A young testicular microenvironment protects Leydig cells against age-related dysfunction in a mouse model of premature aging.
A young testicular microenvironment protects Leydig cells against age-related dysfunction in a mouse model of premature aging.
复制标题
DOI：
10.1096/fj.201800612r
复制
发表时间：
2019-01
期刊：
影响因子：
--
通讯作者：
Smith LB
中科院分区：
文献类型：
--
作者：
Curley M;Milne L;Smith S;Jørgensen A;Frederiksen H;Hadoke P;Potter P;Smith LB
睾丸间质细胞(LCS)是男性循环雄激素的主要来源。随着男性年龄的增长，循环中的雄激素水平会下降。然而，LC类固醇合成减少是由于LCS内衰老的特定影响，还是反映了更广泛的支持微环境的退行性变化，目前尚不清楚；无法将体内LC固有的衰老与睾丸微环境的衰老分开，这使得这个问题难以解决。为了解决这一问题，我们建立了由CDGSH铁硫域2(Cisd2)缺失驱动的新型小鼠过早衰老模型，以分离细胞内在衰老的影响和衰老对LC功能的外在影响。在6个月龄时，结构性Cisd2基因缺陷小鼠表现出过早衰老的迹象，包括睾丸萎缩，LC和支持细胞(SC)数量减少，循环睾酮减少，黄体生成激素/睾酮比值增加，类固醇激素生成mRNAs表达减少，这符合老年男性原发性睾丸功能障碍的模型。然而，仅限于LCS或SCs的Cisd2缺失(因此过早衰老)的小鼠可以防止睾丸退化，这表明与年龄相关的LCS功能障碍不能仅用LC或SC谱系的内在衰老来解释。-Curley，M.，Milne，L.，Smith，S.，Jórgensen，A.，Frederksen，H.，Hadoke，P.，Potter，P.，Smith，L.B.在早衰的小鼠模型中，年轻的睾丸微环境保护间质细胞免受与年龄相关的功能障碍。
Testicular Leydig cells (LCs) are the primary source of circulating androgen in men. As men age, circulating androgen levels decline. However, whether reduced LC steroidogenesis results from specific effects of aging within LCs or reflects degenerative alterations to the wider supporting microenvironment is unclear; inability to separate intrinsic LC aging from that of the testicular microenvironment in vivo has made this question difficult to address. To resolve this, we generated novel mouse models of premature aging, driven by CDGSH iron sulfur domain 2 (Cisd2) deletion, to separate the effects of cell intrinsic aging from extrinsic effects of aging on LC function. At 6 mo of age, constitutive Cisd2-deficient mice display signs of premature aging, including testicular atrophy, reduced LC and Sertoli cell (SC) number, decreased circulating testosterone, increased luteinizing hormone/testosterone ratio, and decreased expression of steroidogenic mRNAs, appropriately modeling primary testicular dysfunction observed in aging men. However, mice with Cisd2 deletion (and thus premature aging) restricted to either LCs or SCs were protected against testicular degeneration, demonstrating that age-related LCs dysfunction cannot be explained by intrinsic aging within either the LC or SC lineages alone. We conclude that age-related LC dysfunction is largely driven by aging of the supporting testicular microenvironment.—Curley, M., Milne, L., Smith, S., Jørgensen, A., Frederiksen, H., Hadoke, P., Potter, P., Smith, L. B. A Young testicular microenvironment protects Leydig cells against age-related dysfunction in a mouse model of premature aging.