A sizable fraction of the many methods demonstrated to slow aging and increase longevity in nematode worms involve increased levels of autophagy. This collection of cellular maintenance and recycling mechanisms becomes more active following any sort of cellular stress, from heat to toxicity to lack of nutrients. Life span in short lived species is highly plastic in response to environmental circumstances; any minor stress can produce a net benefit. This can make it somewhat challenging to determine whether any particular approach shown to slow aging is in fact acting directly or indirectly via the controlling mechanisms of autophagy, or just stressing cells in some novel way. In the case of salicylates, a category that includes acetylsalicylic acid, better known as aspirin, there is by now enough data to be more certain about what is going on under the hood, however.
It is known that salicylates have beneficial activity on several pathways implicated in inflammation. For example, acetylsalicylic acid (ASA) is known to act as an anti-inflammatory. Interestingly, salicylates and other nonsteroidal anti-inflammatory drugs were also shown to extend lifespan of yeast and fly through inhibition of tryptophan uptake. Salicylates have also been shown to activate the adenosine monophosphate-activated protein kinase (AMPK) pathway, which has been suggested to control the aging process in general. Targeting AMPK has been discussed as a potential strategy to slow down aging in humans.
Interestingly, ASA has recently been revealed as a lifespan-extending treatment in both mice and nematodes. Salicylic acid also extends lifespan of C. elegans, albeit with a less pronounced effect than ASA. Work on the molecular mechanism in C. elegans has shown that activation of AAK-2/AMPK and DAF-16/FOXO was required for the lifespan-extending activity of ASA. These results led us to investigate in the present work another salicylic acid derivate, 5-octanoyl salicylic acid (referred to as C8-SA).
Unlike for ASA or salicylic acid, no anti-inflammatory activity has been detected for C8-SA. However, we were able to show that C8-SA displays a similar activity to ASA with regard to lifespan in the roundworm Caenorhabditis elegans. 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.