Identification of longevity compounds with minimized probabilities of side effects
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RESEARCH ARTICLE
Identification of longevity compounds with minimized probabilities of side effects Georges E. Janssens
. Riekelt H. Houtkooper
Received: 27 April 2020 / Accepted: 16 June 2020 Ó The Author(s) 2020
Abstract It is hypothesized that treating the general aging population with compounds that slow aging, geroprotectors, could provide many benefits to society, including a reduction of age-related diseases. It is intuitive that such compounds should cause minimal side effects, since they would be distributed to otherwise healthy individuals for extended periods of time. The question therefore emerges of how we should prioritize geroprotectors discovered in model organisms for clinical testing in humans. In other words, which compounds are least likely to cause harm, while still potentially providing benefit? To systematically answer this question we queried the DrugAge database—containing hundreds of known geroprotectors—and cross-referenced this with a recently published repository of compound side effect predictions. In total, 124 geroprotectors were associated to 800 unique side effects. Geroprotectors with high risks of side effects, some even with risk for death, included lamotrigine and minocycline, while compounds with low side effect risks included spermidine and D-glucosamine. Despite their popularity as top geroprotector candidates for humans, sirolimus
G. E. Janssens (&) R. H. Houtkooper Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands e-mail: [email protected]
and metformin harbored greater risks of side effects than many other candidate geroprotectors, sirolimus being the more severe of the two. Furthermore, we found that a correlation existed between maximum lifespan extension in worms and the likelihood of causing a side effect, suggesting that extreme lifespan extension in model organisms should not necessarily be the priority when screening for novel geroprotectors. We discuss the implications of our findings for prioritizing geroprotectors, suggesting spermidine and D-glucosamine for clinical trials in humans. Keywords Geroprotectors Spermidine D-Glucosamine Side effects Hormesis
Introduction Treating the general aging population with compounds that slow aging, geroprotectors, could provide many benefits to society. Specifically, it is believed that such compounds could reduce the onset of agerelated diseases and thereby result in an extension of the healthy years of life. Meanwhile, the identification of novel compounds that extend lifespan in model organisms has been accelerating at an unprecedented rate, as can be visualized by the geroprotector entries from the DrugAge database (Barardo et al. 2017), plotting number of drugs registered per publication
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Biogerontology
date (Fig. 1a). This phenomenon is likely due to a variety of factors, including
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