CELL BIOLOGY. GATA get a hold on senescence.

A transcription factor's abundance connects autophagy to cellular senescence and a secretory phenotype [Also see Research Article by Kang et al. ] This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aad250

Dynamic modulation of autophagy: implications for aging and cancer.

Reduced autophagy has been implicated in aging, yet whether its loss can promote aging phenotypes and pathologies in mammals, and how reversible this process is, has never been fully explored. Using inducible short hairpin RNA (shRNA) mouse models, we have recently shown that autophagy inhibition accelerates aging, and that even a temporary block in autophagy can create irreversible damage that increases a cancer risk

Chromosome instability and carcinogenesis: insights from murine models of human pancreatic cancer associated with BRCA2 inactivation.

Chromosomal instability is a hallmark of human cancer cells, but its role in carcinogenesis remains poorly resolved. Insights into this role have emerged from studies on the tumour suppressor BRCA2, whose inactivation in human cancers causes chromosomal instability through the loss of essential functions of the BRCA2 protein in the normal mechanisms responsible for the replication, repair and segregation of DNA during cell division. Humans who carry heterozygous germline mutations in the BRCA2 gene are highly predisposed to cancers of the breast, ovary, pancreas, prostate and other tissues. Here, we review recent studies that describe genetically engineered mouse models (GEMMs) for pancreatic cancer associated with BRCA2 mutations. These studies not only surprisingly show that BRCA2 does not follow the classical Knudson "two hit" paradigm for tumour suppression, but also highlight features of the interplay between TP53 inactivation and carcinogenesis in the context of BRCA2 deficiency. Thus, the models reveal novel aspects of cancer evolution in carriers of germline BRCA2 mutations, provide new insights into the tumour suppressive role of BRCA2, and establish valuable new preclinical settings for testing approaches to pancreatic cancer therapy; together, these features emphasize the value of GEMMs in cancer research

Fast and simple spectral FLIM for biochemical and medical imaging.

Spectrally resolved fluorescence lifetime imaging microscopy (λFLIM) has powerful potential for biochemical and medical imaging applications. However, long acquisition times, low spectral resolution and complexity of λFLIM often narrow its use to specialized laboratories. Therefore, we demonstrate here a simple spectral FLIM based on a solid-state detector array providing in-pixel histrogramming and delivering faster acquisition, larger dynamic range, and higher spectral elements than state-of-the-art λFLIM. We successfully apply this novel microscopy system to biochemical and medical imaging demonstrating that solid-state detectors are a key strategic technology to enable complex assays in biomedical laboratories and the clinic.A.E. thanks the EPSRC for the initial funding of the project (EP/F044011/1) from 2009 to 2011. M.P. and L.D.C. were supported by a Programme Grant to A.R.V. from the UK Medical Research Council (MRC). This project was also supported by the MRC’s grant-in-aid to the Cancer Unit, Cambridge (A.E., A.R.V.). C.F.K acknowledges funding from the MRC (grant MR/K015850/1), the Wellcome Trust (grant 089703/Z/09/Z) and the EPSRC (EP/L015889/1).This is the author accepted manuscript. The final version is available from the Optical Society of America via http://dx.doi.org/10.1364/OE.23.02351

IL-1α cleavage by inflammatory caspases of the noncanonical inflammasome controls the senescence-associated secretory phenotype.

Interleukin-1 alpha (IL-1α) is a powerful cytokine that modulates immunity, and requires canonical cleavage by calpain for full activity. Mature IL-1α is produced after inflammasome activation and during cell senescence, but the protease cleaving IL-1α in these contexts is unknown. We show IL-1α is activated by caspase-5 or caspase-11 cleavage at a conserved site. Caspase-5 drives cleaved IL-1α release after human macrophage inflammasome activation, while IL-1α secretion from murine macrophages only requires caspase-11, with IL-1β release needing caspase-11 and caspase-1. Importantly, senescent human cells require caspase-5 for the IL-1α-dependent senescence-associated secretory phenotype (SASP) in vitro, while senescent mouse hepatocytes need caspase-11 for the SASP-driven immune surveillance of senescent cells in vivo. Together, we identify IL-1α as a novel substrate of noncanonical inflammatory caspases and finally provide a mechanism for how IL-1α is activated during senescence. Thus, targeting caspase-5 may reduce inflammation and limit the deleterious effects of accumulated senescent cells during disease and Aging.Work was funded by British Heart Foundation grants FS/13/3/30038, FS/18/19/33371 and RG/16/8/32388 (MC); Cancer Research UK Cambridge Institute Core Grant C14303/A17197, Medical Research Council grants MR/M013049/1 and MR/R010013/1 (MN); and the Cambridge NIHR Biomedical Research Centre

A novel Atg5-shRNA mouse model enables temporal control of Autophagy in vivo.

Macroautophagy/autophagy is an evolutionarily conserved catabolic pathway whose modulation has been linked to diverse disease states, including age-associated disorders. Conventional and conditional whole-body knockout mouse models of key autophagy genes display perinatal death and lethal neurotoxicity, respectively, limiting their applications for in vivo studies. Here, we have developed an inducible shRNA mouse model targeting Atg5, allowing us to dynamically inhibit autophagy in vivo, termed ATG5i mice. The lack of brain-associated shRNA expression in this model circumvents the lethal phenotypes associated with complete autophagy knockouts. We show that ATG5i mice recapitulate many of the previously described phenotypes of tissue-specific knockouts. While restoration of autophagy in the liver rescues hepatomegaly and other pathologies associated with autophagy deficiency, this coincides with the development of hepatic fibrosis. These results highlight the need to consider the potential side effects of systemic anti-autophagy therapies

Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk

Abstract: 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 at the intersection of aging, senescence, and cancer.

Autophagy is an evolutionarily conserved cellular process in which macromolecules undergo lysosomal degradation. It fulfills essential roles in quality controlling cellular constituents and in energy homeostasis. Basal autophagy is also widely accepted to provide a protective role in aging and aging-related disorders, and its decline with age might precipitate the onset of a variety of diseases. In this review, we discuss the role of basal autophagy in maintaining homeostasis, in part through the maintenance of stem cell populations and the prevention of cellular senescence. We also consider how stress-induced senescence, for example, during oncogene activation and in premalignant disease, might rely on autophagy, and the possibility that the age-associated decline in autophagy might promote tumour development through a variety of mechanisms. Ultimately, evidence suggests that autophagy is required for malignant cancer progression in a number of settings. Thus, autophagy appears to be tumour-suppressive during the early stages of tumorigenesis and tumour-promoting at later stages

Dynamic modulation of autophagy: implications for aging and cancer

Reduced autophagy has been implicated in aging, yet whether its loss can promote aging phenotypes and pathologies in mammals, and how reversible this process is, has never been fully explored. Using inducible short hairpin RNA (shRNA) mouse models, we have recently shown that autophagy inhibition accelerates aging, and that even a temporary block in autophagy can create irreversible damage that increases a cancer risk

Regional temperature extremes and vulnerability under net zero CO2 emissions

Signatories to the Paris Agreement have pledged to keep global warming to well below 2 °C above pre-industrial levels and preferably below 1.5 °C above pre-industrial levels. Beyond over-shooting Paris Agreement warming levels followed by net negative emissions, achieving a state of net zero carbon dioxide emissions is required to satisfy Paris Agreement warming goals. Research on climate changes under net zero CO _2 emissions is very limited to date with no comprehensive analysis of changes in extremes. In this study, we use results from Earth System Models in the zero emissions commitment model intercomparison project to understand regional mean-state climate change patterns during a 100 year period following carbon dioxide emissions cessation. We also perform an initial study of the evolution of hot and cold monthly temperature extremes after net zero CO _2 emissions, including an assessment of how the change in frequency of temperature extremes affects areas of different levels of socioeconomic development based on regional Human Development Index (HDI). The results show that most land regions experience a fast and continuous cooling response following emissions cessation, with large areas of significant model agreement. In contrast, the Southern Ocean continues warming over the century after emissions cessation. The frequency of land-based local monthly high temperature extremes generally stays constant or decreases during the century after emissions cessation, however, decreases in heat extreme frequencies are generally less for locations with lower modern HDI than areas with higher HDI which suggests that inequality of climate change will remain an issue even after net zero CO _2 emissions. There is an evident emergence of local monthly cold extremes following emissions cessation with most significant impact over high HDI mid- and high-latitude land regions