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Aspirin Emulates some Aspects of Caloric Restriction

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A substance found in aspirin has been demonstrated to replicate certain beneficial aspects of caloric restriction.

Introduction

Macroautophagy (hereafter referred to as autophagy) acts as a homeostatic pathway at both the cellular and organismal levels (Mizushima and Komatsu, 2011). The finely tuned execution of this multistep process (ensured by the coordinated activity of specifically committed Atg proteins) eventually culminates in the formation of a double-membrane organelle, the autophagosome, in which bulk portions of the cytoplasm or specific organelles are engulfed prior to their lysosomal hydrolase-mediated degradation (He and Klionsky, 2009). Autophagy may be considered as one of the major anti-aging mechanisms because it assures recycling (and hence rejuvenation) of damaged cytoplasmic components, including entire organelles such as mitochondria (Pan et al., 2013; Rubinsztein et al., 2011; Sun et al., 2016). Manipulations aiming at restoring or inducing autophagy can reduce the incidence of age-related disease and extend health span and lifespan (López-Otín et al., 2016). The nature of these interventions can be nutritional (i.e., fasting or caloric restriction) (Heilbronn and Ravussin, 2003; Longo and Mattson, 2014), behavioral (i.e., physical activity) (He et al., 2012), or pharmacological. Thus, mTORC1 inhibition by rapalogs (Lamming et al., 2013), activation of sirtuin-1 (SIRT1) with resveratrol (Wood et al., 2004), and supplementation of the natural polyamine spermidine (Eisenberg et al., 2009) extend lifespan in various model organisms in an autophagy-dependent manner (López-Otín et al., 2016). Importantly, overexpression of the autophagy essential gene Atg5 is sufficient to expand lifespan in mice (Pyo et al., 2013), indicating that autophagy is not only necessary but even sufficient to enhance longevity.

The active molecule in aspirin is a caloric restriction mimetic

Deregulated nutrient sensing is one of the reasons we age and causes a decline of autophagy, our cells’ way of recycling garbage such as unwanted and damaged proteins.

A new study suggests that the reactivation of autophagy may prevent or reduce age-related metabolic dysfunctions, and there is evidence to suggest that autophagy does have an influence on longevity.

Caloric restriction mimetics are compounds that can reduce protein acetylation levels and induce autophagy, which emulates what happens during caloric restriction. The new study suggests that aspirin or one of its active molecules, salicylate, can induce autophagy via its ability to inhibit the acetyltransferase activity of EP300 (Histone acetyltransferase p300).



In humans, EP300 is an enzyme that is encoded by the EP300 gene [2] and regulates the transcription of genes via chromatin remodeling. EP300 plays a key role in regulating cell growth and division, guiding cells to maturity and specialized functions (differentiation), and suppressing tumor development.

While salicylate does trigger autophagy in regular cells, it has no effect on cells lacking EP300 or cells with EP300 mutations that are resistant to stimulation via salicylate.

Conclusion

Aspirin, and its active molecule, salicylate, appear to be evolutionarily conserved caloric restriction mimetics that work the same way in C. Elegans worms, mice, and human cell lines.

While caloric restriction data does not appear to suggest that it can increase human lifespan in a significant way, there is some evidence to suggest that it may be beneficial for healthspan.



Literature

[1] Pietrocola, F., Castoldi, F., Markaki, M., Lachkar, S., Chen, G., Enot, D. P., … & Loos, F. (2018). Aspirin Recapitulates Features of Caloric Restriction. Cell reports, 22(9), 2395-2407.

[2] Eckner, R., Ewen, M. E., Newsome, D., Gerdes, M., DeCaprio, J. A., Lawrence, J. B., & Livingston, D. M. (1994). Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Genes & development, 8(8), 869-884.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
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