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-hhf2Δ) shortens RLS,knocking out the minor copy (hht1-hhf1Δ) 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-hhf1Δ ispartially mediated through the caloric restriction/TOR pathway: tor1Δ and hht1-hhf1Δ 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.

衰老是生物体随时间推移发生的多维度过程，会导致整体生物学功能衰退，使生物体更易罹患与衰老相关的病症与疾病。正如衰老是多数真核生物共有的特征，多个保守的分子通路——如TOR通路（TOR pathway）——已被证实可在不同模式生物中调控衰老。与这些保守机制类似，组蛋白（histone）也被证实可调控真核生物的衰老：研究显示，酵母与哺乳动物体内的组蛋白水平均会随衰老进程降低；而在出芽酵母中补充额外拷贝的组蛋白H3与H4基因对，可延长其寿命，推测这是通过补偿衰老依赖性的组蛋白丢失实现的。然而，组蛋白剂量与长寿之间的关联机制仍存在争议，驱动此类变化的分子通路在很大程度上尚未明确。本研究旨在以酿酒酵母（Saccharomyces cerevisiae）为模式系统，进一步解析组蛋白剂量与复制型寿命（replicative lifespan, RLS）之间的关联及其分子机制。我们发现，敲除主要的H3/H4编码基因（hht2-hhf2Δ）会缩短复制型寿命，而敲除次要拷贝（hht1-hhf1Δ）则可显著延长复制型寿命。组蛋白缺失菌株的染色质处于更‘开放’的状态，并表现出一些独特的表型：比如ATP生物合成增强、线粒体数量增多，这与此前报道的染色质调控因子缺陷细胞的特征相似。这些菌株的转录组也呈现出相似的表达谱，据此我们提出假说：染色质结构异常的细胞会触发某些特定的应激反应。此外，多项证据表明，hht1-hhf1Δ诱导的长寿部分通过热量限制/TOR通路介导：tor1Δ与hht1-hhf1Δ在复制型寿命调控中呈上位性关系，且该组蛋白突变体中的TOR活性被下调。TOR可被多种环境应激所抑制，因此我们推测：染色质缺陷所诱导的应激反应会抑制TOR通路，进而延长寿命。鉴于组蛋白与TOR信号通路在进化过程中均高度保守，本研究的发现或可推广至其他真核生物，为衰老调控提供了一种全新且保守的机制。