Age-associated changes in basal NF-κB function in human CD4+ T lymphocytes via dysregulation of PI3 kinase

Bektas, Arsun; Zhang, Yongqing; Lehmann, Elin; Wood, William H.; Becker, Kevin G.; Madara, Karen; Ferrucci, Luigi; Sen, Ranjan

doi:10.18632/aging.100705

Cited by 42 publications

(48 citation statements)

References 47 publications

(52 reference statements)

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“…For example, gene-expression studies show that CD4 + lymphocytes from older individuals have higher intrinsic activation of the NF-κB pathways than those from younger individuals 120 . After stimulation with anti-CD3, the production of pro-inflammatory cytokines in vitro is lower in cells from older individuals than in cells from younger individuals 120 , a phenomenon that might be related to altered metabolic activity 121 . However, because these studies have been performed only in small populations, their relevance to inflammageing is unknown.…”

Section: Risk Factors and Causes Of Inflammageingmentioning

confidence: 99%

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

2018

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Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty — which affect clinical manifestations, prognosis, and response to treatment — and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.

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“…Increased PI3K signaling has been reported in the peripheral blood mononuclear cells [260] and CD4+ lymphocytes [261] from old human donors. Animal studies also showed that PI3K signaling was increased in skeletal muscle (26 mo vs. 6 mo) [262] and heart of old rats [263], and macrophages of old mice [264].…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress response and Nrf2 signaling in aging

Zhang¹,

Davies

Forman

2015

Free Radical Biology and Medicine

583

432

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Increasing oxidative stress, a major characteristic of aging, has been implicated in variety of age-related pathologies. In aging, oxidant production from several sources is increased while antioxidant enzymes, the primary lines of defense, are decreased. Repair systems, including the proteasomal degradation of damaged proteins also declines. Importantly, the adaptive response to oxidative stress declines with aging. Nrf2/EpRE signaling regulates the basal and inducible expression of many antioxidant enzymes and the proteasome. Nrf2/EpRE activity is regulated at several levels including transcription, post-translation, and interaction with other proteins. This review summarizes current studies on age-related impairment of Nrf2/EpRE function and discusses the change of Nrf2 regulatory mechanisms with aging.

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“…38 For example, a regulator of lung morphogenesis that is lower in childhood, nuclear factor kappa-light-chainenhancer of activated B cells (NF-b), plays a pathologic role in inflammatory diseases and should be evaluated as a protective host factor in pediatric versus adult SARS-CoV-2 infections. 38,39 Indeed, even outside the context of SARS-CoV-2 infections, rates of ARDS are A c c e p t e d M a n u s c r i p t 9 lowest in children and increase with age, suggesting a role for protective host factors in the lungs of children. 40,41 Innate and adaptive Immunity: Th1 responses are thought to be important for immune protection against SARS-CoV-1 since increased Th2 cytokines were identified in patients with fatal disease.…”

Section: Disease Mitigating Characteristics Of Childrenmentioning

confidence: 99%

Lessons From COVID-19 in Children: Key Hypotheses to Guide Preventative and Therapeutic Strategies

Singh

Heston

Langel

et al. 2020

Clinical Infectious Diseases

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The current pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), reveals a peculiar trend of milder disease and lower case fatality in children compared with adults. Consistent epidemiologic evidence of reduced severity of infection in children across different populations and countries suggests there are underlying biological differences between children and adults that mediate differential disease pathogenesis. This presents a unique opportunity to learn about disease-modifying host factors from pediatric populations. Our review summarizes the current knowledge of pediatric clinical disease, role in transmission, risks for severe disease, protective immunity, as well as novel therapies and vaccine trials for children. We then define key hypotheses and areas for future research that can use the pediatric model of disease, transmission, and immunity to develop preventive and therapeutic strategies for people of all age groups.

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“…The imbalance between adaptive and innate immunity seems to be causally involved in the proinflammatory phenotype observed in elderly, which is also related to autoimmunity. In this regard, NF-κB, as the main regulator of innate immunity, is critically involved in thymic involution and in other immune-related alterations (Osorio et al, 2012a;Kawahara et al, 2009;Bektas et al, 2014).…”

Section: Immunosenescencementioning

confidence: 99%

“…In this regard, it has been demonstrated that T cells show age-related NF-κB hyperactivation and subsequently, they secrete higher levels of proinflammatory cytokines (Bektas et al, 2014). The reversal of immune alterations upon NF-κB inhibition in vitro and in vivo demonstrates that this inhibitory strategy could be useful for improving immune activity during ageing (Osorio et al, 2012a;Tilstra et al, 2012;Kawahara et al, 2009;Huang et al, 2008).…”

Section: Immunosenescencementioning

confidence: 99%