Search

Autophagy is an important cellular degradation pathway with a central role in metabolism as well as basic quality control, two processes inextricably linked to ageing. A decrease in autophagy is associated with increasing age, yet it is unknown if this is causal in the ageing process, and whether autophagy restoration can counteract these ageing effects. Here we demonstrate that systemic autophagy inhibition induces the premature acquisition of age-associated phenotypes and pathologies in mammals. Remarkably, autophagy restoration provides a near complete recovery of morbidity and a significant extension of lifespan; however, at the molecular level this rescue appears incomplete. Importantly autophagy-restored mice still succumb earlier due to an increase in spontaneous tumour formation. Thus, our data suggest that chronic autophagy inhibition confers an irreversible increase in cancer risk and uncovers a biphasic role of autophagy in cancer development being both tumour suppressive and oncogenic, sequentially., Autophagy declines with age, yet it is unclear if restoration of autophagy extends lifespan. Here, the authors demonstrate in murine models that the inhibition of Atg5 induces ageing phenotypes and reduces lifespan, whilst autophagy restoration partially reverses these phenotypes with accelerated tumorigenesis.

Cellular senescence is characterized by an irreversible cell cycle arrest and a pro‐inflammatory senescence‐associated secretory phenotype (SASP), which is a major contributor to aging and age‐related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single‐nuclei and single‐cell RNA‐seq in the hippocampus from young and aged mice. We observed an age‐dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK‐ATTAC mice, in which p16Ink4a‐positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof‐of‐concept for senolytic interventions' being a potential therapeutic avenue for alleviating age‐associated cognitive impairment., Senescence is a major contributor to aging and age‐related diseases. However, it is still unknown whether senolytics impact on cognitive function during the aging process. We found that both pharmacogenetic clearance of p16Ink4a senescent cells or treatment with senolytic cocktail Dasatinib and Quercetin, reduced senescent microglia in the hippocampus and improved cognitive function in aged mice.

Increased activation of the major pro-inflammatory NF-κB pathway leads to numerous age-related diseases, including chronic liver disease (CLD). Rapamycin, an inhibitor of mTOR, extends lifespan and healthspan, potentially via suppression of inflammaging, a process which is partially dependent on NF-κB signalling. However, it is unknown if rapamycin has beneficial effects in the context of compromised NF-κB signalling, such as that which occurs in several age-related chronic diseases. In this study, we investigated whether rapamycin could ameliorate age-associated phenotypes in a mouse model of genetically enhanced NF-κB activity (nfκb1−/−) characterized by low-grade chronic inflammation, accelerated aging and CLD. We found that, despite showing no beneficial effects in lifespan and inflammaging, rapamycin reduced frailty and improved long-term memory, neuromuscular coordination and tissue architecture. Importantly, markers of cellular senescence, a known driver of age-related pathology, were alleviated in rapamycin-fed animals. Our results indicate that, in conditions of genetically enhanced NF-κB, rapamycin delays aging phenotypes and improves healthspan uncoupled from its role as a suppressor of inflammation.

Ageing is the biggest risk factor for cardiovascular health and is associated with increased incidence of 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 if 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, p21CIPand p16INK4aand results in a non-canonical senescence-associated secretory phenotype. Pharmacological or genetic clearance of senescent cells in mice alleviates myocardial hypertrophy and fibrosis, detrimental features of cardiac ageing, and promotes cardiomyocyte regeneration. Our data describes a mechanism by which senescence can occur and contribute to ageing in post-mitotic tissues.

Neurons are exposed to high levels of DNA damage from both physiological and pathological sources. Neurons are post-mitotic and their loss cannot be easily recovered from; to cope with DNA damage a complex pathway called the DNA damage response (DDR) has evolved. This recognizes the damage, and through kinases such as ataxia-telangiectasia mutated (ATM) recruits and activates downstream factors that mediate either apoptosis or survival. This choice between these opposing outcomes integrates many inputs primarily through a number of key cross-road proteins, including ATM, p53, and p21. Evidence of re-entry into the cell-cycle by neurons can be seen in aging and diseases such as Alzheimer's disease. This aberrant cell-cycle re-entry is lethal and can lead to the apoptotic death of the neuron. Many downstream factors of the DDR promote cell-cycle arrest in response to damage and appear to protect neurons from apoptotic death. However, neurons surviving with a persistently activated DDR show all the features known from cell senescence; including metabolic dysregulation, mitochondrial dysfunction, and the hyper-production of pro-oxidant, pro-inflammatory and matrix-remodeling factors. These cells, termed senescence-like neurons, can negatively influence the extracellular environment and may promote induction of the same phenotype in surrounding cells, as well as driving aging and age-related diseases. Recently developed interventions targeting the DDR and/or the senescent phenotype in a range of non-neuronal tissues are being reviewed as they might become of therapeutic interest in neurodegenerative diseases.

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 p16(Ink4a)-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.