Phenotypic screening has identified small-molecule modulators of aging, but the mechanism of compound action often remains opaque due to the complexities of mapping protein targets in whole organisms. Here, we combine a library of covalent inhibitors with activity-based protein profiling to coordinately discover bioactive compounds and protein targets that extend lifespan in Caenorhabditis elegans. We identify JZL184-an inhibitor of the mammalian endocannabinoid (eCB) hydrolase monoacylglycerol lipase (MAGL or MGLL)-as a potent inducer of longevity, a result that was initially perplexing as C. elegans does not possess an MAGL ortholog. We instead identify FAAH-4 as a principal target of JZL184 and show that this enzyme, despite lacking homology with MAGL, performs the equivalent metabolic function of degrading eCB-related monoacylglycerides in C. elegans. Small-molecule phenotypic screening thus illuminates pure pharmacological connections marking convergent metabolic functions in distantly related organisms, implicating the FAAH-4/monoacylglyceride pathway as a regulator of lifespan in C. elegans.
Title: Dietary Polyphenols as Potential Remedy for Dementia Desai A Ref: Adv Neurobiol, 12:41, 2016 : PubMed
With increasing life expectancy as a result of better quality of life and improved health care, the incidence of aging related diseases and disorders is heading toward epidemic proportions. Dementia, a spectrum of neurological diseases associated with aging, is an increasingly prevalent disease. No cure exists yet for dementia; however, there are many potential candidates for treatment of dementia that merit more exploration. Polyphenols, which constitute one such class of compounds, are dietary agents that are globally found in commonly consumed food. Many processes that are associated with the pathophysiology of dementia can be modulated by polyphenols. Polyphenolic compounds can alleviate oxidative stress by acting as direct scavengers of free radicals and clearing superoxide and hydroxyl radicals and by increasing the level of antioxidant enzymes such as glutathione peroxidase. They also chelate metal ions to prevent free radical formation. Polyphenols can also combat inflammation by affecting transcription factors such as NF-kappaB. Some polyphenols may have the potential to inhibit excitotoxicity by regulating intracellular calcium ion concentration, inhibiting glutamate receptors and increasing glutamate reuptake at the synapse. The cognitive decline in dementia due to decreased availability of acetylcholine can also be countered by polyphenols that inhibit acetyl-cholinesterase activity. Taken together, these findings suggest that increasing the consumption of polyphenol rich food may alleviate the effects of dementia. Moreover, their effects on controlling multiple mechanisms that are associated with dementia may also prevent or slow down the onset and progress of this devastating disease.
Human chromosome 2 is unique to the human lineage in being the product of a head-to-head fusion of two intermediate-sized ancestral chromosomes. Chromosome 4 has received attention primarily related to the search for the Huntington's disease gene, but also for genes associated with Wolf-Hirschhorn syndrome, polycystic kidney disease and a form of muscular dystrophy. Here we present approximately 237 million base pairs of sequence for chromosome 2, and 186 million base pairs for chromosome 4, representing more than 99.6% of their euchromatic sequences. Our initial analyses have identified 1,346 protein-coding genes and 1,239 pseudogenes on chromosome 2, and 796 protein-coding genes and 778 pseudogenes on chromosome 4. Extensive analyses confirm the underlying construction of the sequence, and expand our understanding of the structure and evolution of mammalian chromosomes, including gene deserts, segmental duplications and highly variant regions.
