October 12, 2015

238 age related gene deletions that can extend lifespan by up to 60% for largest single gene deletion effect

Following an exhaustive, ten-year effort, scientists at the Buck Institute for Research on Aging and the University of Washington have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health. The research was published online on October 8th in the journal Cell Metabolism.

“This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is,” said Brian Kennedy, PhD, lead author and the Buck Institute’s president and CEO. “It also sets up a framework to define the entire network that influences aging in this organism.”

The Kennedy lab collaborated closely with Matt Kaeberlein, PhD, a professor in the Department of Pathology at the University of Washington, and his team. The two groups began the painstaking process of examining 4,698 yeast strains, each with a single gene deletion. To determine which strains yielded increased lifespan, the researchers counted yeast cells, logging how many daughter cells a mother produced before it stopped dividing.

The theoretical applications for combating aging in people could be huge, provided researchers can indeed figure out which genomic targets are amenable to alteration.

Especially when you consider how effective some of the gene deletions were. In the most stunning result of the study, which is published in Cell Metabolism, researchers found that removing a particular gene called LOS1 extended the life of the yeast by 60 percent.

Highlights

•4,698 deletions tested yields the most comprehensive yeast data set on aging
•Longevity clusters center on known, conserved biological processes
•Enrichment of lifespan-extending C. elegans orthologs suggests conservation
•Genome-wide information uncovered aging pathways such as tRNA transport

Summary

Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.



Cell Metabolism - A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging



They had a small needle attached to a microscope, and they used that needle to tease out the daughter cells away from the mother every time it divided and then count how many times the mother cells divides.

These efforts produced a wealth of information about how different genes, and their associated pathways, modulate aging in yeast. Deleting a gene called LOS1 produced particularly stunning results. LOS1 helps relocate transfer RNA (tRNA), which bring amino acids to ribosomes to build proteins. LOS1 is influenced by mTOR, a genetic master switch long associated with caloric restriction and increased lifespan. In turn, LOS1 influences Gcn4, a gene that helps govern DNA damage control.

“Calorie restriction has been known to extend lifespan for a long time.” said Dr. Kennedy. “The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes.”

A number of the age-extending genes the team identified are also found in C. elegans roundworms, indicating these mechanisms are conserved in higher organisms. In fact, many of the anti-aging pathways associated with yeast genes are maintained all the way to humans.

The research produced another positive result: exposing emerging scientists to advanced lab techniques, many for the first time.

“This project has been a great way to get new researchers into the field,” said Dr. Kennedy. “We did a lot of the work by recruiting undergraduates, teaching them how to do experiments and how dedicated you have to be to get results. After a year of dissecting yeast cells, we move them into other projects.”

Though quite extensive, this research is only part of a larger process to map the relationships between all the gene pathways that govern aging, illuminating this critical process in yeast, worms and mammals. The researchers hope that, ultimately, these efforts will produce new therapies.

“Almost half of the genes we found that affect aging are conserved in mammals,” said Dr. Kennedy. “In theory, any of these factors could be therapeutic targets to extend healthspan. What we have to do now is figure out which ones are amenable to targeting.”

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