Moderate Chromatin Architectural Stress Promotes Longevity in Saccharomyces cerevisiae by inhibition of TOR Signaling

Aging is a multidimensional process that occurs in organisms over time and causes an overalldecline of biological functions that predisposes them to age-related conditions and diseases.Just as aging is a common feature among most eukaryotes, several conserved molecularpathways, such as the TOR pathway, have been found to regulate aging in diverse modelorganisms. Like these conserved mechanisms, histone has been implicated as a regulator ofaging among eukaryotes: histone protein levels were shown to be reduced with aging in bothyeast and mammals, and supplementing extra copies of the histone H3 and H4 gene pairextends lifespan in the budding yeast, presumably by compensating the age dependent histoneloss. Yet how histone dosage correlates with longevity is still under debate, and the molecularpathways that lead to such changes are largely undetermined. We aim to further characterizethe correlation between histone dosage and replicative lifespan (RLS) and its molecularmechanism in the model system Saccharomyces cerevisiae.We discovered that while deletion of the major H3/H4 coding gene (hht2-hhf2?) shortens RLS,knocking out the minor copy (hht1-hhf1?) significantly extends RLS. The histone deletion strainshave more 'open' chromatin, and show some unique phenotypes, such as increased ATPbiosynthesis and mitochondria counts, similar to previously reported features for cells withdefect in chromatin regulators. The transcriptomes of these strains also exhibit similarity, whichlead to a hypothesis that certain specific stress responses are triggered by cells withabnormalities in chromatin structure.Furthermore, several lines of evidence suggest that the longevity induced by hht1-hhf1? ispartially mediated through the caloric restriction/TOR pathway: tor1? and hht1-hhf1? areepistatic in RLS and TOR activities are downregulated in this histone mutant. TOR issuppressed by various environmental stresses, thus we hypothesize that the stress responseinduced by chromatin defects inhibits TOR, resulting in lifespan extension. Since both histoneand TOR signaling pathway are highly conserved throughout evolution, our findings may alsohold true in other eukaryotes, providing a novel and conserved aging regulation mechanism.