Repurposed FDA-approved drugs targeting genes influencing aging can extend lifespan and healthspan in rotifers

Abstract

Pharmaceutical interventions can slow aging in animals, and have advantages because their dose can be tightly regulated and the timing of the intervention can be closely controlled. They also may complement environmental interventions like caloric restriction by acting additively. A fertile source for therapies slowing aging is FDA approved drugs whose safety has been investigated. Because drugs bind to several protein targets, they cause multiple effects, many of which have not been characterized. It is possible that some of the side effects of drugs prescribed for one therapy may have benefits in retarding aging. We used computationally guided drug screening for prioritizing drug targets to produce a short list of candidate compounds for in vivo testing. We applied the virtual ligand screening approach FINDSITEcomb for screening potential anti-aging protein targets against FDA approved drugs listed in DrugBank. A short list of 31 promising compounds was screened using a multi-tiered approach with rotifers as an animal model of aging. Primary and secondary survival screens and cohort life table experiments identified four drugs capable of extending rotifer lifespan by 8–42%. Exposures to 1 µM erythromycin, 5 µM carglumic acid, 3 µM capecitabine, and 1 µM ivermectin, extended rotifer lifespan without significant effect on reproduction. Some drugs also extended healthspan, as estimated by mitochondria activity and mobility (swimming speed). Our most promising result is that rotifer lifespan was extended by 7–8.9% even when treatment was started in middle age.

Lysosomes, Autophagy, and Hormesis in Cell Physiology, Pathology, and Age-Related Disease

“…Such interactions will have included cell signaling networks that regulate xenobiotic biotransformation (phase I and II, esterases, etc) mitochondrial and lysosomal function, autophagy, and programmed cell death (see review by Moore). 29 Consequently, these interactions have resulted in the integrated toolbox of evolutionarily highly Abbreviations: Akt, serine/threonine kinase or protein kinase B; AMPK, 5 0 -adenosine monophosphate-activated protein kinase; AP1, activation protein 1; COX-1, cyclooxygenase 1; DNMT1, DNA methyltransferase 1; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; GMP, guanosine monophosphate; GSK3, glycogen synthase kinase-3; LOX, lysyl oxidase; mTOR, mammalian target of rapamycin; NF-kB, nuclear factor kB; NOS, nitric oxide synthase; Nrf2, nuclear factor E2-related factor 2; PGC1-a, peroxisome proliferator-activated receptor-g coactivator 1-a; PI3, phosphatidylinositol-3 kinase; PLA2, phospholipases A2; PPARg, peroxisome proliferator-activated receptor g; PTGS-2, prostaglandin-endoperoxide synthase 2; Scr, homeotic gene sex combs reduced; SIRT1, NAD-dependent deacetylase sirtuin-1; Sirt2, gene coding for SIRT2 -an NAD-dependent deacetylase sirtuin-2; TR, thioredoxin reductase TNF-a, tumor necrosis factor a a Data from Latorre et al, 79 Snell et al, 71 Tsang et al, 80 and Vaiserman and Lushchak. 72 This not intended to be a comprehensive list and only identifies the more prominent compounds currently being investigated.…”

“…As already mentioned, many antiaging interventions may show hormetic features, suggesting that preconditioning might have a preventive medical character ( Figure 3 and Table 1 ). 8 , 34 , 66 - 72 Hence, mild dietary stress (ie, CR without malnutrition or glucose restriction) achieved through various fasting regimes may exert its beneficial effects on life- and health span, at least in part, through hormetic mechanisms. 10 , 30 , 34 , 73 , 74 Glucose restriction has been shown to cause an increase in mitochondrial generation of ROS in a nematode model.…”

“… 75 - 78 Furthermore, various repurposed approved drugs have been found to increase life span and health span in rotifers ( Table 1 ). 71 Similarly, physical exercise may counteract aging by virtue of a hormetic dose–response relationship. Consequently, both lack of physical activity and overexercise are harmful, while regular but moderate exercise is beneficial, probably mediated by exercise generated ROS inducing mild oxidative stress leading to preconditioning ( Figure 3 ).…”

Aging and Chronic Liver Disease

“…Remarkably, the Geroscience Interest Group inside the National Institute on Aging, pointed out that many of these drugs with antiaging effects were clinically approved for treating chronic diseases, and therefore, it would be interesting to screen for other drugs in this category, and test their potential to increase healthspan. 102,136 Considering that the abovementioned drugs target basic aspects of aging, efforts should be made to depict possible synergetic effects when combining different therapies (i.e., lifestyle and pharmacological intervention) to ultimately reach the maximum effect delaying age-related diseases with minimal adverse effects.…”

Specially regulated electron deprivation extremely prolongs lifespan and delays aging in middle-aged rotifers

“…In recent years the use of rotifers became emphasized as in vivo models for screening antiaging [Snell et al, 2016[Snell et al, , 2018, metabolic modulator [Datki et al, 2019] or adverse effects of pharmaceuticals [Park et al, 2018]. Screening of existing and approved by the United States Food and Drug Administration drugs with rotifers could list potential compounds with anti-aging effects [Snell et al, 2016].…”