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背景下，T细胞和骨之间的动态相互作用已被广泛探讨。然而，在老年人中存在的某些克隆扩增的记忆性CD8 T细胞群体与骨稳态之间的潜在关系从未被研究过。拟议的跨学科研究将测试新的假设，即CD8 T细胞的复制衰老过程对骨维护产生有害影响。衰老的人具有高比例的具有复制性衰老特征的CD8 T细胞，即，不可逆的细胞周期停滞、CD28基因表达的永久性丧失、凋亡抗性、对细胞应激的反应降低和端粒缩短。临床研究已经证明了高比例的携带衰老标记物的CD8 T细胞与老年人的骨质疏松性骨折的相关性。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力，也可能通过产生可溶性因子在与年龄相关的骨变化中发挥作用。 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，已知脂质氧化产物会激活T细胞。 本研究的具体目的是：（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。一个细胞培养模型，广泛用于解剖衰老过程中的免疫变化，将比较早期传代和衰老T细胞在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细胞向复制性衰老的进展中的潜在作用也将被探索。(2)为了测试老年人中存在的具有“衰老”表型的T细胞是否显示出与目标1中针对体外被驱动复制性衰老的T细胞所鉴定的那些相似的特征。(3)开始使用体内小鼠骨质疏松症模型，探讨血脂异常和氧化脂质在慢性T细胞活化诱导的骨丢失中的潜在作用。拟议的研究，特别是将衰老过程中记忆T细胞的变化与骨量的变化联系起来，将导致新的治疗干预措施，可以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.