A null mutation in SERPINE1 protects against biological aging in humans.
A null mutation in SERPINE1 protects against biological aging in humans.
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DOI：
10.1126/sciadv.aao1617
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发表时间：
2017-11
期刊：
影响因子：
13.6
通讯作者：
Vaughan DE
中科院分区：
文献类型：
--
作者：
Khan SS;Shah SJ;Klyachko E;Baldridge AS;Eren M;Place AT;Aviv A;Puterman E;Lloyd-Jones DM;Heiman M;Miyata T;Gupta S;Shapiro AD;Vaughan DE
具有SERPINE1罕见基因突变的人类寿命更长，并显示出对衰老相关疾病的保护作用。纤溶酶原激活物抑制物-1(PAI-1)是衰老相关分泌组的关键成分，是细胞衰老的直接介质。在加速衰老的小鼠模型中，遗传缺陷和PAI-1的靶向抑制可以保护小鼠免受衰老样病理的影响，延长寿命。然而，PAI-1在人类长寿中的作用尚不清楚。我们推测，编码PAI-1的SERPINE1(c.699_700dupTA)罕见的功能缺失突变可能在人类的长寿和代谢中发挥作用。我们研究了伯尔尼阿米什社区的177名成员，其中包括43名SERPINE1零突变携带者。杂合子与显著较长的白细胞端粒长度、较低的空腹胰岛素水平和较低的糖尿病患病率相关。在扩大的阿米什家族中，携带空SERPINE1等位基因的人寿命更长。我们的研究表明，PAI-1对人类寿命有因果影响，这可能是通过新陈代谢的变化来调节的。我们的发现证明了在地理和遗传隔离的人群中研究功能丧失突变的实用性，并阐明了衰老的新治疗靶点。
Humans with a rare gene mutation in SERPINE1 live longer and show evidence of protection from aging-related morbidity. Plasminogen activator inhibitor–1 (PAI-1) has been shown to be a key component of the senescence-related secretome and a direct mediator of cellular senescence. In murine models of accelerated aging, genetic deficiency and targeted inhibition of PAI-1 protect against aging-like pathology and prolong life span. However, the role of PAI-1 in human longevity remains unclear. We hypothesized that a rare loss-of-function mutation in SERPINE1 (c.699_700dupTA), which encodes PAI-1, could play a role in longevity and metabolism in humans. We studied 177 members of the Berne Amish community, which included 43 carriers of the null SERPINE1 mutation. Heterozygosity was associated with significantly longer leukocyte telomere length, lower fasting insulin levels, and lower prevalence of diabetes mellitus. In the extended Amish kindred, carriers of the null SERPINE1 allele had a longer life span. Our study indicates a causal effect of PAI-1 on human longevity, which may be mediated by alterations in metabolism. Our findings demonstrate the utility of studying loss-of-function mutations in populations with geographic and genetic isolation and shed light on a novel therapeutic target for aging.
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影响因子：
7.8
作者：
Benetos A;Kark JD;Susser E;Kimura M;Sinnreich R;Chen W;Steenstrup T;Christensen K;Herbig U;von Bornemann Hjelmborg J;Srinivasan SR;Berenson GS;Labat C;Aviv A
通讯作者：
Aviv A
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
DOI：
10.1038/nrg3246
发表时间：
2012-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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影响因子：
--
作者：
D'Mello, Matthew J. J.;Ross, Stephanie A.;Pare, Guillaume
通讯作者：
Pare, Guillaume
影响因子：
3.1
作者：
Cesari M;Pahor M;Incalzi RA
通讯作者：
Incalzi RA