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

Summary NAD+ is an important co-factor regulating metabolic homeostasis and a rate-limiting substrate for sirtuin deacylase. We show that NAD+ levels are reduced in aged mice and C. elegans and that decreasing NAD+ levels results in a further reduction in worm lifespan. Conversely, genetic or pharmacological restoration of NAD+ prevents age-associated metabolic decline and promotes longevity in worms. These effects are dependent upon the protein deacetylase sir-2.1 and involve the induction of mitonuclear protein imbalance as well as activation of stress signaling via the mitochondrial unfolded protein response (UPRmt) and the nuclear translocation and activation of FOXO transcription factor DAF-16. Our data suggest that augmenting mitochondrial stress signaling through the modulation of NAD+ levels may be a target to improve mitochondrial function and prevent or treat age-associated decline.

The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the pomegranate fruit, as well as in nuts and berries. We identified urolithin A (UA) as a first-in-class natural compound that induces mitophagy both in vitro and in vivo following oral consumption. In C. elegans, UA prevented the accumulation of dysfunctional mitochondria with age and extended lifespan. Likewise, UA prolonged normal activity during aging in C. elegans, including mobility and pharyngeal pumping, while maintaining mitochondrial respiratory capacity. These effects translated to rodents, where UA improved exercise capacity in two different mouse models of age-related decline of muscle function, as well as in young rats. Our findings highlight the health benefits of urolithin A and its potential application in strategies to improve mitochondrial and muscle function.

Alzheimer’s disease (AD) is a common and devastating disease characterized by the aggregation of amyloid-β peptide (Aβ), yet we know relatively little about the underlying molecular mechanisms or how to treat AD patients. Here, we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in Aβ proteotoxic diseases in human, mouse and C. elegans, and which involves the UPRmt and mitophagy pathways. Using the worm model of Aβ proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed the induction of this mitochondrial stress response as key to maintain mitochondrial proteostasis and health. Importantly, boosting mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms, and in AD transgenic mice. Our data support the relevance of enhancing mitochondrial proteostasis to delay Aβ proteotoxic diseases, such as AD.