Abstract
Screening a library of drugs with known safety profiles in humans yielded 30 drugs that reliably protected mammalian neurons against glucose toxicity. Subsequent screening demonstrated that 6 of these 30 drugs increase lifespan in C. elegans: caffeine, ciclopirox olamine, tannic acid, acetaminophen, bacitracin, and baicalein. Every drug significantly reduced the age-dependent acceleration of mortality rate. These protective effects were blocked by RNAi inhibition of cbp-1 in adults only, which also blocks protective effects of dietary restriction. Only 2 drugs, caffeine and tannic acid, exhibited a similar dependency on DAF-16. Caffeine, tannic acid, and bacitracin also reduced pathology in a transgenic model of proteotoxicity associated with Alzheimer's disease. These results further support a key role for glucose toxicity in driving age-related pathologies and for CBP-1 in protection against age-related pathologies. These results also provide novel lead compounds with known safety profiles in human for treatment of age-related diseases, including Alzheimer's disease and diabetic complications.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Aging / drug effects*
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Alzheimer Disease / chemically induced
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Alzheimer Disease / genetics
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Alzheimer Disease / prevention & control*
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Animals
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Animals, Genetically Modified
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / growth & development
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Caenorhabditis elegans / metabolism
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Caenorhabditis elegans Proteins / antagonists & inhibitors
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism*
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Disease Models, Animal
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Drug Approval*
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Forkhead Transcription Factors
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Glucose / toxicity*
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Histone Acetyltransferases / antagonists & inhibitors
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Histone Acetyltransferases / genetics
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Histone Acetyltransferases / metabolism*
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Humans
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Neurons / cytology
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Neurons / drug effects*
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Pharmaceutical Preparations / administration & dosage*
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RNA, Small Interfering / genetics
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Signal Transduction / drug effects
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Survival Rate
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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United States
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United States Food and Drug Administration
Substances
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Caenorhabditis elegans Proteins
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Forkhead Transcription Factors
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Pharmaceutical Preparations
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RNA, Small Interfering
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Transcription Factors
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daf-16 protein, C elegans
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CBP-1 protein, C elegans
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Histone Acetyltransferases
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Glucose