Review
doi: 10.1038/nature08981.Lessons on longevity from budding yeast
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- PMID:20336133
- PMCID: PMC3696189
- DOI: 10.1038/nature08981
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Review
Lessons on longevity from budding yeast
Matt Kaeberlein. Nature..
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- Nature. 2010 Apr 29;464(7293):1390
Abstract
The past decade has seen fundamental advances in our understanding of the ageing process and raised optimism that interventions to slow ageing may be on the horizon. Studies of budding yeast have made immense contributions to this progress. Yeast longevity factors have now been shown to modulate ageing in invertebrate and mammalian models, and studies of yeast have resulted in some of the best candidates for anti-ageing drugs currently in development. The first interventions to slow human ageing may spring from the humble yeast.
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In chronologically ageing yeast, damage accumulates in non-dividing cells. In the external medium, ethanol initially accumulates and is converted to acetic acid, which induces an apoptosis-like response and cell death. Inside the chronologically ageing cell, damaged mitochondria and oxidized proteins also accumulate and probably contribute to chronological senescence. In replicatively ageing yeast cells, damage is asymmetrically inherited by the mother cell and removed from the daughter cell. Nuclear extrachromosomal ribosomal DNA circles, cytoplasmic oxidized proteins and damaged mitochondria contribute to replicative senescence. In very old mother cells, asymmetry breaks down and the daughter cell can inherit sufficient damage to become prematurely aged.
Yeast cells are typically aged in synthetic medium containing 2% glucose. Under these conditions, cells ferment pyruvate to ethanol. After glucose depletion, ethanol is metabolized leading to the production of acetic acid, which is toxic to yeast cells and induces an apoptosis-like response that limits CLS. Under conditions of dietary restriction, the glucose concentration of the growth medium is reduced to 0.5% or lower, resulting in direct use of pyruvate by mitochondrial respiration, decreased acetic acid production and increased CLS.
Decreased TOR activity increases both RLS and CLS by several possible mechanisms. Reduced rDNA recombination and reduced mRNA translation probably contribute to increased RLS, whereas decreased production of acetic acid increases CLS. Resistance to oxidative stress, improved mitochondrial function and enhanced clearance of damaged proteins probably contributes to both RLS and CLS. Increased Sir2 activity extends RLS but not CLS. Sir2 represses rDNA recombination, promotes asymmetrical segregation of oxidized proteins to the mother cell and maintains chromatin structure near telomeres and possibly other loci.
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