RESUMO
Current clinical trials are testing the life-extending benefits of the diabetes drug metformin in healthy individuals without diabetes. However, the metabolic response of a non-diabetic cohort to metformin treatment has not been studied. Here, we show in C. elegans and human primary cells that metformin shortens lifespan when provided in late life, contrary to its positive effects in young organisms. We find that metformin exacerbates ageing-associated mitochondrial dysfunction, causing respiratory failure. Age-related failure to induce glycolysis and activate the dietary-restriction-like mobilization of lipid reserves in response to metformin result in lethal ATP exhaustion in metformin-treated aged worms and late-passage human cells, which can be rescued by ectopic stabilization of cellular ATP content. Metformin toxicity is alleviated in worms harbouring disruptions in insulin-receptor signalling, which show enhanced resilience to mitochondrial distortions at old age. Together, our data show that metformin induces deleterious changes of conserved metabolic pathways in late life, which could bring into question its benefits for older individuals without diabetes.
Assuntos
Envelhecimento , Caenorhabditis elegans , Hipoglicemiantes/toxicidade , Metabolismo/efeitos dos fármacos , Metformina/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Restrição Calórica , Glicólise , Humanos , Expectativa de Vida , Metabolismo dos Lipídeos , Microbiota , Doenças Mitocondriais/metabolismo , Cultura Primária de Células , Receptor de Insulina/metabolismo , Transdução de SinaisRESUMO
The impact of DNA damage-induced immune responses on aging and disease development is a topic of growing scientific interest and debate. While abundant data links persistent genotoxic stress and associated inflammatory activity to organ decline and cancer development, evidence of pro-homeostatic nature of immune responses triggered by transient DNA damage gradually accumulates. Current review focuses on comparing systemic outcomes of transient genotoxicity with effects of persistent DNA damage from the angle of associated immune activity. We discuss genotoxic stress as a potential damage associated molecular pattern (DAMP) which alerts the organism of the upcoming systemic dysfunction and pre-conditions the body for damage tolerance and repair.