Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process.
View Article and Find Full Text PDFOver half a century has passed since Alexey Olovnikov's groundbreaking proposal of the end-replication problem in 1971, laying the foundation for our understanding of telomeres and their pivotal role in cellular senescence. This review paper delves into the intricate and multifaceted relationship between cellular senescence, the influence of telomeres in this process, and the far-reaching consequences of telomeres in the context of aging and age-related diseases. Additionally, the paper investigates the various factors that can influence telomere shortening beyond the confines of the end-replication problem and how telomeres can exert their impact on aging, even in the absence of significant shortening.
View Article and Find Full Text PDFJ Gerontol A Biol Sci Med Sci
February 2024
The geroscience hypothesis suggests that addressing the fundamental mechanisms driving aging biology will prevent or mitigate the onset of multiple chronic diseases, for which the largest risk factor is advanced age. Research that investigates the root causes of aging is therefore of critical importance given the rising healthcare burden attributable to age-related diseases. The third annual Midwest Aging Consortium symposium was convened as a showcase of such research performed by investigators from institutions across the Midwestern United States.
View Article and Find Full Text PDFHuman lifespan continues to extend as an unprecedented number of people reach their seventh and eighth decades of life, unveiling chronic conditions that affect the older adult. Age-related skin conditions include senile purpura, seborrheic keratoses, pemphigus vulgaris, bullous pemphigoid, diabetic foot wounds and skin cancer. Current methods of drug testing prior to clinical trials require the use of pre-clinical animal models, which are often unable to adequately replicate human skin response.
View Article and Find Full Text PDFPatients with cholestatic liver disease, including those with primary biliary cholangitis, can experience symptoms of impaired cognition or brain fog. This phenomenon remains unexplained and is currently untreatable. Bile duct ligation (BDL) is an established rodent model of cholestasis.
View Article and Find Full Text PDFEndogenous cytoplasmic DNA (cytoDNA) species are emerging as key mediators of inflammation in diverse physiological and pathological contexts. Although the role of endogenous cytoDNA in innate immune activation is well established, the cytoDNA species themselves are often poorly characterized and difficult to distinguish, and their mechanisms of formation, scope of function and contribution to disease are incompletely understood. Here, we summarize current knowledge in this rapidly progressing field with emphases on similarities and differences between distinct cytoDNAs, their underlying molecular mechanisms of formation and function, interactions between cytoDNA pathways, and therapeutic opportunities in the treatment of age-associated diseases.
View Article and Find Full Text PDFCellular senescence is characterized by an irreversible cell cycle arrest as well as a pro-inflammatory phenotype, thought to contribute to aging and age-related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age-related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood.
View Article and Find Full Text PDFCellular senescence is an irreversible cell cycle arrest, which can be triggered by a number of stressors, including telomere damage. Among many other phenotypic changes, senescence is accompanied by increased secretion of pro-inflammatory molecules, also known as the senescence-associated secretory phenotype (SASP). It is thought that accumulation of senescent cells contributes to age-associated tissue dysfunction partly by inducing senescence in neighboring cells through mechanisms involving SASP factors.
View Article and Find Full Text PDFEBioMedicine
February 2020
Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16 during human skin ageing.
View Article and Find Full Text PDFBackground: Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans.
View Article and Find Full Text PDFCardiovascular disease is the leading cause of death in individuals over 60 years old. Aging is associated with an increased prevalence of coronary artery disease and a poorer prognosis following acute myocardial infarction (MI). With age, senescent cells accumulate in tissues, including the heart, and contribute to age-related pathologies.
View Article and Find Full Text PDFAgeing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age-related cardiac dysfunction.
View Article and Find Full Text PDFCellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin.
View Article and Find Full Text PDFCumulative evidence suggests that cellular senescence plays a variety of important physiological roles, including tumor suppression, embryonic development and ageing. Senescent cells are characterized by increased production of reactive oxygen species (ROS), mostly produced by dysfunctional mitochondria. Both intracellular and extracellular ROS have been shown to contribute to the induction of senescence.
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