View Full Version : Rare mutation protects against aging

17-11-17, 18:38
Well, this is very interesting. It seems to be related to a certain type of metabolism. The long lived group they studied is part of the Amish people. I wonder if long lived people in other parts of the world share the same mutation?


"Plasminogen activator inhibitor–1 (PAI-1) has been shown to be a key component of the senescence-related secretomeand a direct mediator of cellular senescence. In murine models of accelerated aging, genetic deficiency and targetedinhibition of PAI-1 protect against aging-like pathology and prolong life span. However, the role of PAI-1 in humanlongevity 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 BerneAmish community, which included 43 carriers of the null SERPINE1 mutation. Heterozygosity was associated with significantlylonger leukocyte telomere length, lower fasting insulin levels, and lower prevalence of diabetes mellitus. Inthe extended Amish kindred, carriers of the null SERPINE1 allele had a longer life span. Our study indicates a causaleffect of PAI-1 on human longevity, which may be mediated by alterations in metabolism. Our findings demonstratethe utility of studying loss-of-function mutations in populations with geographic and genetic isolation and shed lighton a novel therapeutic target for aging."

18-11-17, 08:58
Unfortunately they don't mention the SNP in the paper. But it could be rs1799889 (https://www.snpedia.com/index.php/Rs1799889), is an insertion/deletion polymorphism in the promoter region of the SERPINE1 gene, which is also known as plasminogen activator inhibitor type 1 (or PAI1 or PAI-1). It is not tested by 23andMe, etc., but another closely related SNP is tested (rs1799768 (https://www.snpedia.com/index.php/Rs1799768)) for that deletion. Those SNP's have been linked to a number of conditions, including gastric cancer, metabolic syndrome, high LDL cholesterol, hypertension, migraine, bacterial osteomyelitis and a number of female reproductive disorders.

That deletion is not so rare. In fact, according to NCBI (https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1799768), it is found in over half of Eurasians, a third of Amerindians and a quarter of Africans. But that includes both heterozygous (DI) and homozygous (DD) carriers. However the study says that some benefits were similar for both heterozygous and homozygous.

20-11-17, 05:28
The SNP in question does not have an rsID ... yet ...