The secreted metabolite sensor CtBP2 links metabolism to healthy lifespan.

IF 19.4 Q1 CELL BIOLOGY

Nature aging Pub Date : 2025-10-08 DOI:10.1038/s43587-025-00973-4

Motohiro Sekiya, Kenta Kainoh, Wanpei Chen, Daichi Yamazaki, Tomomi Tsuyuzaki, Yuto Kobari, Ayumi Nakata, Kenji Saito, Nao Aono-Soma, Ali Majid, Hiroshi Ohno, Takafumi Miyamoto, Takashi Matsuzaka, Rikako Nakajima, Takaaki Matsuda, Yuki Murayama, Yoko Sugano, Yoshinori Osaki, Hitoshi Iwasaki, Hitoshi Shimano

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Abstract

Within each cell, metabolite-sensing factors respond to coordinate metabolic homeostasis. How metabolic homeostasis is regulated intercellularly and how this may become dysregulated with age, however, remains underexplored. Here we describe a system regulated by a metabolite sensor, CtBP2. CtBP2 is secreted via exosomes in response to reductive metabolism, which is suppressed by oxidative stress. Exosomal CtBP2 administration extends lifespan in aged mice and improves healthspan in particular by reducing frailty. Mechanistically, we identify activation of CYB5R3 and AMPK downstream of exosomal CtBP2. Consistently, serum CtBP2 levels decrease with age and are negatively associated with cardiovascular disease incidence in humans yet are elevated in individuals from families with a history of longevity. Together our findings define a CtBP2-mediated metabolic system with potential for future clinical applications.

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分泌代谢物传感器CtBP2将代谢与健康寿命联系起来。

在每个细胞内，代谢物感应因子响应协调代谢稳态。然而，代谢稳态是如何在细胞间调节的，以及如何随着年龄的增长而变得失调，这一点仍未得到充分的研究。在这里，我们描述了一个由代谢物传感器CtBP2调节的系统。CtBP2通过外泌体分泌，响应氧化应激抑制的还原性代谢。外泌体CtBP2给药可延长老年小鼠的寿命，特别是通过减少虚弱来改善健康寿命。在机制上，我们确定了外泌体CtBP2下游的CYB5R3和AMPK的激活。一贯地，血清CtBP2水平随着年龄的增长而下降，并与人类心血管疾病的发病率呈负相关，但在有长寿史的家庭中，CtBP2水平升高。总之，我们的发现确定了ctbp2介导的代谢系统，具有未来临床应用的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature aging

CiteScore

14.70

自引率

0.00%

发文量