A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

Abstract

Plant extracts containing salicylates are probably the most ancient remedies to reduce fever and ease aches of all kind. Recently, it has been shown that salicylates activate adenosine monophosphate‐activated kinase (AMPK), which is now considered as a promising target to slow down aging and prevent age‐related diseases in humans. Beneficial effects of AMPK activation on lifespan have been discovered in the model organism Caenorhabditis elegans (C. elegans). Indeed, salicylic acid and acetylsalicylic acid extend lifespan in worms by activating AMPK and the forkhead transcription factor DAF‐16/FOXO. Here, we investigated whether another salicylic acid derivative 5‐octanoyl salicylic acid (C8‐SA), developed as a controlled skin exfoliating ingredient, had similar properties using C. elegans as a model. We show that C8‐SA increases lifespan of C. elegans and that a variety of pathways and genes are required for C8‐SA‐mediated lifespan extension. C8‐SA activates AMPK and inhibits TOR both in nematodes and in primary human keratinocytes. We also show that C8‐SA can induce both autophagy and the mitochondrial unfolded protein response (UPRmit) in nematodes. This induction of both processes is fully required for lifespan extension in the worm. In addition, we found that the activation of autophagy by C8‐SA fails to occur in worms with compromised UPRmit, suggesting a mechanistic link between these two processes. Mutants that are defective in the mitochondrial unfolded protein response exhibit constitutive high autophagy levels. Taken together, these data therefore suggest that C8‐SA positively impacts longevity in worms through induction of autophagy and the UPRmit.

Chorismate synthase mediates cerebral malaria pathogenesis by eliciting salicylic acid-dependent autophagy response in parasite

“…The ability of SA and its derivatives to induce autophagy is well explored in several other organisms ( Pietrocola et al, 2018 ; Shamalnasab et al, 2018 ). However, the role of SA in Plasmodium remains elusive.…”

Insight into the mitochondrial unfolded protein response and cancer: opportunities and challenges

“…Statins, cholesterol-lowering drugs targeting the mevalonate pathway, have been shown to trigger the UPR mt [ 15 ]. Furthermore, a salicylic acid derivative, C8-SA, activates the UPR mt , and this response is associated with increased lifespan in C. elegans (Table 1 ) [ 16 ]. Through a screen of the C. elegans genome, a previous study showed that knockout of many mitochondrial process-related genes induced UPR mt , which explained the role of these genes in the maintenance of mitochondrial homeostasis (Table 2 ) [ 17 ].…”

Targeting the Mitochondria-Proteostasis Axis to Delay Aging

“…In fact, autophagy activation is a common hallmark among nutritional anti-aging interventions ( Madeo et al, 2015 ), although the causal involvement of this activation in the context of CR and fasting remains surprisingly poorly investigated and has mainly been investigated in C. elegans mutants that only exhibit CR-like responses ( Hansen et al, 2008 ). Nevertheless, autophagy is essential for the lifespan extending effects of AMP-activated kinase (AMPK) stimulation by salicylic acid derivatives ( Shamalnasab et al, 2018 ). Other AMPK agonists, like metformin have been shown to counteract aging-related inflammation (“inflammaging”) processes through autophagy activation ( Bharath et al, 2020 ).…”