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The identification of genes that confer either extension of life span or accelerate age-related decline was a step forward in understanding the mechanisms of aging and revealed that it is partially controlled by genetics and transcriptional programs. Here, we discovered that the human DNA sequence C16ORF70 encodes a protein, named MYTHO (macroautophagy and youth optimizer), which controls life span and health span. MYTHO protein is conserved from Caenorhabditis elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the orthologous myt-1 gene in C. elegans dramatically shortened life span and decreased animal survival upon exposure to oxidative stress. Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy aging., Introduction In nature, organisms are continuously exposed to environmental stresses that challenge their survival. The species that quickly and efficiently adapt to hostile conditions are positively selected. This response is [...]

There is intense interest in identifying compounds that selectively kill senescent cells, termed senolytics, for ameliorating age-related comorbidities. However, screening for senolytic compounds currently relies on primary cells or cell lines where senescence is induced in vitro. Given the complexity of senescent cells across tissues and diseases, this approach may not target the senescent cells that develop under specific conditions in vivo. In this issue of the JCI, Lee et al. describe a pipeline for high- throughput drug screening of senolytic compounds where senescence was induced in vivo and identify the HSP90 inhibitor XL888 as a candidate senolytic to treat idiopathic pulmonary fibrosis., The complexity of cellular senescence With population aging, considerable resources are being invested in developing pharmaceutical interventions to increase healthspan and perhaps even lifespan. Underpinning this effort is the geroscience [...]

The appearance of senescent cells in age-related diseases has spurred the search for compounds that can target senescent cells in tissues, termed senolytics. However, a major caveat with current senolytic screens is the use of cell lines as targets where senescence is induced in vitro, which does not necessarily reflect the identity and function of pathogenic senescent cells in vivo. Here, we developed a new pipeline leveraging a fluorescent murine reporter that allows for isolation and quantification of [p16.sup.Ink4a+] cells in diseased tissues. By high-throughput screening in vitro, precision-cut lung slice (PCLS) screening ex vivo, and phenotypic screening in vivo, we identified a HSP90 inhibitor, XL888, as a potent senolytic in tissue fibrosis. XL888 treatment eliminated pathogenic [p16.sup.Ink4a+] fibroblasts in a murine model of lung fibrosis and reduced fibrotic burden. Finally, XL888 preferentially targeted [p16.sup.INK4a-hi] human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF), and reduced [p16.sup.INK4a+] fibroblasts from IPF PCLS ex vivo. This study provides proof of concept for a platform where [p16.sup.INK4a+] cells are directly isolated from diseased tissues to identify compounds with in vivo and ex vivo efficacy in mice and humans, respectively, and provides a senolytic screening platform for other age-related diseases., Introduction Hayflick's original description of a stereotyped proliferative arrest for primary cells in culture as 'senescence at the cellular level' (1) gave way to geroscience that seeks to unravel the [...]

Acute kidney injury (AKI) is a common clinical complication characterized by a sudden deterioration of the kidney's excretory function, which normally occurs secondary to another serious illness. AKI is an important risk factor for chronic kidney disease (CKD) occurrence and progression to kidney failure. It is, therefore, crucial to block the development of AKI as early as possible. To date, existing animal studies have shown that senescence occurs in the early stage of AKI and is extremely critical to prognosis. Cellular senescence is an irreversible process of cell cycle arrest that is accompanied by alterations at the transcriptional, metabolic, and secretory levels along with modified cellular morphology and chromatin organization. Acute cellular senescence tends to play an active role, whereas chronic senescence plays a dominant role in the progression of AKI to CKD. The occurrence of chronic senescence is inseparable from senescence-associated secretory phenotype (SASP) and senescence-related pathways. SASP acts on normal cells to amplify the senescence signal through senescence-related pathways. Senescence can be improved by initiating reprogramming, which plays a crucial role in blocking the progression of AKI to CKD. This review integrates the existing studies on senescence in AKI from several aspects to find meaningful research directions to improve the prognosis of AKI and prevent the progression of CKD., Author(s): Xiaoxi Lin [sup.1] , Heng Jin [sup.1] , Yanfen Chai [sup.1] , Songtao Shou [sup.1] Author Affiliations: (1) grid.412645.0, 0000 0004 1757 9434, Department of Emergency Medicine, Tianjin Medical [...]

Background: The present study examined whether mitochondrial DNA copy number (mtDNAcn) and telomere length--key markers of cellular aging--were altered in male and female participants with obsessive-compulsive disorder (OCD) compared to healthy controls. We also tested for associations between these alterations and OCD-related clinical features and inflammatory index. Methods: A total of 235 patients with OCD (38.7% female) and 234 healthy controls (41.5% female) were included. We quantified whole-blood mtDNAcn and leukocyte telomere length using quantitative polymerase chain reaction. We also calculated the neutrophil-to- lymphocyte ratio from complete blood cell counts. Results: Multivariate analysis of covariance showed that OCD status had a significant overall effect on cellular aging markers in men (Wilks [lambda] = 0.889, [F.sub.2,275] = 17.13, p < 0.001) and women (Wilks [lambda] = 0.742, [F.sub.2,182] = 31.61, p < 0.001) after controlling for age, body mass index and childhood trauma. In post-hoc comparisons, men with OCD had lower mtDNAcn than controls (p < 0.001), but we found no between-group difference for telomere length (p = 0.55). Women with OCD had a significantly lower mtDNAcn (p < 0.001) and shortened telomere length (p = 0.023) compared to controls. Moreover, the lower mtDNAcn shown in the OCD group was significantly correlated with an increase in systemic inflammation for both sexes, as measured by neutrophil-to-lymphocyte ratio. Limitations: The present cross-sectional design did not allow us to infer a causal relationship between OCD disease status and cellular aging markers. Conclusion: The present study is, to our knowledge, the first to demonstrate alterations in mtDNAcn and telomere shortening in OCD. These results suggest that aging-associated molecular mechanisms may be important in the pathophysiology of OCD., Introduction Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatrie disorder characterized by repetitive, intrusive and time-consuming thoughts (obsessions) and irresistible irrational behaviours or rituals (compulsions), which can cause severe distress to [...]

Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress. Senescent cells (SnCs) can develop a characteristic pathogenic senescence-associated secretory phenotype (SASP) that drives secondary senescence and disrupts tissue homeostasis, resulting in loss of tissue repair and regeneration. The use of transgenic mouse models in which SnCs can be genetically ablated has established a key role for SnCs in driving aging and age-related disease. Importantly, senotherapeutics have been developed to pharmacologically eliminate SnCs, termed senolytics, or suppress the SASP and other markers of senescence, termed senomorphics. Based on extensive preclinical studies as well as small clinical trials demonstrating the benefits of senotherapeutics, multiple clinical trials are under way. This Review discusses the role of SnCs in aging and age-related diseases, strategies to target SnCs, approaches to discover and develop senotherapeutics, and preclinical and clinical advances of senolytics., Introduction Aging is a complex process driven, at least in part, by hallmarks of aging, including cellular senescence, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, [...]

Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood and solid tissues, termed inflammaging. Inflammaging has been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function. The search for mechanisms that underlie inflammaging focused initially on the hallmarks of aging, but it is rapidly expanding in multiple directions. Here, we discuss the threads connecting cellular senescence and mitochondrial dysfunction to impaired mitophagy and DNA damage, which may act as a hub for inflammaging. We explore the emerging multi-omics efforts that aspire to define the complexity of inflammaging - and identify molecular signatures and novel targets for interventions aimed at counteracting excessive inflammation and its deleterious consequences while preserving the physiological immune response. Finally, we review the emerging evidence that inflammation is involved in brain aging and neurodegenerative diseases. Our goal is to broaden the research agenda for inflammaging with an eye on new therapeutic opportunities., Aging has been conceptualized as a continuous duel between damage accumulation--due to a combination of environmental and endogenous processes--and resilience mechanisms that cope with such stressors and resolve damage (1). [...]

Researchers are beginning to work out the part senescent cells play in the respiratory disease. Researchers are beginning to work out the part senescent cells play in the respiratory disease., Author(s): Anthony King Author Affiliations: Zombie cells hold clues to COPD progression Credit: Sam Chivers [see PDF for image] An illustrated large black cell in the centre reaches out and [...]