哈钦森-吉尔福德早老综合征（Hutchinson-Gilford progeria syndrome,HGPS）是极度罕见的致死性遗传病。HGPS患者出生时完全正常，但随后表现出生长发育迟缓并加速衰老，患儿通常在十三岁时死于心肌梗死或中风【1】。在HGPS中，编码核纤层蛋白lamin A/C的LMNA基因发生突变，产生了缺失Zmpste24水解位点的prelamin A，被称为早老素（progerin），永久性地锚定在核膜上【2, 3】。Zmpste24敲除小鼠出生时完全正常，但离乳时即出现显著的生长发育迟滞和衰老加速等表型，常被用作早老症的小鼠模型【4, 5】。

HGPS患者表现出与生理性衰老相类似的诸多表型。同时，progerin在生理性衰老中逐渐累积【6, 7】。迄今为止，progerin诱导早衰最广为人知的假说是细胞核畸形学说【8, 9】和基因组不稳定学说【10, 11】。然而，无论是药物恢复细胞核正常形态【12】，还是遗传抑制基因组不稳定所激活的肿瘤抑制蛋白p53【13】，都只能有限地延长Zmpste24 KO小鼠寿命。据此推测，除细胞核畸形和基因组不稳定外，progerin极可能还通过其它分子机制诱导HGPS。

生长激素（growth hormone,GH）/胰岛素样生长因子-1（insulin-like growth factor 1,IGF-1）轴通过IGF-1R/Akt/mTOR信号通路调控机体生长发育和代谢【14-16】。一直以来，抑制IGF-1R被认为是促长寿的经典策略【17】。另外，随年龄增加，机体中IGF-1水平逐渐降低【18】。生理性衰老中progerin的累积与IGF-1/Akt信号的削弱之间的关联尚不清楚。2022年7月8日，中国医科大学曹流教授团队在Science Advances在线发表题为Progerin modulates the IGF-1R/Akt signaling involved in aging的研究长文，报道了progerin通过调控IGF-1R/Akt信号通路参与衰老的新机制。

本研究发现：progerin能定位到细胞核外，结合并下调IGF-1R，进而抑制IGF-1/Akt信号转导，抑制细胞能量代谢和细胞生长并加速细胞老化。遗传抑制Akt1进一步加剧了Zmpste24 KO小鼠早衰表型，表现为体重显著下降，寿命急剧缩短。药物抑制Akt负性调节蛋白PTEN能够恢复Akt活性，并显著改善Zmpste24 KO小鼠生长阻滞等衰老表型，延长早老小鼠寿命。

(A-B) Progerin/prelamin A定位于细胞核外；(C-D) Progerin结合IGF-1R并抑制IGF-1/Akt信号；(E-G) Akt1遗传缺失加剧了Zmpste24 KO小鼠早衰表型；(H-J) PTEN抑制剂bpV(HOpic)改善了Zmpste24 KO小鼠的早衰表型。

肿瘤抑制因子p53在对抗肿瘤增形成过程中，常常以引发细胞与个体衰老为代价，即抗肿瘤促衰老的“双刃剑”效应【19-21】，抑癌基因PTEN在衰老中的作用尚不完全清楚【22,23】。

本研究通过解析progerin影响IGF-1R/PTEN/Akt信号通路的新机制，揭示了IGF-1/Akt信号通路在对抗衰老发生发展中的关键作用，为靶向抑制PTEN恢复Akt活性治疗HGPS提供了科学依据，为IGF-1/PTEN/Akt信号通路参与生理性衰老提供了新视角。

中国医科大学基础医学院/健康科学研究院曹流教授团队姜波讲师和吴璇副研究员为该论文的共同第一作者，曹流教授为该论文的通讯作者。

http://doi.org/10.1126/sciadv.abo0322

制版人：十一

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