One of the hallmarks of human aging is the decline in mitochondrial function with advancing years. Model systems have demonstrated a signaling pathway that communicates the functional state of the mitochondria to the nucleus to coordinate a transcriptional response. Using a unique reporter system that monitors changes in nuclear transcription, we uncovered a new mitochondrial-nuclear signaling pathway that revealed the importance of the b-subunit of the F1F0-ATP synthase complex, encoded in Saccharomyces cerevisiae by the ATP2 gene. We found that cells lacking the ATP2 gene had a short lifespan, which was surprising since RNAi experiments in Caenorhabditis elegans indicated that reducing expression of other F1F0- ATP synthase subunits extends lifespan. We made the exciting discovery that either a modest decrease or increase in ATP2 expression extends S. cerevisiae lifespan. We hypothesize that misregulation of b-subunit levels causes a decrease in ATP levels. As the F1F0-ATP synthase is conserved from bacteria to humans, understanding how it can extend yeast lifespan and if this effect is evolutionarily conserved will have wide impact on our understanding of aging. To identify additional longevity pathways, we developed a new aging assay in Schizosaccharomyces pombe that recapitulates the evolutionarily conserved properties of lifespan extension by caloric restriction and stress resistance of long-lived cells. This assay allows the direct and unbiased selection of long-lived mutants from populations of random mutants. We have constructed a large bank of S. pombe DNA insertion mutants that will allow an isolation of long-lived mutants and rapid identification of the affected genes. Our long-term goals are to understand the genetic pathways that control aging, which we will approach by characterizing evolutionarily conserved pathways in model systems.
Our specific aims will answer the following questions: 1. Is the lifespan extension of mutants misregulated in the F1F0-ATP synthase b-subunit related to a reduction in the ability to produce ATP? We will determine if the long-lived mutants have altered ATP levels and mitochondrial functions, and test whether the b-subunit must be localized to mitochondria to extend lifespan. 2. Are the lifespan extending effects of misregulating the b-subunit of the F1F0-ATP synthase evolutionarily conserved? We will test if misregulating the b-subunit increases Drosophila or S. pombe lifespan. 3. Does the unbiased isolation of long-lived mutants in our unique S. pombe aging assay reveal new pathways to extend chronological lifespan? We will characterize the mechanism of lifespan extension in S. pombe by caloric restriction and use this system to identify new lifespan extending mutations. Our results will provide new insights into evolutionarily conserved pathways that will impact the understanding of the biology of human aging.
All cells in the human body rely on mitochondria to produce energy and to carry out a wide variety of processes required for life. Using yeast as a model for human cells, we found that a small increase in a mitochondrial protein can increase lifespan by 20%. We have also discovered a way to find many new mutations that prolong life in yeast that can reveal similar ways to prolong life in human cells.
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