Aspirin as a Calorie Restriction Mimetic that Enhances Autophagy

One of the better ways to dampen down the unhelpful hype generated by one or another new supplement or drug alleged to modestly slow aging on the basis of animal data is to point out that aspirin does just as good a job in animal studies. We all know what aspirin does for human life span, which is to say pretty much nothing, while still managing to be a useful tool in the pharmaceutical toolbox. Chasing marginal outcomes in human longevity will at best achieve marginal outcomes - and that is the major problem with the mainstream focus on trying to recapture the beneficial effects of calorie restriction through any number of candidate calorie restriction mimetic drugs. We need to do better, to aim higher. This means more work focused on the development of therapies after the SENS model, those that repair the molecular damage that causes aging and thus are capable in principle of achieving rejuvenation and significant extension of healthy human life.

The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300.

We demonstrate that aspirin fails to modulate autophagic flux in cells lacking EP300 or cells in which EP300 has been engineered to avoid aspirin binding to the enzyme. As a confirmation of the evolutionarily conserved nature of this process, we demonstrate that aspirin failed to further induce autophagy in Caenorhabditis elegans strains deficient for the EP300 homolog CBP-1 or the essential autophagy gene products ATG-7 and BEC-1.

Based on the results described in this paper, aspirin may be classified as a CRM. Indeed, aspirin fulfills all the criteria of a CRM as it (1) reduces protein acetylation by virtue of its ability to inhibit the acetyltransferase activity of EP300, (2) stimulates autophagic flux, and (3) has no cytotoxic activity. At this point, it remains to be determined to which extent EP300 inhibition and autophagy activation may effectively contribute to these aspirin effects that apparently transcend its well-established anti-inflammatory effects.

Pre-clinical evidence suggests that a brain-permeable aspirin derivative can reduce tau-mediated neurodegeneration in an EP300-dependent fashion. However, the role of autophagy has not been explored in this setting. Epidemiological and experimental data indicate that a high nutritional uptake of the EP300 inhibitor spermidine counteracts cardiac aging, both in humans and rodents. In addition, spermidine reduces arteriosclerosis and colon carcinogenesis in mouse models. These spermidine effects hence show a notable overlap with those of aspirin, in accord with the observation that both compounds inhibit EP300.

Link: https://doi.org/10.1016/j.celrep.2018.02.024

Comments

believe it or not....

It turns out that aspirin not only increases the function of mitochondria, it also increases the number of mitochondria. Using a staining method called MitoTracker Green dye, the researchers discovered that aspirin increased the total concentration of mitochondria by two to three times. Since the most notable hallmark of aging is decreased numbers of mitochondria with decreased mitochondrial function, this data makes aspirin look like the best anti-aging substance that has ever come along.

So should we all run out and start taking aspirin every day? I think there is a better way. It turns out that within a matter of less than 15 minutes, the liver converts aspirin to another substance called salicylic acid. So the researchers reasoned that the effects of aspirin might be from salicylic acid instead of from aspirin itself. So to test for that, they repeated the same experiments using salicylic acid instead of aspirin. And guess what? The results were the same! The salicylic acid did just as well as the aspirin. And salicylic acid does not have the side effect baggage that aspirin has. So how can we take advantage of this new information? It's quite easy.

Willow bark is an herb that contains the substance salicin. And when we eat willow bark, our livers convert the salicin to salicylic acid. So by taking willow bark, it is possible to get the same mitochondrial-stimulating effects that come from aspirin.

Dr. Frank Shallenberger

Posted by: bob at March 13th, 2018 8:56 AM

Thanks for that extraordinary information, Frank. I have been taking aspirin for about 40 years, and for much of that time much more than the 81mg tablets often taken daily nowadays. I have reduced my intake to two of the small tablets/day in recent years, and in the last two years, have added white willow bark, which as you say, is an excellent source of salicylic acid.

Posted by: Biotechy at March 14th, 2018 7:45 AM

PS: There was a 2016 study of six different plant extracts on longevity in yeast at Concordia Colege in Canada. They found that white willow bark greatly extended the lifespan of yeast on average of 475% and maximum lifespan by 369%...truly astonishing results. This is why I began taking white willow bark 2 years ago.

Posted by: Biotechy at March 14th, 2018 8:32 AM

Thank you Dr. Shallenberger! As a big fan of your work I'm delighted every time I see your input on this blog! Indeed the studies on White Willow Bark are quite compelling, some might even think that it's the most important anti-aging compound of all!

Posted by: August at January 1st, 2019 1:59 PM

Why should I take white willow bark when aspirin is dirt cheap and probably has higher manufacturing standards?

Posted by: Jeff at February 22nd, 2019 6:04 PM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.