Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9

Abstract

While screening our in-house 1072 marketed drugs for their ability to extend the lifespan using Caenorhabditis elegans (C. elegans) as an animal model, crotamiton (N-ethyl-o-crotonotoluidide) showed anti-aging activity and was selected for further structural optimization. After replacing the ortho-methyl of crotamiton with ortho-fluoro, crotamiton derivative JM03 was obtained and showed better activity in terms of lifespan-extension and stress resistance than crotamiton. It was further explored that JM03 extended the lifespan of C. elegans through osmotic avoidance abnormal-9 (OSM-9). Besides, JM03 improves the ability of nematode to resist oxidative stress and hypertonic stress through OSM-9, but not osm-9/capsaicin receptor related-2 (OCR-2). Then the inhibition of OSM-9 by JM03 reduces the aggregation of Q35 in C. elegans via upregulating the genes associated with proteostasis. SKN-1 signaling was also found to be activated after JM03 treatment, which might contribute to proteostasis, stress resistance and lifespan extension. In summary, this study explored a new small molecule derived from crotamiton, which has efficient anti-oxidative, anti-hypertonic, and anti-aging effects, and could further lead to promising application prospects.

Do Antioxidants Extend Longevity in Invertebrate and Vertebrate Animals?

“…In addition to these more traditional antioxidants, multiple studies have demonstrated a beneficial effect (i.e., increased survival) of various supplements that act either directly as antioxidants or that induce antioxidant activity in invertebrate models. Many of these compounds are derived from plants, such as hawthorn [109] and canary seed [110] or from fungi, such as shitake mushroom [111], but also include synthetic drugs [112]. While most of these studies have been conducted in C. elegans, similar findings have been seen with plant extracts in D. melanogaster [113][114][115], yeast [116,117] and rotifers [118].…”

Betulinic acid counteracts the lipid accumulation in Caenorhabditis elegans by modulation of nhr-49 expression

“…Slight modifications were included to the procedures described earlier [17,18]. Briefly, for estimation of the impact of BA and glucose on worm reproductive capacity, fecundity assay was performed.…”

“…Bending rate of the worms was performed according to [17,18] with some minor modifications. Following treatment with BA at different concentrations, nematodes in L4 larval stage were placed in a drop of M9 buffer on an NGM plate without OP50 and then were allowed to adapt for 30 s. The number of bending movements during locomotion over 30 s were counted.…”

Sitagliptin Extends Lifespan of Caenorhabditis elegans by Inhibiting Insulin/Insulin-Like Signaling and Activating Dietary Restriction-Like Signaling Pathways

“…Therefore, effective and safe pharmacological interference is the best choice to ameliorate aging and promote healthy aging. To date, numerous studies have identified many drugs with potential antiaging effects, including natural molecules (i.e., resveratrol [7] and urolithin A [8]), pharmaceutical drugs (i.e., metformin [9] and aspirin [10]), endogenous metabolites (i.e., xanthine [11] and hypotaurine [12]), and synthetic compounds (i.e., TES991 [13] and JM03 [14]). However, FDA-approved pharmaceutical drugs present many advantages and value in the development of potential antiaging drugs, due to preexisting clinical data and a well-characterized toxicity profile in humans.…”