AD, the first cofactor described, was discovered in 1906 (ref. 1 ), when it was observed that yeast juice separated into low-and high-molecular-weight fractions lost the capacity to perform alcoholic fermentation. However, addition of the lowmolecular-weight fraction to yeast accelerated the fermentation reaction, even if it was boiled beforehand. This observation suggested that a yet-unknown heat-stable factor present in the lowmolecular-weight fraction was required for fermentation. At that time, this factor was named 'cozymase' . Almost three decades later, the chemical composition of cozymase, comprising an adenine, a phosphate and a reducing-sugar group, was reported 2 . The actual function of NAD + , however, remained unclear until 1936, when cozymase was shown to be capable of transferring hydride between molecules with the nicotinamide base as its redox site 3 . This research on NAD + was rewarded by three Nobel prizes. In the early 2000s, interest in NAD + experienced a resurrection, after a novel role of NAD + as a cosubstrate for the sirtuin enzyme family, important regulators of longevity and metabolism, was discovered 4-6 .Brain 98 NMNaT3Testis 307 Intestine, spleen, brain, SM, lung, pancreas, blood, WaT 98,307

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.

Graphical Abstract Highlights d PUM2, and its ortholog in C. elegans, PUF-8, are upregulated upon aging d PUM2 represses Mff translation and impairs mitochondrial fission d The PUM2/MFF axis regulates mitophagy and mitochondrial function d Depletion of puf-8 and Pum2 in old worms and mice improves mitochondrial homeostasis