Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging
Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging
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DOI：
10.1038/nm1786
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发表时间：
2008-07-01
期刊：
影响因子：
82.9
通讯作者：
Lopez-Otin, Carlos
中科院分区：
文献类型：
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作者：
Varela, Ignacio;Pereira, Sandrine;Lopez-Otin, Carlos
几种人类早衰症，包括 Hutchinson-Gilford 早衰综合症 (HGPS)，是由截短的前核纤层蛋白 A 的法尼基化形式在核膜上积累引起的，这种蛋白质在正常衰老过程中也会发生变化 (1,2)。先前对 HGPS 个体细胞的研究表明，法呢基转移酶抑制剂 (FTI) 可改善与 prelamin A 积累相关的核异常，表明这些化合物可能代表这种毁灭性早衰综合症的治疗方法 (3)。我们在此表明，在法呢基转移酶抑制的情况下，prelamin A 及其截短形式 progerin/LA Delta 50 都经历了香叶基香叶基转移酶的选择性异戊二烯化，这可以解释 FTI 在改善早衰小鼠模型表型方面的低效率。我们还发现，他汀类药物和氨基二磷酸盐的组合可有效抑制早老蛋白和 prelamin A 的法呢基化和香叶基香叶基化，并显着改善金属蛋白酶 Zmpste24 缺陷小鼠的衰老样表型，包括生长迟缓、体重减轻、脂肪营养不良、脱发和骨缺陷。同样，这些小鼠的寿命也大大延长。这些发现为与核包膜异常相关的人类早衰综合症开辟了一种新的治疗方法。
Several human progerias, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by the accumulation at the nuclear envelope of farnesylated forms of truncated prelamin A, a protein that is also altered during normal aging(1,2). Previous studies in cells from individuals with HGPS have shown that farnesyltransferase inhibitors (FTIs) improve nuclear abnormalities associated with prelamin A accumulation, suggesting that these compounds could represent a therapeutic approach for this devastating progeroid syndrome(3). We show herein that both prelamin A and its truncated form progerin/LA Delta 50 undergo alternative prenylation by geranylgeranyltransferase in the setting of farnesyltransferase inhibition, which could explain the low efficiency of FTIs in ameliorating the phenotypes of progeroid mouse models. We also show that a combination of statins and aminobisphosphonates efficiently inhibits both farnesylation and geranylgeranylation of progerin and prelamin A and markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects. Likewise, the longevity of these mice is substantially extended. These findings open a new therapeutic approach for human progeroid syndromes associated with nuclear-envelope abnormalities.