Yeast as a tool to identify anti-aging compounds

Abstract

In the search for interventions against aging and age-related diseases, biological screening platforms are indispensable tools to identify anti-aging compounds among large substance libraries. The budding yeast, Saccharomyces cerevisiae, has emerged as a powerful chemical and genetic screening platform, as it combines a rapid workflow with experimental amenability and the availability of a wide range of genetic mutant libraries. Given the amount of conserved genes and aging mechanisms between yeast and human, testing candidate anti-aging substances in yeast gene-deletion or overexpression collections, or de novo derived mutants, has proven highly successful in finding potential molecular targets. Yeast-based studies, for example, have led to the discovery of the polyphenol resveratrol and the natural polyamine spermidine as potential anti-aging agents. Here, we present strategies for pharmacological anti-aging screens in yeast, discuss common pitfalls and summarize studies that have used yeast for drug discovery and target identification.

An optimized competitive-aging method reveals gene-drug interactions underlying the chronological lifespan of Saccharomyces cerevisiae

“…We have illustrated the potential of competitive-aging screening by characterizing an array of yeast deletion strains exposed to metformin. A number of lifespan-extending pharmacological interventions are already being tested for age-related diseases in humans, even when the mechanisms underlying their beneficial effects are frequently not fully understood 32,33 . Given that lifespan is a complex phenotype, identifying conserved gene-drug interactions could shed light on the modes of action and to pinpoint genetic modifiers of the drug's effects 33 .…”

“…A number of lifespan-extending pharmacological interventions are already being tested for age-related diseases in humans, even when the mechanisms underlying their beneficial effects are frequently not fully understood 32,33 . Given that lifespan is a complex phenotype, identifying conserved gene-drug interactions could shed light on the modes of action and to pinpoint genetic modifiers of the drug's effects 33 . By screening an array of 76 gene deletions aged with metformin, we found a number of cases in which metformin buffers both short-or long-lifespan mutant phenotypes.…”

“…411 We have illustrated the potential of competitive-aging screening by characterizing an 412 array of yeast deletion strains exposed to metformin. A number of lifespan-extending 413 pharmacological interventions are already being tested for age-related diseases in 414 humans, even when the mechanisms underlying their beneficial effects are frequently 415 21 not fully understood (Mullard, 2018;Zimmermann et al, 2018). Given that lifespan is a curves of wild-type (light colors) and gene-deletion (dark colors) strains in nominal SC medium (green) or SC with metformin (orange); 95% CI were calculated from at least three replicates (shaded area).…”

A CellAgeClock for expedited discovery of anti-ageing compounds

“…Existing screens in C. elegans commonly use live E. coli as food 29,30 , which is a disadvantage as drugs are metabolised first by the bacteria making their effect on worms secondary, which may lead to confounded results 31,32 . Yeast drug screens lack the crucial aspect of tissue toxicity 33 . In addition, all longevity assays require constant supply of the drug, making them highly expensive.…”

Almond Skin Extracts and Chlorogenic Acid Delay Replicative Aging by Enhanced Oxidative Stress Response Involving SIR2 and SOD2 in Yeast

“…Evidence that phytochemicals such as resveratrol and quercetin have extended the lifespan of different models, acting through a well-conserved mechanism, has been identified, first in yeast and then confirmed in other models such Caenorhabditis elegans, Drosophila melanogaster and mice [12,16,17]. Yeast have emerged as an effective tool to identify anti-aging compounds [18,19]. This is not surprising given the high level of gene conservation and aging mechanism between the yeast and humans [18,20], as well as the successful identification of the candidate anti-aging test substance after their evaluation in yeast [12][13][14][15]18].…”