Journal
AGING-US
Volume 8, Issue 8, Pages 1759-1780Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.101011
Keywords
C. elegans; aging; SIR-2.1; ETS transcription factors; oxidative stress
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Funding
- NIH [HL121174, HL095797]
- Parker B. Francis Foundation fellowship
- NIEHS [R01 ES10563, R01 ES020852, R01 ES07331]
- Vanderbilt University Training Program in Environmental Toxicology [T32ES007028-38]
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Isoketals (IsoKs) are highly reactive gamma-ketoaldehyde products of lipid peroxidation that covalently adduct lysine side chains in proteins, impairing their function. Using C. elegans as a model organism, we sought to test the hypothesis that IsoKs contribute to molecular aging through adduction and inactivation of specific protein targets, and that this process can be abrogated using salicylamine (SA), a selective IsoK scavenger. Treatment with SA extends adult nematode longevity by nearly 56% and prevents multiple deleterious age-related biochemical and functional changes. Testing of a variety of molecular targets for SA's action revealed the sirtuin SIR-2.1 as the leading candidate. When SA was administered to a SIR-2.1 knockout strain, the effects on lifespan and healthspan extension were abolished. The SIR-2.1-dependent effects of SA were not mediated by large changes in gene expression programs or by significant changes in mitochondrial function. However, expression array analysis did show SA-dependent regulation of the transcription factor ets-7 and associated genes. In ets-7 knockout worms, SA's longevity effects were abolished, similar to sir-2.1 knockouts. However, SA dose-dependently increases ets-7 mRNA levels in non-functional SIR-2.1 mutant, suggesting that both are necessary for SA's complete lifespan and healthspan extension.
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