One of the hallmarks of aging is the progressive accumulation of senescent cells in organisms, which has been proposed to be a contributing factor to age‐dependent organ dysfunction. We recently reported that Bruton's tyrosine kinase (BTK) is an upstream component of the p53 responses to DNA damage. BTK binds to and phosphorylates p53 and MDM2, which results in increased p53 activity. Consistent with this, blocking BTK impairs p53‐induced senescence. This suggests that sustained BTK inhibition could have an effect on organismal aging by reducing the presence of senescent cells in tissues. Here, we show that ibrutinib, a clinically approved covalent inhibitor of BTK, prolonged the maximum lifespan of a Zmpste24^−/− progeroid mice, which also showed a reduction in general age‐related fitness loss. Importantly, we found that certain brain functions were preserved, as seen by reduced anxiety‐like behaviour and better long‐term spatial memory. This was concomitant to a decrease in the expression of specific markers of senescence in the brain, which confirms a lower accumulation of senescent cells after BTK inhibition. Our data show that blocking BTK has a modest increase in lifespan in Zmpste24^−/− mice and protects them from a decline in brain performance. This suggests that specific inhibitors could be used in humans to treat progeroid syndromes and prevent the age‐related degeneration of organs such as the brain.

中文翻译：

---

通过布鲁顿酪氨酸激酶抑制改善与年龄有关的脑功能下降。

衰老的标志之一是生物中衰老细胞的逐步积累，已提出这是导致衰老的器官功能障碍的一个因素。最近，我们报道了布鲁顿酪氨酸激酶（BTK）是p53对DNA损伤反应的上游成分。BTK与p53和MDM2结合并使其磷酸化，从而导致p53活性增加。与此相一致，阻断BTK会削弱p53诱导的衰老。这表明持续抑制BTK可能通过减少组织中衰老细胞的存在而对机体衰老产生影响。在这里，我们显示临床批准的BTK共价抑制剂依鲁替尼可延长Zmpste24的最大寿命^-/-早老小鼠，也显示出与年龄相关的一般性体能丧失的减少。重要的是，我们发现某些大脑功能得以保留，如减少焦虑样行为和更好的长期空间记忆所见。这伴随着大脑中衰老的特定标志物表达的减少，这证实了BTK抑制后衰老细胞的蓄积减少。我们的数据表明，阻断BTK在Zmpste24 ^-/-小鼠中的寿命会适度增加，并保护它们免受脑功能下降的影响。这表明特定的抑制剂可用于人类，以治疗早衰综合症，并预防与年龄有关的器官（如大脑）退化。