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Gene Discovery Could Help in Hunt for Novel Diabetes Drugs

Lisa Nainggolan
November 16, 2017

A genetic mutation that seems to be present only in members of an Old Order Amish community in Indiana appears to protect against multiple aspects of aging in humans, researchers have shown.

Those with the mutation have significantly less diabetes and lower fasting insulin levels, and their vascular age also appears to be lower than those members of their community who don't have this variation.

All told, the affected individuals live 13% longer — on average to the age of 85 compared with 75 — and appear to have 10% longer telomeres, a biological indicator of aging, compared with Amish who don't have the mutation.

The findings are published in Science Advances by Sadiya S Khan, MD, of Northwestern University Feinberg School of Medicine, Chicago, IL and colleagues.

The mutation — in the SERPINE1 gene — leads to low levels of plasminogen activator inhibitor 1 (PAI-1), a protein involved in blood clotting.

"The findings astonished us because of the consistency of the antiaging benefits across multiple body systems," says senior author cardiologist Douglas Vaughan, MD, also of Northwestern University Feinberg School of Medicine, in a press release issued by his institution.

"For the first time we are seeing a molecular marker of aging (telomere length), a metabolic marker of aging (fasting insulin levels), and a cardiovascular marker of aging (blood pressure and blood vessel stiffness) all tracking in the same direction in that these individuals were generally protected from age-related changes."

Now the research team is hoping to start trials of a PAI-1 inhibitor, TM5614, to examine its effects on insulin sensitivity in individuals with type 2 diabetes and obesity.

A Novel Therapeutic Target for Aging; Validated With CARDIA Data

Dr Vaughan first became aware of the mutation after a paper was published in the early 1990s detailing the genetics behind a very rare bleeding disorder that had previously been identified among this order of Amish. This showed that the disorder was due to the SERPINE1 gene mutation and those individuals carrying two copies (homozygous) did not produce PAI-1 and therefore their blood was unable to clot.

The mutation is present only among this particular order, the Amish Kindred of Indiana, who are all ancestors of Amish who emigrated from Berne, Switzerland, in the 19th century and who have remained genetically and culturally isolated, with most people being distantly related.

Initially interested in the effects of the PAI-1 mutation on cardiovascular function, Dr Vaughn soon broadened his team's efforts when it became clear through their laboratory work that the deficiency in this protein was also somehow related to aging — transgenic mice engineered to overexpress PAI-1 were bald and had heart attacks, for example.

So the next step was to see if this rare loss-of-function mutation in SERPINE1 played any role in longevity and metabolism in humans.

For the current study, the researchers set up testing stations in a community center near to where the Amish live and examined 177 members of the Berne Amish community. They identified 43 carriers of one copy (heterozygous) of the SERPINE1 mutation and compared them with the remaining 127 Amish who didn't have the mutation. (They excluded the seven individuals they found who were homozygous, with two copies of the mutation, who had no circulating PAI-1).

Those with the single mutation had 50% lower circulating PAI-1 levels compared with unaffected individuals, and they had significantly longer leukocyte telomere length and nearly 30% lower fasting insulin levels and appeared to be completely protected from diabetes. The carriers of one copy of the mutation also had a longer life span.

The researchers also included a group of vascular measurements that track strongly with biological age, including brachial pulse pressure and pulse-wave velocity.

"Although there were strong trends indicative of preserved vascular function in the carriers of the mutation, our study was underpowered, so none reached statistical significance," Dr Vaughan told Medscape Medical News.

"So we combined them into an index, and the [mutation] carriers have a lower score, perhaps indicative of a more 'youthful' vasculature," he added.

"We then asked if the vascular score index is actually relevant. Using the Coronary Artery Risk Development in Young Adults Study (CARDIA) data set, we found that the same index predicts cardiovascular events and, importantly, correlates with plasma PAI-1 levels," he explained.

In conclusion, the "study indicates a causal effect of PAI-1 on human longevity, which may be mediated by alterations in metabolism," he and his coauthors reiterate.

The drug that the team hopes to trial, TM5614, was developed by researchers in Japan, who have already successfully tested it in healthy volunteers. They are now about to conduct phase 2 trials to see if inhibiting PAI-1 can help boost numbers of red and white blood cells and platelets in patients who have undergone chemotherapy.

The agent is also being trialed as a topical formulation for the treatment of male pattern baldness, by the US company Eirion Therapeutics, after Dr Vaughan found that it caused the bald transgenic mice who overexpressed PAI-1 to grow hair.

The authors report no relevant financial relationships.

SOURCE: Medscape, November 16, 2017. Sci Adv. Published online November 15, 2017.





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