SENS5 - Aspirin, the oldest new anti-aging drug

© SENS Foundation 2011 - http://www.sens.org

The Fifth SENS conference - Robert Shmookler-Reis

Authors:
R.J. Shmookler Reis, S. Ayyadevara, C.P. Hu, M. Khaidakov, P. Bharill, J.L. Mehta
Central Arkansas Veterans Healthcare Service, and University of Arkansas for Medical Sciences

Although introduced over a century ago, aspirin (acetylsalicylic acid) is still one of the most frequently utilized drugs worldwide, and is employed for a remarkable variety of beneficial effects. Even at low dose (81 mg or less per day), it provides protection against cardiovascular disease, stroke, and even against a number of cancers. Aspirin appears to delay cardiovascular aging through both organ-specific and global mechanisms. Reported activities of aspirin that might attenuate senescence include (a.) inhibition of cyclo-oxygenases (COX), blocking conversion of arachidonic acid into pro-inflammatory prostaglandins, with resultant disruption of platelet activation; (b.) scavenging of reactive oxygen species (ROS); (c.) uncoupling of mitochondrial respiration leading to reduced ROS generation; and/or (d.) prevention of the aging-associated decline in telomere length. In animal models, aspirin retards the development of multiple age-associated diseases, including atherosclerosis, diabetes, and hypertension associated with endothelial senescence. Recent studies have reported life-extending effects of aspirin in male mice, delayed onset of cellular senescence in endothelial cells, and reduced total mortality for men taking aspirin in large clinical trials. Are these extensions of lifespan just the sum of its documented disease-specific effects, or might aspirin actually retard aging? If aspirin opposes one or more basic mechanisms of senescence, then the amelioration and postponement of multiple diseases could be interpreted as secondary to slowed aging. Our data show that aspirin increases C. elegans lifespan and protects worms from oxidative damage due to hydrogen peroxide. Five distinct physiological and molecular indices of aging are all abetted or delayed by aspirin, and to a lesser or similar extent by salicylate. Thus, we regard the nematode as a tractable model in which to discover mechanisms through which aspirin impacts longevity. We find that aspirin acts, in part, by activating FOXO transcription factors otherwise silenced through insulinlike signaling, but that it also induces genes involved in anti-inflammatory and oxidative-stress responses.