T Cell Replicative Senescence & Bone Loss During Aging

描述（由申请人提供）：与衰老相关的主要生理变化之一是骨质流失。在类风湿性关节炎和雌激素缺乏的情况下，T细胞与骨之间的动态相互作用已被广泛探讨。然而，老年人中存在的某些克隆扩增记忆CD8 T细胞群与骨稳态之间的潜在关系从未被研究过。提出的跨学科研究将验证CD8 T细胞的复制衰老过程对骨维持产生有害影响的新假设。衰老人类的CD8 T细胞比例较高，具有复制性衰老的特征，即细胞周期不可逆阻滞，CD28基因表达永久性丧失，细胞凋亡抵抗，细胞应激反应降低，端粒缩短。临床研究表明，老年人骨质疏松性骨折与携带衰老标志物的CD8 T细胞比例高相关。因此，衰老的T细胞，已经被证明会阻碍老年人对感染的免疫，也可能通过产生可溶性因子在与年龄相关的骨骼变化中发挥作用。T细胞介导的骨效应可能会因年龄相关的脂质氧化产物增加而加剧，脂质氧化产物被认为可以激活T细胞。本探索性R21研究项目的具体目的是：(1)分析人CD8 T细胞复制性衰老对破骨细胞和成骨细胞的影响。细胞培养模型广泛用于解剖衰老过程中的免疫变化，将用于比较早期传代和衰老T细胞对体外生成和激活破骨细胞和成骨细胞的影响。氧化脂质在加速T细胞向复制性衰老进程中的潜在作用也将被探讨。(2)测试老年人中存在的“衰老”表型T细胞是否在体外具有与Aim 1中鉴定的被驱动到复制性衰老的T细胞相似的特征。(3)利用体内骨质疏松小鼠模型，开始探讨血脂异常和氧化脂质在慢性T细胞激活诱导的骨质流失中的潜在作用。这些研究，特别是将衰老过程中记忆T细胞的变化与骨量的改变联系起来，将导致新的治疗干预措施，可能同时增强老年人的免疫功能和骨骼维护。

DESCRIPTION (provided by applicant): One of the major physiological changes associated with aging is bone loss. The dynamic interaction between T cells and bone has been explored extensively in the context of rheumatoid arthritis and estrogen deficiency. However, the potential relationship between certain populations of clonally expanded memory CD8 T cells present in the elderly and bone homeostasis has never been investigated. The proposed interdisciplinary research will test the novel hypothesis that the process of replicative senescence in CD8 T cells exerts a deleterious effect on bone maintenance. Aging humans have a high proportion of CD8 T cells with features of replicative senescence, i.e., irreversible cell cycle arrest, permanent loss of CD28 gene expression, apoptosis resistance, reduced response to cellular stress, and shortened telomeres. Clinical studies have documented the correlation of high proportions of CD8 T cells bearing senescent markers with osteoporotic fractures in the elderly. Thus, senescent T cells, already documented to hinder immunity to infection in the elderly, may also play a role in age-related bone changes, via production of soluble factors. The T cell-mediated bone effects may be exacerbated by the age- associated increase in lipid oxidation products, which are known to activate T cells. The Specific Aims of this exploratory R21 research project are: (1) To analyze the effect of human CD8 T cell replicative senescence on osteoclasts and osteoblasts. A cell culture model, used extensively to dissect immune changes during aging, will be employed to compare early passage and senescent T cell effects on the in vitro generation and activation of osteoclasts and osteoblasts. The potential role of oxidized lipids in accelerating the progression of T cells to replicative senescence will also be explored. (2) To test whether T cells with the "senescent" phenotype present in elderly persons show similar characteristics to those identified in Aim 1 for T cells that are driven to replicative senescence in vitro. (3) To begin to address the potential role of dyslipidemia and oxidized lipids in chronic T cell activation-induced bone loss, using an in vivo mouse model of osteoporosis. The proposed studies, specifically linking memory T cell changes during aging with alterations in bone mass, will lead to novel therapeutic interventions that may simultaneously enhance both immune function and bone maintenance in the elderly.