Abstract
There is great interest in drugs that are capable of modulating multiple aging pathways, thereby delaying the onset and progression of aging. Effective strategies for drug development include the repurposing of existing drugs already approved by the FDA for human therapy. FDA approved drugs have known mechanisms of action and have been thoroughly screened for safety. Although there has been extensive scientific activity in repurposing drugs for disease therapy, there has been little testing of these drugs for their effects on aging. The pool of FDA approved drugs therefore represents a large reservoir of drug candidates with substantial potential for anti-aging therapy. In this paper we employ FINDSITEcomb, a powerful ligand homology modeling program, to identify binding partners for proteins produced by temperature sensing genes that have been implicated in aging. This list of drugs with potential to modulate aging rates was then tested experimentally for lifespan and healthspan extension using a small invertebrate model. Three protein targets of the rotifer Brachionus manjavacas corresponding to products of the transient receptor potential gene 7, ribosomal protein S6 polypeptide 2 gene, or forkhead box C gene, were screened against a compound library consisting of DrugBank drugs including 1347 FDA approved, non-nutraceutical molecules. Twenty nine drugs ranked in the top 1 % for binding to each target were subsequently included in our experimental analysis. Continuous exposure of rotifers to 1 µM naproxen significantly extended rotifer mean lifespan by 14 %. We used three endpoints to estimate rotifer health: swimming speed (mobility proxy), reproduction (overall vitality), and mitochondria activity (cellular senescence proxy). The natural decline in swimming speed with aging was more gradual when rotifers were exposed to three drugs, so that on day 6, mean swimming speed of females was 1.19 mm/s for naproxen (P = 0.038), 1.20 for fludarabine (P = 0.040), 1.35 for hydralazine (P = 0.038), as compared to 0.88 mm/s in the control. The average reproduction of control females in the second half of their reproductive lifespan was 1.08 per day. In contrast, females treated with 1 µM naproxen produced 1.4 offspring per day (P = 0.027) and females treated with 10 µM fludarabine or 1 µM hydralazine produced 1.72 (P = <0.001) and 1.66 (P = 0.001) offspring per day, respectively. Mitochondrial activity naturally declines with rotifer aging, but B. manjavacas treated with 1 µM hydralazine or 10 µM fludarabine retained 49 % (P = 0.038) and 89 % (P = 0.002) greater mitochondria activity, respectively, than untreated controls. Our results demonstrate that coupling computation to experimentation can quickly identify new drug candidates with anti-aging potential. Screening drugs for anti-aging effects using a rotifer bioassay is a powerful first step in identifying compounds worthy of follow-up in vertebrate models. Even if lifespan extension is not observed, certain drugs could improve healthspan, slowing age-dependent losses in mobility and vitality.
Highlights
There is great interest in finding drugs capable of extending human lifespan and healthspan (Armanios et al 2015)
Our results demonstrate that coupling computation to experimentation can quickly identify new drug candidates with antiaging potential
The pool of FDA approved drugs represents a large reservoir of drug candidates with substantial potential for antiaging therapy
Summary
There is great interest in finding drugs capable of extending human lifespan and healthspan (Armanios et al 2015). Conserved aging pathways have been identified using experimental animal models (de Cabo et al 2014), and some compounds capable of delaying the onset and progression of aging have been identified; these include spermidine, rapamycin, metformin and resveratrol. One of the most effective strategies for drug development is the repurposing of existing drugs that have been approved by the FDA for human therapy (Ashburn and Thor 2004; Pantziarka et al 2014). Repurposing existing drugs could have a rapid impact on human aging if drugs can be shown to have efficacy in slowing the progression of agerelated diseases. A strategy for rapidly finding such drugs is to screen the suite of existing drugs computationally and to test the predictions experimentally using a short-lived invertebrate model. Promising results can be followed up in vertebrate and mammalian experimental models, confirmed in human clinical trials
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