Browsing by Subject "senescence"

Now showing 1 - 6 of 6
  • Thumbnail Image
    ItemOpen Access
  • Thumbnail Image
    ItemOpen Access
    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.
  • Thumbnail Image
    ItemOpen Access
    Glioblastoma as an age-related neurological disorder in adults.
    (Neuro-oncology advances, 2021-01) Kim, Miri; Ladomersky, Erik; Mozny, Andreas; Kocherginsky, Masha; O'Shea, Kaitlyn; Reinstein, Zachary Z; Zhai, Lijie; Bell, April; Lauing, Kristen L; Bollu, Lakshmi; Rabin, Erik; Dixit, Karan; Kumthekar, Priya; Platanias, Leonidas C; Hou, Lifang; Zheng, Yinan; Wu, Jennifer; Zhang, Bin; Hrachova, Maya; Merrill, Sarah A; Mrugala, Maciej M; Prabhu, Vikram C; Horbinski, Craig; James, Charles David; Yamini, Bakhtiar; Ostrom, Quinn T; Johnson, Margaret O; Reardon, David A; Lukas, Rimas V; Wainwright, Derek A

    Background

    Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDHwt GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDHwt GBM have a median age of diagnosis at 68-70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM.

    Methods

    The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship.

    Results

    Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve.

    Conclusions

    Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDHwt GBM patient outcomes.
  • Thumbnail Image
    ItemOpen Access
    Pathogenic triad in COPD: oxidative stress, protease-antiprotease imbalance, and inflammation.
    (Int J Chron Obstruct Pulmon Dis, 2011) Fischer, Bernard M; Pavlisko, Elizabeth; Voynow, Judith A
    Patients with chronic obstructive pulmonary disease (COPD) exhibit dominant features of chronic bronchitis, emphysema, and/or asthma, with a common phenotype of airflow obstruction. COPD pulmonary physiology reflects the sum of pathological changes in COPD, which can occur in large central airways, small peripheral airways, and the lung parenchyma. Quantitative or high-resolution computed tomography is used as a surrogate measure for assessment of disease progression. Different biological or molecular markers have been reported that reflect the mechanistic or pathogenic triad of inflammation, proteases, and oxidants and correspond to the different aspects of COPD histopathology. Similar to the pathogenic triad markers, genetic variations or polymorphisms have also been linked to COPD-associated inflammation, protease-antiprotease imbalance, and oxidative stress. Furthermore, in recent years, there have been reports identifying aging-associated mechanistic markers as downstream consequences of the pathogenic triad in the lungs from COPD patients. For this review, the authors have limited their discussion to a review of mechanistic markers and genetic variations and their association with COPD histopathology and disease status.
  • Thumbnail Image
    ItemOpen Access
    The emergence of longevous populations.
    (Proc Natl Acad Sci U S A, 2016-11-29) Colchero, Fernando; Rau, Roland; Jones, Owen R; Barthold, Julia A; Conde, Dalia A; Lenart, Adam; Nemeth, Laszlo; Scheuerlein, Alexander; Schoeley, Jonas; Torres, Catalina; Zarulli, Virginia; Altmann, Jeanne; Brockman, Diane K; Bronikowski, Anne M; Fedigan, Linda M; Pusey, Anne E; Stoinski, Tara S; Strier, Karen B; Baudisch, Annette; Alberts, Susan C; Vaupel, James W
    The human lifespan has traversed a long evolutionary and historical path, from short-lived primate ancestors to contemporary Japan, Sweden, and other longevity frontrunners. Analyzing this trajectory is crucial for understanding biological and sociocultural processes that determine the span of life. Here we reveal a fundamental regularity. Two straight lines describe the joint rise of life expectancy and lifespan equality: one for primates and the second one over the full range of human experience from average lifespans as low as 2 y during mortality crises to more than 87 y for Japanese women today. Across the primate order and across human populations, the lives of females tend to be longer and less variable than the lives of males, suggesting deep evolutionary roots to the male disadvantage. Our findings cast fresh light on primate evolution and human history, opening directions for research on inequality, sociality, and aging.
  • Thumbnail Image
    ItemOpen Access
    UHRF1 is required for basal stem cell proliferation in response to airway injury.
    (Cell Discov, 2017) Xiang, Handan; Yuan, Lifeng; Gao, Xia; Alexander, Peter B; Lopez, Omar; Lau, Calvin; Ding, Yi; Chong, Mengyang; Sun, Tao; Chen, Rui; Liu, Si-Qi; Wu, Haiyang; Wan, Ying; Randell, Scott H; Li, Qi-Jing; Wang, Xiao-Fan
    Cellular senescence is a cell fate characterized by an irreversible cell cycle arrest, but the molecular mechanism underlying this senescence hallmark remains poorly understood. Through an unbiased search for novel senescence regulators in airway basal cells, we discovered that the epigenetic regulator ubiquitin-like with PHD and ring finger domain-containing protein 1 (UHRF1) is critical for regulating cell cycle progression. Upon injury, basal cells in the mouse airway rapidly induce the expression of UHRF1 in order to stimulate stem cell proliferation and tissue repair. Targeted depletion of Uhrf1 specifically in airway basal cells causes a profound defect in cell cycle progression. Consistently, cultured primary human basal cells lacking UHRF1 do not exhibit cell death or differentiation phenotypes but undergo a spontaneous program of senescence. Mechanistically, UHRF1 loss induces G1 cell cycle arrest by abrogating DNA replication factory formation as evidenced by loss of proliferating cell nuclear antigen (PCNA) puncta and an inability to enter the first cell cycle. This proliferation defect is partially mediated by the p15 pathway. Overall, our study provides the first evidence of an indispensable role of UHRF1 in somatic stem cells proliferation during the process of airway regeneration.