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.