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Virus-induced senescence is a central pathogenic feature in COVID-19, and senolytics, which promote apoptosis of senescent cells, can reduce disease severity in hamsters,mice, as well as humans infected with SARS-CoV-2.
During cellular senescence in human and mouse cells, L1 transposons become transcriptionally derepressed and trigger a type-1 interferon response, which contributes to age-associated inflammation and age-related phenotypes.
REV-ERBs, nuclear hormone receptors that regulate transcription as part of the circadian clock cell machinery, inhibit autophagy and lipogenesis in premalignant and malignant cells and impair tumour growth in vivo.
Cellular senescence induced by chemotherapy leads to the acquisition of stemness in cancer cells, which results in enhanced tumour-promoting capacity after forced release or spontaneous escape from the senescent cell-cycle arrest.
Cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS–STING pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer.
When senescent cells accumulate during adulthood they negatively influence lifespan and promote age-dependent changes in several organs; clearance of these cells delayed tumorigenesis in mice and attenuated age-related deterioration of several organs without overt side effects, suggesting that the therapeutic removal of senescent cells may be able to extend healthy lifespan.
The regenerative properties of muscle stem cells decline with age as the stem cells enter an irreversible state of senescence; a study of mouse muscle stem cells reveals that entry into senescence is an autophagy-dependent process and promoting autophagy in old satellite cells can reverse senescence and restore their regenerative properties in an injury model.
In response to cancer-associated stress, autophagy machinery mediates degradation of nuclear lamina components in mammals, suggesting that cells might degrade nuclear components to prevent tumorigenesis.
Neutrophil ageing, which encourages inflammation and vaso-occlusion in a mouse model of sickle-cell disease, is shown to depend on the intestinal microbiota and activation of the TLR/Myd88 signalling pathways.
Cellular senescence has recently been shown to have roles in complex biological processes other than protection against cancer, and to represent a series of progressive and diverse cellular states after initial growth arrest; better understanding of mechanisms underlying its progression and of acute and chronic senescent cells may lead to new therapeutic strategies for age-related pathologies.
This study shows that ageing satellite cells undergo an irreversible transition from a quiescent to a pre-senescent state that results in the loss of muscle regeneration in sarcopenia; furthermore, increased expression of p16INK4a is identified as a common feature of senescent satellite cells.
Pyruvate dehydrogenase (PDH) is identified as a crucial mediator of BRAFV600E-induced cellular senescence: PDH is activated by BRAF-mediated suppression of PDK1, enhancing oxidative glucose metabolism, and PDK1 depletion eradicates mutant BRAF melanomas, indicating that this relationship between cell senescence and metabolism might be exploited therapeutically.
Calcineurin inhibitors are the mainstay of immunosuppressive treatment for organ transplant recipients. However, treatment with these drugs commonly leads to squamous cell carcinoma (SCC) of the skin. It is shown here that an intact calcineurin/NFAT signalling pathway is important for suppressing SCC development. Inhibition of this pathway leads to increased expression of the ATF3 protein, which has a key role in tumorigenesis.
Cellular senescence — an irreversible cell-cycle arrest — has been implicated in suppressing tumour formation or growth. A new cellular signalling pathway that drives senescence has now been identified. This pathway does not involve most known mediators of senescence, and instead signals via the proteins Atf4, p27 and p21. Inactivating the proto-oncogene Skp2 in the context of oncogenic signalling can induce senescence through this new pathway, indicating that drugs that target Skp2 might be useful in cancer treatment.