Cellular Senescence and Aging

描述（申请人提供）：生物医学研究的一个挑战是随着人们进入老年而压缩虚弱和残疾的时间。细胞衰老，当细胞经历潜在的致癌性损伤时发生的生长停滞，已被提出有助于与年龄相关的功能障碍。目前还没有确凿的证据证明这一点。 为了了解衰老细胞在年龄相关功能障碍中的作用，我们建立了一种小鼠模型，从中可以选择性地去除表达p16的衰老细胞。我们设计了基于机制的干预措施，干扰炎症性衰老相关分泌表型（SASP），这可能是许多年龄相关疾病和虚弱的炎症基础。我们发现了SASP和免疫系统功能障碍之间的联系，并找到了打破这种联系的潜在方法。我们的统一假设是，防止衰老细胞的积累或其影响可以恢复与年龄相关的功能衰退。我们提出以下具体目标。目的1去除衰老细胞。我们将使用一种创新的动物模型，从中我们可以选择性地去除衰老的，潜在的癌细胞，以确定这种干预是否会减弱与年龄相关的功能衰退和脆弱的发展，并提高健康寿命。目的2通过操纵Jak/Stat抑制SASP。我们发现SASP通过抑制Jak/Stat而减弱，这是一种显著降低与癌症和血液系统疾病相关的脆弱性的干预措施。我们将测试这种干预对年龄相关功能障碍的影响。目的3通过调控mTOR抑制SASP。我们还发现，抑制mTOR通路的组分抑制SASP，而不干扰防御癌症的衰老相关复制停滞。我们将确定这种抑制是否以及如何减少与年龄相关的功能障碍。目的4打破SASP与炎性小体活化之间的联系。我们发现SASP激活炎性小体，同时抑制它恢复老年动物的免疫功能。我们将测试炎性小体抑制剂是否减少与年龄相关的衰老细胞积累和功能障碍。这些目标将在由行政、小鼠表型和病理学评估（MPPA）以及系统生物学/生物信息学核心支持的四个子项目中进行测试。我们将使用创新的培养系统，新颖的动物模型和全面的健康跨度表型来测试我们的假设，最初专注于脆弱/肌肉，代谢/脂肪，皮肤和免疫功能。我们的方法将提供及时，创新和临床相关的干预结果，基于解决细胞衰老的作用这一多年来一直没有答案的基本问题。

DESCRIPTION (provided by applicant): A challenge of biomedical research is to compress the period of frailty and disability as people reach advanced age. Cellular senescence, the growth arrest that occurs when cells experience potentially oncogenic insults, has been proposed to contribute to age-related dysfunction. There is as yet no definitive evidence for this. To understand the role of senescent cells in age-related dysfunction, we created a mouse model from which p16-expressing senescent cells can be removed selectively. We devised mechanism-based interventions that interfere with the inflammatory senescence-associated secretory phenotype (SASP), which may be the basis of the inflammation that underlies many age-related diseases and frailty. We discovered a link between the SASP and immune system dysfunction, and found potential ways to break this link. Our unifying hypothesis is that preventing the accumulation of senescent cells or their effects can restore age-related decrements in function. We propose the following Specific Aims. Aim 1 Eliminate senescent cells. We will use an innovative animal model from which we can selectively remove senescent, potentially cancerous cells to determine if this intervention attenuates development of age-related functional decrements and frailty and enhances health span. Aim 2 Inhibit the SASP by manipulating Jak/Stat. We found the SASP is attenuated by inhibiting Jak/Stat, an intervention that dramatically reduces the frailty associated with cancer and hematological disorders. We will test the impact of this intervention on age-related dysfunction. Aim 3 Inhibit the SASP by manipulating mTOR. We also found that inhibiting components of the mTOR pathway inhibits the SASP without interfering with the senescence-associated replicative arrest that defends against cancer. We will determine whether and how this inhibition reduces age-related dysfunction. Aim 4 Break the link between the SASP and inflammasomal activation. We found the SASP activates the inflammasome, while inhibiting it restored immune function in old animals. We will test if inflammasome inhibitors reduce age-related senescent cell accumulation and dysfunction. These Aims will be tested in four Subprojects supported by Administrative, Mouse Phenotyping and Pathological Assessment (MPPA), and Systems Biology/ Bioinformatics Cores. We will use innovative culture systems, novel animal models, and comprehensive health span phenotyping to test our hypothesis, focusing on frailty/muscle, metabolic/fat, skin, and immune function initially. Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years.