Abstract
One goal of aging research is to find drugs that delay the onset of age-associated disease. Studies in invertebrates, particularly Caenorhabditis elegans, have uncovered numerous genes involved in aging, many conserved in mammals. However, which of these encode proteins suitable for drug targeting is unknown. To investigate this question, we screened a library of compounds with known mammalian pharmacology for compounds that increase C. elegans lifespan. We identified 60 compounds that increase longevity in C. elegans, 33 of which also increased resistance to oxidative stress. Many of these compounds are drugs approved for human use. Enhanced resistance to oxidative stress was associated primarily with compounds that target receptors for biogenic amines, such as dopamine or serotonin. A pharmacological network constructed with these data reveal that lifespan extension and increased stress resistance cluster together in a few pharmacological classes, most involved in intercellular signaling. These studies identify compounds that can now be explored for beneficial effects on aging in mammals, as well as tools that can be used to further investigate the mechanisms underlying aging in C. elegans.
Highlights
Using the obtained estimate for γ we generated a parametric regression survival-time model for DMSO control animals (Supplementary Fig. To simulate the death times for control and drug -treated animals, the quantile function, defined as the inverse of the cumulative distribution (14) for t he Gompertz was obtained (17).
19.9 no no Bisoprolol hemifumarate salt Bretylium tosylate BRL 37344 sodium Bromoacetyl alprenolol menthane CGP 20712A methanesulfonate Chloroethylclonidine dihydrochloride Cirazoline hydrochloride CL 316,243 Clonidine hydrochloride Desipramine hydrochloride Dobutamine hydrochloride Doxazosin mesylate Doxepin hydrochloride DSP-4 hydrochloride Fenoterol hydrobromide Fenspiride hydrochloride Fiduxosin hydrochloride Formoterol Guanabenz acetate Guanfacine hydrochloride ICI 118,551 hydrochloride Imiloxan hydrochloride Isotharine mesylate L(-)-Norepinephrine bitartrate L-765,314 Labetalol hydrochloride Maprotiline hydrochloride Metaproterenol hemisulfate Methoxamine hydrochloride MHPG piperazine MHPG sulfate potassium MK-912 Moxisylyte hydrochloride Moxonidine hydrochloride Naftopidil dihydrochloride Naphazoline hydrochloride Nisoxetine hydrochloride Nortriptyline hydrochloride Nylidrin hydrochloride Oxymetazoline hydrochloride p-Aminoclonidine hydrochloride Phenoxybenzamine hydrochloride Phentolamine mesylate Phenylephrine hydrochloride Pindolol p-Iodoclonidine hydrochloride
(±)-Butaclamol hydrochloride (±)-Chloro-APB hydrobromide (±)-Octoclothepin maleate (±)-PD 128,907 hydrochloride (±)-PPHT hydrochloride (±)-Quinpirole dihydrochloride (±)-SKF 38393, N-allyl-, hydrobromide (±)-SKF-38393 hydrochloride (±)-Sulpiride 1-(4-Hydroxybenzyl)imidazole-2-thiol 1-Phenyl-3-(2-thiazolyl)-2-thiourea 3,4-Dihydroxyphenylacetic acid
Summary
Using the obtained estimate for γ we generated a parametric regression survival-time model for DMSO control animals (Supplementary Fig. To simulate the death times for control and drug -treated animals, the quantile function, defined as the inverse of the cumulative distribution (14) for t he Gompertz was obtained (17).
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