Anti-senescence interventions to improve healthspan in mice
Satomi Miwa, Edward Fielder, Mikolaj Ogrodnik, Thomas von Zglinicki
Newcastle University Institute for Ageing and Institute for Cell and Molecular Biology, University of Newcastle, UK
Cell senescence is a permanent cell cycle arrest associated with mitochondrial dysfunction (SAMD) and secretion of bioactive molecules including cytokines, chemokines, reactive oxygen species and others (SASP). Such secreted factors spread senescence in a paracrine manner, and this bystander effect is a major cause for the accumulation of senescent cells with age in vivo (da Silva et al. 2018). Importantly, we have shown that a senescent phenotype is triggered by DNA damage in ageing post-mitotic cells, e.g. neurons (Jurk et al. 2012) or skeletal muscle (da Silva). Specific ablation of senescent cells by pharmacogenetic intervention or by drugs that selectively kill senescent cells (senolytics) ameliorates a wide variety of degenerative ageing-associated dysfunctions and diseases. In a mouse model of radiation-induced premature ageing, senolytics dasatinib+quercetin and navitoclax suppress premature frailty and improve neuromuscular coordination. Dietary restriction and dietary restriction mimetics (rapamycin, metformin) activate mitophagy and improve mitochondrial function, thus correcting SAMD and reducing the SASP (senostatic activity). In an immunocompetent host in vivo, this enables efficient reduction of senescent cell frequencies by immunosurveillance. Accordingly, treatment of prematurely ageing mice with metformin reduced frailty and improved neuromuscular and cognitive function as efficiently as senolytic interventions. We conclude that a senostatic dietary restriction mimetic might be a low-risk, low-cost treatment for tumour therapy-induced premature frailty.
Disclosure of financial interests: TvZ received research funding from Nuchido Ltd and consultancy fees from Novartis.
Newcastle University Institute for Ageing and Institute for Cell and Molecular Biology, University of Newcastle, UK
Cell senescence is a permanent cell cycle arrest associated with mitochondrial dysfunction (SAMD) and secretion of bioactive molecules including cytokines, chemokines, reactive oxygen species and others (SASP). Such secreted factors spread senescence in a paracrine manner, and this bystander effect is a major cause for the accumulation of senescent cells with age in vivo (da Silva et al. 2018). Importantly, we have shown that a senescent phenotype is triggered by DNA damage in ageing post-mitotic cells, e.g. neurons (Jurk et al. 2012) or skeletal muscle (da Silva). Specific ablation of senescent cells by pharmacogenetic intervention or by drugs that selectively kill senescent cells (senolytics) ameliorates a wide variety of degenerative ageing-associated dysfunctions and diseases. In a mouse model of radiation-induced premature ageing, senolytics dasatinib+quercetin and navitoclax suppress premature frailty and improve neuromuscular coordination. Dietary restriction and dietary restriction mimetics (rapamycin, metformin) activate mitophagy and improve mitochondrial function, thus correcting SAMD and reducing the SASP (senostatic activity). In an immunocompetent host in vivo, this enables efficient reduction of senescent cell frequencies by immunosurveillance. Accordingly, treatment of prematurely ageing mice with metformin reduced frailty and improved neuromuscular and cognitive function as efficiently as senolytic interventions. We conclude that a senostatic dietary restriction mimetic might be a low-risk, low-cost treatment for tumour therapy-induced premature frailty.
Disclosure of financial interests: TvZ received research funding from Nuchido Ltd and consultancy fees from Novartis.
