Chemical activation of a food deprivation signal extends lifespan

Abstract

SummaryModel organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug‐like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the perception of food and which normally acts to decrease glutamate signals. Our results describe the activation of a dietary restriction response through the pharmacological masking of a novel sensory pathway that signals the presence of food. This suggests that primary sensory pathways may represent novel targets for human pharmacology.

Automated Lifespan Determination Across Caenorhabditis Strains and Species Reveals Assay-Specific Effects of Chemical Interventions

“…The original description of the ALM technology included comparison of Automated Lifespan Machine results with standard lifespan assays (Stroustrup et al 2013). This comparison, along with our own preliminary results with the platform (Lucanic et al 2016), suggested that pursuing this technology could increase throughput and perhaps reduce variability among experiments. Here we present an assessment of the ALM platform and ask whether ALM technology can be utilized to measure survivorship of different strains and species.…”

“…We selected five chemical treatments that we had previously characterized using CITP experimental design: NP1, resveratrol, propyl gallate, AKG and ThT. NP1 is a compound that exerts positive effects in both C. elegans and C. briggsae strains that appears to engage dietary restriction-like metabolism (Lucanic et al 2016); resveratrol is well known as a positive bioactive component of red wine (Wood et al 2004); propyl gallate (Wood et al 2004) and AKG (Chin et al 2014;Mishur et al 2016) were known to exert potent lifespan extension in C. elegans N2; and ThT is an amyloid binding compound that extends Caenorhabditis lifespan (Alavez et al 2011;Lucanic et al 2017).…”

1,2,3-Triazolyl ester of ketorolac (15K): Boosting both heat-endurance and lifespan of <i>C. elegans</i> by down-regulating PAK1 at nM levels

“…Furthermore, a new synthetic chemical called NP1 that causes diet restriction also extends the lifespan of this worm at 50 μM (18). Thus, one could easily anticipate that even Ketorolac, an old synthetic pain-killer, which is 500 times less potent than 15K, also might extend the healthy lifespan of this worm at around 25 μM, although so far nobody appears to have tested its "elixir" (longevity-promoting) potential as yet.…”

Transcriptomics-Based Screening Identifies Pharmacological Inhibition of Hsp90 as a Means to Defer Aging

“…Efforts are underway to explore these possibilities and to identify aging-preventive compounds, so-called “geroprotectors.” However, the list of candidates that are thought to confer such health and lifespan benefits to humans has remained very small ( Barzilai et al., 2016 , Kumar and Lombard, 2016 ). Even though screens covering tens of thousands of bio-active molecules have identified many drugs that extend the lifespan in simple model organisms ( Lucanic et al., 2016 , Petrascheck et al., 2007 , Ye et al., 2014 ), validating their potential efficacy in humans is extremely time-consuming, limited in throughput, and restricted by ethical considerations. Thus, the sheer candidate numbers from such screens and their expected high frequency of a non-conserved effect in humans have discouraged their further evaluation ( Kumar and Lombard, 2016 ).…”