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A gene mutation that makes humans live longer
According to scientists at Northwestern Medicine, Northwestern University, Evanston, Illinois, an internal fountain of youth has been discovered in some of the Amish living in the vicinity of Berne, Indiana. This genetic mutation allows those who carry it to live 13 percent longer than those who so not carry the gene. That means living to 85 years of age instead of 75 years of age as do those who don't carry the mutation. This is the first genetic mutation discovered to protect against multiple aspects of aging in humans.
An experimental "longevity" drug that recreates the effect of the mutation is now being tested in human trials to see if it provides protection against some aging-related illnesses. Surprisingly it is chemically closely related to a drug being developed for topical treatment of baldness.
Immediate family and relatives of those Indiana Amish with the mutation have at least 10 percent longer telomeres - the protective caps located at the end of each chromosom. Telomeres are a biological marker of aging. Also, a composite measure reflecting vascular age in these individuals indicates the retained flexibility in blood vessels in the carriers of the mutation as well. The research is published in the journal Science Advances.
These particular Amish have very low levels of the PAI-1 (plasminogen activator inhibitor) protein that makes up part of a "molecular fingerprint" related to aging or the senescence of cells. It was previously known that PAI-1 is related to aging in animals but it was unclear how it affected aging in humans.
"The findings astonished us because of the consistency of the anti-aging benefits across multiple body systems."
"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," Vaughan said. "That played out in them having a longer lifespan. Not only do they live longer, they live healthier. It's a desirable form of longevity. It's their 'health span.'"
Northwestern has partnered with Tohoku University in Japan in the development and testing of an oral drug, TM5614, that inhibits the action of PAI-1. The drug has already been tested in a phase 1 trial in Japan and is now in phase 2 trials there. Northwestern will apply for FDA approval to start an early phase trial in the USA, possibly to begin within the next six months. The proposed Northwestern trial will investigate the effects of the new drug on insulin sensitivity on individuals with type 2 diabetes and obesity because of the mutation's effect on insulin levels in the Amish.
In the new study, Northwestern scientists looked at individuals who had one mutant copy of the gene, rendering their level of PAI-1 to about half the level of kindred with two normal copies. Those carriers of the gene mutation had nearly 30 percent lower fasting insulin levels and were completely protected from diabetes.
"We were definitely surprised," Vaughan said. "Even when we analyze it factoring for their relatedness, the mutation is still an important predictor of whether they'll get diabetes." Vaughan found 7 percent of the kindred with two normal copies of the gene have diabetes, out of the 177 Amish participants in the study.
Scientists also saw an improvement in lower blood pressure and more flexible blood vessels. Although the improvement did not reach statistical significance, the carriers of the gene mutation have a younger appearing cardiovascular system, with the oldest third of the group having a reduced pulse pressure, indicative of more flexible arteries. Cognitive testing will be part of future measurements. Experimental data in mice shows lower levels of PAI-1 can protect against Alzheimer's-like pathology. "We hope to be able to revisit them regularly and do additional testing to look at the velocity of aging in the kindred and unearth more details about the protective effect of this mutation," Vaughan said.
The mutation was introduced into the Amish kindred by farmers from Switzerland. Two of their descendants carried the mutation, and then married into the Amish community. The Amish community outside the Berne area does not carry the mutation. Vaughan: "This is the only kindred on the planet that has this mutation. It's a 'private mutation." People carrying the mutation live to be 85 on average, significantly longer than the predicted average lifespan of 71 for Amish in general, which hasn't changed much over the last century.
In the U.S., Northwestern is partnering with a Japanese startup company (Renascience) to develop a new class of drugs that specifically target PAI-1. The drugs are the brainchild of Vaughan's collaborator, Dr. Toshio Miyata, who leads a drug discovery program at Tohoku University in northern Japan. Miyata initially contacted Vaughan to use his transgenic models of mice that overexpress human PAI-1. The mice, developed in Vaughan's lab, are bald, have heart attacks and other pathologies caused by an excess of PAI-1. Miyata, a nephrologist, was developing an oral drug to slow the progression of diabetic kidney disease, which is driven in part by PAI-1.
Miyata sent the experimental drug to Vaughan, who fed it to his bald mice for six weeks. Vaughan had tested other PAI-1 inhibiting drugs from large pharmaceutical companies, but none of them had worked. But then Vaughan noticed something. He called Miyata and announced, "The mice are growing hair. Your drug works! The impact we saw in those transgenic animals was unmistakable," Vaughan said.
Because of the drug's effect on hair growth in mice, Renascience has licensed a formulation to an American company, Eirion Therapeutics, Inc., that is advancing the development of a topical formula that will be tested for treating male pattern baldness. In the phase 1 Japanese studies, completed this past summer, the drug was given to about 160 healthy individuals to test its safety. After proving to be safe and nontoxic, the drug is now being tested in a phase 2 trial to see if inhibiting PAI-1 affects the migration of stem cells from the bone marrow. Scientists want to see if giving the PAI-1 inhibitor drug boosts the number of red and white blood cells and platelets of patients who have undergone chemotherapy, which results in low counts. That could reduce complications, which include infections, bleeding and anemia. Since PAI-1 controls the mobilization and release of stem cells from the bone marrow, scientists hypothesize that partial inhibition of PAI-1 will accelerate the recovery of normal cell counts in the blood.
Vaughn's previous research in a 2014 paper published in the Proceedings of the National Academy of Sciences showed the drug prolonged the lifespan in a mouse model of accelerated aging. In that study, the rapidly aging mice fed the experimental drug lived more than three times longer than a control group, and their lungs and vascular system were protected from aging-like pathology, including emphysema and arteriosclerosis.
When cells or tissue age, they lose the ability to regenerate and secrete certain proteins creating a distinctive fingerprint. One of those is PAI-1.
An earlier formulation of the experimental drug, TM5441, is one of only several chosen each year by the National Institute on Aging to be tested in its Interventions Testing Program, which investigates treatments with the potential to extend lifespan and delay disease in mice.
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.
Authors: Sadiya S. Khan, Sanjiv J. Shah, Ekaterina Klyachko, Abigail S. Baldridge, Mesut Eren, Aaron T. Place, Abraham Aviv, Eli Puterman, Donald M. Lloyd-Jones, Meadow Heiman, Toshio Miyata, Sweta Gupta, Amy D. Shapiro and Douglas E. Vaughan.
Other authors on the paper are co-first authors Dr. Sadiya S. Khan, and Dr. Sanjiv J. Shah, Ekaterina Klyachko, Abigail S. Baldridge, Mesut Eren, Aaron T. Place, Dr. Abraham Aviv, Eli Puterman, Dr. Donald M. Lloyd-Jones, Meadow Heiman, Dr. Toshio Miyata, Dr. Sweta Gupta and Dr. Amy D. Shapiro.
The research was supported by grant HL51387 from the National Heart, Lung and Blood Institute of the National Institutes of Health.
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Indiana Amish with a specific gene mutation live 10 percent longer when compared to other Amish.
They have very low levels of a protein related to senescence in cells. Getty Images.