Pharmacological approaches to restore mitochondrial function

Mitochondrial dysfunction is not only a hallmark of rare inherited mitochondrial disorders but also implicated in age-related diseases, including those that affect the metabolic and nervous system, such as type 2 diabetes and Parkinson's disease. Numerous pathways maintain and/or restore proper mitochondrial function, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy and the mitochondrial unfolded protein response. New and powerful phenotypic assays in cell-based models as well as multicellular organisms have been developed to explore these different aspects of mitochondrial function. Modulating mitochondrial function has therefore emerged as an attractive therapeutic strategy for several diseases, which has spurred active drug discovery efforts in this area

Mitochondrial ribosomal proteins as aging regulators

The present invention relates to methods of increasing lifespan, delaying aging, and/or preventing or treating an age-related disease or a mitochondrialdisease in a subject, comprising inducing a nuclear-mitochondrial OXPHOS protein dyssynchrony, including inhibiting the mitochondrial translation machinery function, as well as methods forscreening agents that are able to increase lifespan, inhibit or delay aging, and/or prevent or treat an age-related disease or disorder, or a mitochondrial disease or disorder, in a subject

Aging biomarkers

The present invention relates to novel biomarkers for aging and healthspan, methods and uses thereof, in particular, for determining the biological age of a subject and/or preventing or delaying aging process in a subject, and kits for use in said methods

Mitonuclear protein imbalance as a conserved longevity mechanism

Longevity is regulated by a network of closely linked metabolic systems. We used a combination of mouse population genetics and RNA interference in Caenorhabditis elegans to identify mitochondrial ribosomal protein S5 (Mrps5) and other mitochondrial ribosomal proteins as metabolic and longevity regulators. MRP knockdown triggers mitonuclear protein imbalance, reducing mitochondrial respiration and activating the mitochondrial unfolded protein response. Specific antibiotics targeting mitochondrial translation and ethidium bromide (which impairs mitochondrial DNA transcription) pharmacologically mimic mrp knockdown and extend worm lifespan by inducing mitonuclear protein imbalance, a stoichiometric imbalance between nuclear and mitochondrially encoded proteins. This mechanism was also conserved in mammalian cells. In addition, resveratrol and rapamycin, longevity compounds acting on different molecular targets, similarly induced mitonuclear protein imbalance, the mitochondrial unfolded protein response and lifespan extension in C. elegans. Collectively these data demonstrate that MRPs represent an evolutionarily conserved protein family that ties the mitochondrial ribosome and mitonuclear protein imbalance to the mitochondrial unfolded protein response, an overarching longevity pathway across many species