Aspirin/Salicylates are calorie restriction mimetics

LeeLemonoil

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Aspirin—another caloric-restriction mimetic​

Federico Pietrocola, Francesca Castoldi, Maria Chiara Maiuri & Guido Kroemer ORCID Icon
Pages 1162-1163 | Received 02 Mar 2018, Accepted 16 Mar 2018, Accepted author version posted online: 21 Jun 2018, Published online: 18 Jul 2018
ABSTRACT
The capacity of cells and organisms to sustain, and to eventually adapt to, environmental and genetic insults declines with age. Because macroautophagy/autophagy is regarded as one of the major determinants of cellular fitness in vitro and in vivo, maneuvers that aim at promoting autophagy may slow down aging and promote health span. Caloric restriction (CR), a reduction in caloric intake without malnutrition, efficiently counteracts aging-associated features, yet is difficult to be applied to humans. Caloric-restriction mimetics (CRMs) are pharmacological agents that recapitulate the main biochemical properties of CR, namely a global reduction of protein acetylation and the induction of autophagy. We found that the ancient drug aspirin and its active metabolite salicylate stimulate autophagic flux by virtue of their inhibitory action on acetyltransferase EP300. The inhibition of EP300 results from a direct competition between salicylate and acetyl coenzyme A for binding to the catalytic domain of the enzyme. This mode of action appears to be conserved across evolution as it accounts for the induction of autophagy by aspirin in various mouse models and in the nematode Caenorhabditis elegans. In sum, aspirin acts as a CRM.
 

schultz

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Just adding to this thread a study I came across and found interesting from November 2020. They basically discuss some of the benefits of aspirin working through autophagy and these benefits being lost in "knock-out" mice. I'm always a wee bit sceptical of studies using "knock-out" mice to prove a specific pathyway, but the regular mice still demonstrate aspirins benefit well enough. The last paragraph discusses how FFA can interfere with autophagy (Peat has mentioned this) and prevent aspirin from producing some of its positive effects. Interestingly, aspirin lowers FFA. It's possible a higher dose of aspirin would lower FFA enough to produce better results, or combining aspirin with some other thing that lowers FFA might be synergistic (niacin).


"By inhibiting EP300, aspirin stimulates autophagy, a cytoplasmic renewal process that has prominent cardioprotective and antineoplastic effects.

Aspirin can improve metabolic syndrome in the context of high-fat diet (HFD). Accordingly, constant treatment with aspirin reduced the weight gain induced by HFD in WT mice. Moreover, mice under HFD (3 months) that were daily treated with aspirin exhibited improved glucose tolerance and insulin responses... Additionally, in WT mice subjected to HFD, aspirin significantly reduced fat mass and increased lean mass, decreased adipocyte size, and attenuated hepatosteatosis.

Aspirin produced major metabolic changes that were similar to those induced by fasting, in line with the idea that this drug acts as a caloric restriction mimetic.

In mice bearing genetically determined defects in the autophagic pathway, aspirin lost its favorable effects on high-fat diet-induced metabolic syndrome. Autophagy is inhibited in human obesity because of the suppressive effects of high metabolite concentrations (in particular glucose and free fatty acids) and high levels of trophic hormones (in particular insulin and insulin growth factor)49,50. It remains to be seen whether such an acquired autophagic defect would ‘lock’ the morbidly obese subjects in a therapy-refractory state causing resistance against the beneficial effects of aspirin and other caloric restriction mimetics."



Here is the Peat article and some quotes where he mentions FFA, calorie restriction and also niacin.


Regenerative healing also requires freedom from substances that inhibit the digestion of the debris. The great decline in proteolytic autophagy that occurs with aging (Del Roso, et al., 2003) can be reduced by inhibiting the release of fatty acids. This effect is additive to the antiaging effects of calorie restriction, suggesting that it is largely the decrease of dietary fats that makes calorie restriction effective (Donati, et al., 2004, 2008).

Niacinamide is a nutrient that inhibits the release of fatty acids, and it also activates phagocytic activity and lowers phosphate. It protects against the development of scars in spinal cord injuries, facilitates recovery from traumatic brain injury, and accelerates healing generally. While it generally supports immunity, it’s protective against autoimmunity. It can cause tumor cells to either mature or disintegrate, but it prolongs the replicative life of cultured cells, and protects against excitotoxicity.



Anyway, just a few more pieces of the puzzle.
 

Ben.

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I thought calorie restriction and its mimics are not good?

Reminds me of all the counterarguments against david sinclairs proposal of calorie restriction and resveratol coming from this very forum.
 
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