T Cell Replicative Senescence & Bone Loss During Aging

描述(申请人提供)：与衰老相关的主要生理变化之一是骨丢失。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经被广泛地探索。然而，老年人中存在的某些克隆性扩增记忆CD8 T细胞群体与骨稳态之间的潜在关系从未被研究过。这项拟议的跨学科研究将检验这一新的假设，即CD8T细胞的复制衰老过程对骨骼维护产生有害影响。随着年龄的增长，CD8 T细胞中有较高比例的细胞呈现复制性衰老的特征，即不可逆性细胞周期停滞、CD28基因表达永久性丧失、细胞凋亡抵抗、对细胞应激反应减弱、端粒缩短等。临床研究已经证明，携带衰老标志物的CD8T细胞比例高与老年人骨质疏松性骨折有关。因此，衰老的T细胞，已经被证明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细胞介导的骨骼效应可能会因为与年龄相关的脂氧化产物的增加而加剧，脂氧化产物是已知的激活T细胞的物质。本探索性R21研究项目的具体目的是：(1)分析人CD8 T细胞复制衰老对破骨细胞和成骨细胞的影响。一个细胞培养模型，被广泛用于解剖衰老过程中的免疫变化，将被用来比较早期传代和衰老的T细胞在体外对破骨细胞和成骨细胞生成和激活的影响。氧化脂质在加速T细胞进入复制衰老过程中的潜在作用也将被探索。(2)测试老年人中具有“衰老”表型的T细胞是否表现出与Aim 1中所鉴定的T细胞相似的特征，这些T细胞在体外被驱动到复制性衰老。(3)利用活体小鼠骨质疏松症模型，开始研究血脂异常和氧化脂质在慢性T细胞活化导致骨丢失中的潜在作用。这项拟议的研究，特别是将衰老过程中记忆T细胞的变化与骨量变化联系起来，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.