown‐like structures, abundance of T cells and macrophages in pgWAT (all p ≤ 0.04). In the liver and skeletal muscle, we did not find a robust effect of D&Q on senescence and inflammatory SASP markers. Although we did not observe an age‐related difference in glucose tolerance, D&Q treatment improved fasting blood glucose ( p = 0.001) and glucose tolerance ( p = 0.007) in old mice that was concomitant with lower hepatic gluconeogenesis. Additionally, D&Q improved insulin‐stimulated suppression of plasma NEFAs ( p = 0.01), reduced fed and fasted plasma triglycerides (both p ≤ 0.04), and improved systemic lipid tolerance ( p = 0.006). Collectively, results from this study suggest that D&Q attenuates adipose tissue inflammation and improves systemic metabolic function in old age. These findings have implications for the development of therapeutic agents to combat metabolic dysfunction and diseases in old age.

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Section: Introductionmentioning

confidence: 84%

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age

et al. 2023

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“…Alternatively, changes in the abundance of other immune cell populations mediated by the loss of γδ T cells may facilitate the overall decrease in inflammation. For example, CD4 + and CD8 + T conv cells are increased in adipose tissue with age and promote inflammation [ 43 , 65 , 66 ]. We show that these cells are reduced in aged TCRδ KO mice, thus potentially lessening age-related T conv cell-mediated inflammation.…”

Section: Discussionmentioning

confidence: 99%

Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation

et al. 2022

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Adipose tissue dysfunction is strongly linked to the development of chronic inflammation and cardiometabolic disorders in aging. While much attention has been given to the role of resident adipose tissue immune cells in the disruption of homeostasis in obesity, age-specific effects remain understudied. Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue (VAT) of both mice and humans. Diet-induced obesity likewise increased γδ T cell numbers; however, the effect was greater in the aged where the increase was independent of fat mass. γδ T cells in VAT express a tissue-resident memory T cell phenotype (CD44hiCD62LlowCD69+) and are predominantly IL-17A-producing cells. Transcriptome analyses of immunomagnetically purified γδ T cells identified significant age-associated differences in expression of genes related to inflammation, immune cell composition, and adipocyte differentiation, suggesting age-dependent qualitative changes in addition to the quantitative increase. Genetic deficiency of γδ T cells in old age improved the metabolic phenotype, characterized by increased respiratory exchange ratio, and lowered levels of IL-6 both systemically and locally in VAT. Decreased IL-6 was predominantly due to reduced production by non-immune stromal cells, primarily preadipocytes, and adipose-derived stem cells. Collectively, these findings suggest that an age-dependent increase of tissue-resident γδ T cells in VAT contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.

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“…Recent study reported that. T lymphocyte depletion ameliorates age-related metabolic impairments in mice [38]. The study also reported that age-related insulin resistance (IR) was associated with increased in T cells infiltration in skeletal muscle of old mice with IR [38].…”

Section: Plos Onementioning

confidence: 92%

“…T lymphocyte depletion ameliorates age-related metabolic impairments in mice [38]. The study also reported that age-related insulin resistance (IR) was associated with increased in T cells infiltration in skeletal muscle of old mice with IR [38]. Previous study reported a close relationship between IR and disease progression and complications development of NAFLD [39].…”

Section: Plos Onementioning

confidence: 94%

Obeticholic acid treatment ameliorates the cardiac dysfunction in NASH mice

et al. 2022

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Background Suppression of cardiac iinflammasome, which can be inhibited by Farnesoid X receptor (FXR) agonist, can ameliorate cardiac inflammation and fibrosis. Increased cardiac inflammasome decrease the abundance of regulatory T (Treg) cells and exacerbate cardiac dysfunction. Interaction between cardiomyocytes and Treg cells is involved in the development of nonalcoholic steatohepatitis (NASH)-related cardiac dysfunction. Aims This study evaluates whether the FXR agonist obeticholic acid (OCA) treatment improves NASH-associated cardiac dysfunction. Methods The in vivo and in vitro mechanisms and effects of two weeks of OCA treatment on inflammasome and Treg dysregulation-related cardiac dysfunction in NASH mice (NASH-OCA) at systemic, tissue and cellular levels were investigated. Results The OCA treatment suppressed the serum and cardiac inflammasome levels, reduced the cardiac infiltrated CD3+ T cells, increased the cardiac Treg-represented anti-inflammatory cytokines (IL-10/IL-10R) and improved cardiac inflammation, fibrosis and function [decreased left ventricle (LV) mass and increased fractional shortening (FS)] in NASH-OCA mice. The percentages of OCA-decreased cardiac fibrosis and OCA-increased FS were positively correlated with the percentage of OCA-increased levels of cardiac FXR and IL-10/IL-10R. In the Treg cells from NASH-OCA mice spleen, in comparison with the Treg cells of the NASH group, higher intracellular FXR but lower inflammasome levels, and more proliferative/active and less apoptotic cells were observed. Incubation of H9c2 cardiomyoblasts with Treg-NASHcm [supernatant of Treg from NASH mice as condition medium (cm)], increased inflammasome levels, decreased the proliferative/active cells, suppressed the intracellular FXR, and downregulated differentiation/contraction marker. The Treg-NASHcm-induced hypocontractility of H9c2 can be attenuated by co-incubation with OCA, and the OCA-related effects were abolished by siIL-10R pretreatment. Conclusions Chronic FXR activation with OCA is a potential strategy for activating IL-10/IL-10R signalling, reversing cardiac regulatory T cell dysfunction, and improving inflammasome-mediated NASH-related cardiac dysfunction.

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T lymphocyte depletion ameliorates age-related metabolic impairments in mice

Cited by 16 publications

References 42 publications

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age

Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation

Obeticholic acid treatment ameliorates the cardiac dysfunction in NASH mice

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