A young testicular microenvironment protects Leydig cells against age‐related dysfunction in a mouse model of premature aging

Abstract

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.

Ablation of the canonical testosterone production pathway via knockout of the steroidogenic enzyme HSD17B3, reveals a novel mechanism of testicular testosterone production

“…The steroids in mouse plasma and testis lysate were measured using an isotope-dilution TurboFlow liquid chromatography-tandem mass spectrometry method as previously described. 14,16 For progesterone, 17-OH-progesterone (17-OHP), androstenedione, and testosterone the limits of quantification were 0.036 nM, 0.1 pM, 0.012 nM, and 0.042 nM, respectively, and the interday variation, expressed as the relative standard deviation for these analytes were testosterone was ≤5.3% and ≤4.2% for low and high spike levels of control materials, respectively, included three times each in every analytical batch. Chemical analyses were performed at the Dept.…”

Restorative functions of Autologous Stem Leydig Cell transplantation in a Testosterone-deficient non-human primate model

“…Moreover, the aging microenvironment has been shown to dictate stem cell behavior 89 . Similarly, Curley M, et al reported that age-related disruption of the testicular microenvironment or wider endocrine milieu likely plays a critical role in LC dysfunction 90 . To improve the therapeutic effects of SLCs transplantation, we need to develop better ways to rejuvenate aged SLCs in vitro and improve the aging microenvironment in vivo in future studies.…”

Deficiency in insulin‐like growth factors signalling in mouse Leydig cells increase conversion of testosterone to estradiol because of feminization

“…(d) There is de novo recruitment of Leydig cells committed progenitors confirmed at P20 mice having the steroidogenic tissue‐specific deletion of Insr and Igf1r 16 but it remains unknown what happens in the population of mature ALCs, after P80. (e) It was reported that young testicular microenvironment protects Leydig cells against age‐related dysfunction in a mouse model of premature ageing 22 . Besides, the Leydig cells from DKO mice stay in “the previous”/undeveloped stage.…”