调控衰老的关键表观遗传改变及重要信号通路

Aging is the biggest risk factor for various aging-associated diseases. Aging is characterized by gradual decline of physiological functions and fertility in response to various environmental or endogenous stresses. Aging processes progress slowly over a long period of time associated with various alterations in gene expression and epigenetics, making it difficult to distinguish changes that trigger aging from those altered by aging/senescence. Human premature aging syndromes caused by mutations in a particular gene provide excellent tools for dissecting the complex aging processes into simpler events triggered by defined molecules. Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder of early onset premature aging, predominantly caused by partially processed truncated prelamin A termed progerin. Mice deficient in Zmpste24, a metalloproteinase responsible for prelamin A processing, exhibit progeroid features found in HGPS. It has been shown that low level of progerin is expressed in cells from normal individuals and level of progerin increases along aging. In addition, similar epigenetic alterations were observed in specific histone modifications in both HGPS and normal aging, suggesting a possible paralleled molecular mechanism between premature aging and normal aging. Taking advantages of two independent premature aging mouse models, we propose to systematically profile and compare alterations in epigenetics, transcription and genome maintenance among normal aging, human HGPS and premature aging mouse models (Zmpste24 deficient and Klotho deficient mice). We aim to identify critical genes/signaling pathways driving aging processes. We hope to delay the onset of aging and extend the healthspan by targeting the key regulatory pathways of aging. This work will provide fundamental knowledge of aging and to significantly decrease the risk for aging associated disease in elderly.

衰老是各种老年疾病的最大危险因子。衰老过程缓慢而复杂，伴随大量基因表达改变与信号通路紊乱。衰老的渐进性导致很难区分诱导衰老的重要信号以及衰老过程伴随的基因表达的改变。研究单一基因突变导致的快速衰老对理解复杂的衰老具有重要提示。研究表明，导致儿童早老症的早老素在正常衰老过程显著上升，而且两者间有共同的特定表观遗传学改变，提示早老与衰老具有共同的分子机制。本课题通过研究不同早老动物模型（Zmpste24-/-；Klotho-/-），结合人类早老症(HGPS)及正常衰老，寻求调控衰老的关键基因及重要信号通路的改变，从信号通路，表观遗传以及基因组稳定三个方面深入探讨衰老分子机制。通过有针对性的干预延缓衰老，延长健康寿命。为延缓并降低老年疾病的发生，提高老年人群健康寿命提供重要依据。

衰老是众多老年性疾病的最大危险因子，其分子机制极为复杂，目前尚不完全清楚。正常机体的老化过程渐进而缓慢，但是核纤层蛋白Lamin A异常或SIRT6蛋白缺失会引起基因表达改变与细胞信号传导紊乱，加速机体老化，从而导致人类儿童早老症或小鼠早衰。由于正常衰老过程中也存在异常Lamin A蛋白累积且伴随SIRT6下调，因此，正常衰老、儿童早老症与SIRT6缺陷所致小鼠早老可能具有某种共同的分子机制。本课题以正常衰老细胞、儿童早老症细胞、两种早老小鼠及正常老龄小鼠为模型，通过对表观遗传，基因表达，及蛋白修饰调控的分析，阐述了lamin A 调控表观遗传学的机制，详尽分析了Sirt6衰老小鼠与Zmpste24早衰小鼠的基因表达的共同变化，揭示了Lamin A， SIRT6衰老小鼠中 p53的活化与衰老的关系，发现了一个新的调控衰老的通路 Lamin A- SIRT6-p53。并通过对p53 的干预进一步验证了该通路在衰老过程的重要作用。 我们在国际上首次在哺乳动物中将早老小鼠的寿命延长了10倍以上，具有极为重要的科学意义和广泛的应用前景。本研究将对日益老龄化的中国如何应对老年疾病带来的社会及经济负担具有重要的理论指导意义。