Telomeres are specialized nucleoprotein structures, which protect chromosome ends and have been implicated in the ageing process. Telomere shortening has been shown to contribute to a persistent DNA ...damage response (DDR) during replicative senescence, the irreversible loss of division potential of somatic cells. Similarly, persistent DDR foci can be found in stress-induced senescence, although their nature is not understood. Here we show, using immuno-fluorescent in situ hybridization and ChIP, that up to half of the DNA damage foci in stress-induced senescence are located at telomeres irrespective of telomerase activity. Moreover, live-cell imaging experiments reveal that all persistent foci are associated with telomeres. Finally, we report an age-dependent increase in frequencies of telomere-associated foci in gut and liver of mice, occurring irrespectively of telomere length. We conclude that telomeres are important targets for stress in vitro and in vivo and this has important consequences for the ageing process.
Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription ...factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1(-/-) fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1(-/-) tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor.
Osteoarthritis (OA) is the leading form of arthritis in the elderly, causing pain, disability, and immobility. OA has been associated with accumulation of senescent cells in or near joints. However, ...evidence for a causal link between OA and cellular senescence is lacking. Here, we present a novel senescent cell transplantation model involving injection of small numbers of senescent or nonsenescent cells from the ear cartilage of luciferase-expressing mice into the knee joint area of wild-type mice. By using bioluminescence and 18FDG PET imaging, we could track the injected cells in vivo for more than 10 days. Transplanting senescent cells into the knee region caused leg pain, impaired mobility, and radiographic and histological changes suggestive of OA. Transplanting nonsenescent cells had less of these effects. Thus, senescent cells can induce an OA-like state and targeting senescent cells could be a promising strategy for treating OA.
Cellular 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 p16Ink4a-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin. We found that obesity results in the accumulation of senescent glial cells in proximity to the lateral ventricle, a region in which adult neurogenesis occurs. Furthermore, senescent glial cells exhibit excessive fat deposits, a phenotype we termed “accumulation of lipids in senescence.” Clearing senescent cells from high fat-fed or leptin receptor-deficient obese mice restored neurogenesis and alleviated anxiety-related behavior. Our study provides proof-of-concept evidence that senescent cells are major contributors to obesity-induced anxiety and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.
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•Obesity drives senescence in glial cells in the LV of mouse brains•Obesity-induced senescence drives fat deposits in PV areas of the brain•Senescent cell clearance in obesity restores neurogenesis in the SVZ•Senescent cell clearance alleviates obesity-induced anxiety-like behavior
Obesity, a growing health problem in western societies, is associated with increased senescent cells and neuropsychiatric disorders, including anxiety and depression. Ogrodnik and colleagues found that clearance of senescent cells in obese mice alleviates anxiety. Our study provides proof-of-concept evidence that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.
Cellular senescence is a pivotal factor contributing to aging and the pathophysiology of age-related diseases. Despite the presence of inflammation and abnormal immune system function in both ...inflammatory bowel diseases (IBD) and senescence, the relationship between the two remains largely unexplored. Therefore, our study aimed to investigate the intricate connection between cellular senescence, telomeres, and IBD. The review highlights the presence of senescence markers, particularly p16 and p21, in IBD patients, suggesting their potential association with disease progression and mucosal inflammation. We emphasize the critical role of macrophages in eliminating senescent cells and how disturbance in effective clearance may contribute to persistent senescence and inflammation in IBD. Additionally, we shed light on the involvement of telomeres in IBD, as their dysfunction impairs enterocyte function and disrupts colonic barrier integrity, potentially exacerbating the pathogenesis of the disease. Targeting senescence and telomere dysfunctions holds promise for the development of innovative therapeutic approaches to mitigate intestinal inflammation and alleviate symptoms in IBD patients. By unraveling the precise role of senescence in IBD, we can pave the way for the discovery of novel therapeutic interventions that effectively address the underlying mechanisms of intestinal inflammation, offering hope for improved management and treatment of IBD patients.
•Senescence may be intricately associated with inflammatory bowel diseases (IBD).•Disrupted macrophage functions may contribute to senescence and IBD inflammation.•Telomere dysfunction can impair gut integrity, potentially exacerbating IBD.•Exploring senescence unveils prospects for innovative IBD treatment strategies.
Ageing 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. During ageing, human and murine cardiomyocytes acquire a senescent‐like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length. Length‐independent telomere damage in cardiomyocytes activates the classical senescence‐inducing pathways, p21CIP and p16INK4a, and results in a non‐canonical senescence‐associated secretory phenotype, which is pro‐fibrotic and pro‐hypertrophic. Pharmacological or genetic clearance of senescent cells in mice alleviates detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis. Our data describe a mechanism by which senescence can occur and contribute to age‐related myocardial dysfunction and in the wider setting to ageing in post‐mitotic tissues.
Synopsis
Cellular senescence induced by telomere shortening during cell division has been implicated in age‐related tissue dysfunction. In rarely dividing post‐mitotic cells, telomeric DNA damage leading to senescence is triggered by mitochondria‐derived reactive oxygen species (ROS), suggesting new avenues for improved cardiac regeneration therapies.
Length‐independent telomere damage occurs in ageing post‐mitotic cardiomyocytes.
Mitochondrial dysfunction and ROS drive telomere dysfunction in aged cardiomyocytes.
Senescent cell clearance reduces hypertrophy and fibrosis in aged hearts.
The heart responds to senescent cell clearance with limited cardiomyocyte regeneration.
Mitochondria derived reactive oxygen species trigger persistent DNA damage at telomeres, cardiomyocyte senescence and heart dysfunction during ageing.
Cell senescence is an important tumour suppressor mechanism and driver of ageing. Both functions are dependent on the development of the senescent phenotype, which involves an overproduction of ...pro‐inflammatory and pro‐oxidant signals. However, the exact mechanisms regulating these phenotypes remain poorly understood. Here, we show the critical role of mitochondria in cellular senescence. In multiple models of senescence, absence of mitochondria reduced a spectrum of senescence effectors and phenotypes while preserving ATP production via enhanced glycolysis. Global transcriptomic analysis by RNA sequencing revealed that a vast number of senescent‐associated changes are dependent on mitochondria, particularly the pro‐inflammatory phenotype. Mechanistically, we show that the ATM, Akt and mTORC1 phosphorylation cascade integrates signals from the DNA damage response (DDR) towards PGC‐1β‐dependent mitochondrial biogenesis, contributing to a ROS‐mediated activation of the DDR and cell cycle arrest. Finally, we demonstrate that the reduction in mitochondrial content in vivo, by either mTORC1 inhibition or PGC‐1β deletion, prevents senescence in the ageing mouse liver. Our results suggest that mitochondria are a candidate target for interventions to reduce the deleterious impact of senescence in ageing tissues.
Synopsis
Cellular senescence serves as an important anticancer growth arrest mechanism, but also contributes to ageing. This study shows that mitochondria are necessary for the pro‐inflammatory phenotype during senescence and that senescence can be induced by mitochondrial biogenesis.
Mitochondria are required for the development of the pro‐oxidant and pro‐inflammatory features of senescence.
ATM, Akt, mTOR and PGC‐1β‐mediated mitochondrial biogenesis are involved in a novel senescence signalling pathway.
Mitochondrial biogenesis stabilizes senescence via a positive feedback loop involving ROS and the DDR.
Cellular senescence serves as an important anticancer growth arrest mechanism, but also contributes to ageing. This study shows that mitochondria are necessary for the pro‐inflammatory phenotype during senescence and that senescence can be induced by mitochondrial biogenesis.
Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)
. Mitochondria are major regulators of the SASP; ...however, the underlying mechanisms have not been elucidated
. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die
. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
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