Cellular Senescence and Aging

描述(由申请人提供)：生物医学研究的一个挑战是压缩人们到高龄时的脆弱和残疾时期。细胞衰老是当细胞经历潜在的致癌损伤时发生的生长停滞，已被认为是导致年龄相关功能障碍的原因之一。到目前为止，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，我们建立了一个小鼠模型，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基础炎症的基础。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，阻止衰老细胞的积累或其影响可以恢复与年龄相关的功能减退。我们提出了以下具体目标。目的1消除衰老细胞。我们将使用一种创新的动物模型，从该模型中我们可以选择性地移除衰老的、潜在的癌细胞，以确定这种干预是否可以减缓与年龄相关的功能衰退和虚弱的发展，并提高健康寿命。目的2通过操纵JAK/STAT抑制SASP。我们发现，通过抑制JAK/STAT可以减弱SASP，这是一种干预措施，显著降低了与癌症和血液疾病相关的脆弱性。我们将测试这种干预对年龄相关功能障碍的影响。目的3通过操纵mTOR抑制SASP。我们还发现，mTOR途径的抑制成分可以抑制SASP，而不会干扰与衰老相关的复制抑制，从而防御癌症。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与炎症激活之间的联系。我们发现SASP可以激活炎症体，而抑制它可以恢复老年动物的免疫功能。我们将测试炎症体抑制剂是否减少与年龄相关的衰老细胞堆积和功能障碍。这些目标将在行政、老鼠表型和病理评估(MPPA)和系统生物学/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、新的动物模型和全面的健康跨度表型来验证我们的假设，最初重点关注脆弱/肌肉、代谢/脂肪、皮肤和免疫功能。我们的方法将提供及时的、创新的和临床相关的干预结果，基于多年来一直没有得到回答的细胞衰老这一根本问题。

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.