A laboratory test of evolutionary aging theories

high‐throughput chemical genetic screen of chemical compounds from several commercial libraries has revealed that lithocholic bile acid (LCA), and some other bile acids, can slow yeast chronological aging [1]. The robust geroprotective effect of exogenously added LCA is due to its ability to enter chronologically aging yeast cells, be sorted to both mitochondrial membranes and alter mitochondrial lipidome [2]. This elicits considerable changes in mitochondrial morphology and functionality, thus allowing mitochondria to operate as a signaling platform that institutes and maintains an aging-delaying pattern of the entire cell [3]. LCA and other bile acids are mildly toxic molecules that cause a so-called ″hormetic″ stress response in animals; because bile acids elicit chemical hormesis, they act as endobiotic geroprotective regulators that can delay the onset and slow the progression of animal aging [4]. Yeast cells do not synthesize LCA and other bile acids found in animals [5]. To explain how these natural molecules can delay yeast chronological aging, we proposed a hypothesis of the hormetic selective forces driving the evolution of longevity regulation mechanisms within ecosystems [5]. This hypothesis posits that after animals inhabiting an ecosystem release bile acids into the environment, these mildly toxic chemicals may create hormetic selective force that drives the evolution of certain protective mechanisms in yeast within this ecosystem. These mechanisms protect yeast against bile acid-induced cellular damage [5]. Our hypothesis further suggests that some of these mechanisms of protection against broad cellular damage elicited by bile acids can also protect yeast against damage and stress accumulated purely with age. Therefore, those yeast species that have developed such longevity regulation mechanisms are expected to live longer [5]. As a laboratory test of this hypothesis, we recently conducted a multistep selection of long-lived yeast species by a lasting exposure of yeast cells to different concentrations of exogenously added LCA [6]. This test yielded twenty long-lived yeast mutants, three of which were capable of maintaining their considerably prolonged chronological lifespans after numerous passages in medium without LCA [6]. Our genetic analyses have revealed that the extended longevity of each of the three selected long-lived yeast mutants was a polygenic genetic trait caused by mutations in more Editorial than two nuclear genes [6]. In further support of the hypothesis on hormetic selective forces driving the ecosystemic evolution of longevity regulation mechanisms, none of the yeast cells that were not exposed to exogenous bile acids had chronological lifespan above a …