Browsing by Subject "SASP"

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    Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype.
    (Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2023-11) Liang, Yaosi; Pan, Christopher; Yin, Tao; Wang, Lu; Gao, Xia; Wang, Ergang; Quang, Holly; Huang, De; Tan, Lianmei; Xiang, Kun; Wang, Yu; Alexander, Peter B; Li, Qi-Jing; Yao, Tso-Pang; Zhang, Zhao; Wang, Xiao-Fan
    The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence-associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation-related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age-related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age-related and inflammatory diseases.
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    Senescence Associated Secretory Phenotype Regulation in Lung Aging and Malignancy Progression
    (2018) Chong, Meng-Yang

    Cellular senescence is a unique cell fate characterized by stable cell cycle arrest and the extensive production and secretion of various cytokines, chemokines, proteases, and growth factors, a phenomenon known as the senescence-associated secretory phenotype (SASP). Although secreted factors are known to have important biological effects on both senescent and non-senescent cells in the contexts of normal aging and disease, the precise molecular mechanisms responsible for generating a SASP in response to senescent stimuli have remained largely obscure. To identify the major initiator, we used an unbiased profiling strategy and discovered a multi-ligand scavenger receptor CD36 is rapidly upregulated in multiple cell types in response to replicative, oncogenic and chemical senescent stimuli. Moreover, ectopic CD36 expression in dividing mammalian cells is sufficient to initiate the production of a large subset of known components of the SASP via activation of the canonical Src-NFκB pathway, resulting in the subsequent onset of a full senescent state. The CD36-mediated secretome is further shown to be ligand-dependent, as fibroblast cultures lacking the CD36 ligand amyloid beta (Aβ) are unresponsive to CD36 upregulation but can be driven to senesce by the addition of exogenous ligand. Finally, loss-of-function experiments revealed a strict requirement for CD36 in secretory molecule production during conventional senescence reprogramming. These results uncover the Aβ-CD36-NFκB signaling axis as an important regulator of the senescent cell fate via induction of the SASP.

    To further explore the possible implication of Aβ-CD36-NFκB-SASP signaling, we found that the CD36 expression is significantly down-regulated in the context of lung malignant tissues, specifically in cancer cells. Subsequent explorations revealed CD36 as a strong tumor suppressor by secreting pro-inflammatory cytokines and recruiting cytotoxic T. For the CD36 ligand - Aβ, we observed a major accumulation in the tumor region which might serve as the tumor-suppressing signaling initiation cue once CD36 is introduced. The findings indicate a possible tumor suppressive signaling lead by Aβ-CD36.

    Taken together, we discovered a novel signaling of Aβ-CD36-NFκB in regulating SASP during the process of lung aging and the progression of lung malignancy.