Defining chromostasis - a candidate regulator of healthy aging and longevity

项目摘要 染色质是细胞表型和功能的关键决定因素。因此，在整个生命周期内， 可能是维持细胞和组织表型和功能并因此保持健康先决条件 老化和长寿。然而，染色质并不是一个静态的固定结构，而是一种动态的、可塑性的“呼吸” 组装件.作为一个动态和可塑性的实体，染色质很容易发生变化或漂移，这一过程可能会加剧 通过内在的细胞过程和外在的/环境的影响。因此，这种动态染色质可能 代表了细胞实现表型稳定性、健康衰老和长寿的挑战，特别是对于长寿命的细胞， 活细胞换句话说，考虑到它们的动态染色质，健康的人类神经元和心肌细胞 几十年来一直如此？为了解释这一点，我们提出细胞具有染色质的机制， 稳态或染色质稳态，其保持染色质完整性，抑制表型不稳定性或“可塑性”， 从而减缓衰老的速度，促进健康的衰老。我们将测试这个假设如下： 具体目标1。测试核小体稳定性的改变是否影响染色体停滞和细胞表型的特征 可塑性。 具体目标2。鉴定候选抑色基因和小分子调节剂，并测试它们对 细胞表型可塑性 具体目标3。测试增强的染色体稳定性是否促进健康衰老和长寿。 这一提议具有广泛的意义，因为它将揭示生理染色质/表观遗传的基本机制。 控制以及这如何影响健康的衰老和寿命，病理状态，如细胞转化， 和治疗应用如细胞重编程。因此，这一建议可能对以下方面产生重大影响： 科学认识和人类健康的揭示：1）机制，基础稳定的细胞表型; 2） 与年龄相关的退化和疾病易感性的生物标志物; 3）促进 健康衰老、预防退行性疾病和癌症以及促进治疗性细胞重编程。

PROJECT SUMMARY Chromatin is a key determinant of cell phenotype and function. Therefore, chromatin stability over the lifespan is presumably a pre-requisite for maintenance of cell and tissue phenotype and function, and hence healthy aging and longevity. However, chromatin is not a static fixed structure, but is a dynamic and plastic “breathing” assembly. As a dynamic and plastic entity, chromatin is prone to change or drift, a process likely exacerbated by intrinsic cellular processes and extrinsic/environmental influences. Therefore, this dynamic chromatin likely represents a challenge for a cell to achieve phenotypic stability, healthy aging and longevity, especially for long- lived cells. In other words, given their dynamic chromatin, how do healthy human neurons and cardiomyocytes remain as such for decades? To explain this, we have proposed that cells possess mechanisms of chromatin homeostasis, or chromostasis, that preserve chromatin integrity, suppress phenotypic instability or “plasticity”, and so slow the pace of aging and promote healthy aging. We will test this hypothesis as follows: Specific Aim 1. Test whether altered nucleosome stability affects features of chromostasis and cell phenotypic plasticity. Specific Aim 2. Identify candidate chromostasis genes and small molecule modulators and test their impact on cell phenotypic plasticity. Specific Aim 3. Test whether enhanced chromostasis promotes healthy aging and longevity. This proposal is broadly significant because it will reveal basic mechanisms of physiological chromatin/epigenetic control and how this impinges on healthy aging and longevity, pathological states such as cell transformation, and therapeutic applications such as cell reprogramming. Accordingly, this proposal can have a major impact on scientific understanding and human health by revealing: 1) mechanisms that underlie stable cell phenotype; 2) biomarkers of age-associated degeneration and predisposition to disease; 3) targets for interventions to promote healthy aging, prevent degenerative disease and cancer, and facilitate therapeutic cell reprogramming.