酮体β-羟丁酸通过乙酰化上调Foxo3a延缓睾丸间质干细胞衰老的作用机制研究

睾丸衰老严重影响男性健康并与重大疾病密切相关，目前缺乏理想疗法。我们前期研究证实睾丸间质干细胞（SLC）移植治疗睾丸衰老安全有效，但老年SLC发生衰老，极大限制了其治疗潜能。逆转内源性SLC衰老是治疗睾丸衰老的理想策略。预实验发现酮体代谢障碍与SLC衰老密切相关，在SLC中下调酮体代谢限速酶Hmgcs2加速SLC衰老；补充酮体代谢产物β-OHB可逆转SLC衰老，恢复睾丸功能；进一步研究发现β-OHB通过乙酰化上调抗衰老关键转录因子Foxo3a，但其深入的分子机制有待阐明。据此，我们提出“酮体β-OHB通过乙酰化上调Foxo3a调控SLC衰老”的科学假说。拟通过RNA-seq、ChIP等技术深入解析其机制，并通过条件敲除鼠、BrdU体内示踪等实验，从细胞和动物层面探讨β-OHB在SLC衰老及睾丸衰老中的潜在应用价值。研究结果将有助于阐明SLC衰老的分子机制，并为睾丸衰老的防治提供新思路。

Testicular aging seriously affects men's health and is closely related to major diseases, which lacks ideal treatments. Previously, our group has carried out a series of studies and confirmed that stem Leydig cells (SLC) transplantation is a safe and effective way to treat testicular aging. However, the senescence of aged SLC greatly limits its therapeutic potential. Rejuvenation of endogenous SLC is an ideal strategy to treat testicular aging. Our preliminary experiments have found that the disorder of ketone body metabolism is closely related to SLC senescence. Down-regulation of the key enzyme Hmgcs2 for ketone body metabolism in SLC accelerates SLC senescence. Supplementation of ketone body β-hydroxybutyrate (β-OHB) can reverse SLC senescence and restore testicular function. Further studies have found that β-OHB up-regulates Foxo3a, a key anti-aging transcription factor, through acetylation. But the underlying molecular mechanism remains to be elucidated. Based on this, we speculate that the ketone body β-OHB can prevent SLC senescence through up-regulation of Foxo3a, mediated by histone acetylation. We intend to analyze the involved mechanisms through RNA-seq, ChIP and other technologies, and uncover the potential application of β-OHB in SLC senescence and testicular aging using conditional knockout mice, BrdU in vivo tracing and et al. on both in vitro and in vivo level. The present study will reveal the molecular mechanisms of SLC senescence and provide new ideal methods for the prevention and treatment of testicular aging.