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 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.
Highlights
Treating the general aging population with compounds that slow aging, geroprotectors, could provide many benefits to society
Many classes of compounds extend lifespan in model organisms (Carretero et al 2015; Barardo et al 2017; Partridge et al 2020), including mTOR inhibitors (Johnson et al 2013), HDAC inhibitors
We performed a systematic evaluation of the potential for the use of geroprotector’s in humans, and identified Dglucosamine and spermidine as top candidate compounds
Summary
Treating the general aging population with compounds that slow aging, geroprotectors, could provide many benefits to society. 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 date (Fig. 1a) This phenomenon is likely due to a variety of factors, including the increased use of short lived model organisms such as Caenorhabditis elegans (worms), the invention and implementation of higher throughput technologies to assess lifespans, and computational drug screening approaches helping to identify novel geroprotectors (Stroustrup et al 2013; Carretero et al 2015; Janssens et al 2019; Calvert et al 2016; Petrascheck et al 2007; Ye et al 2014). Recent work in the field of aging research has consolidated a primary set of criteria to help prioritize geroprotectors for human use, which states that these compounds should have been demonstrated to (i) increase lifespan, (ii) ameliorate human aging biomarkers, (iii) have acceptable toxicity, (iv) cause minimal side effects at therapeutic dosage, and Biogerontology (2020) 21:709–719
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