Researchers have found a noteworthy effect on longevity in a small study population that includes the only known individuals with a loss of function mutation in plasminogen activator inhibitor-1 (PAI-1). Individuals with the mutation live seven years longer on average than near relatives without it. Repeating the study with larger groups of people obviously isn't a practical option in the case of rare mutations - we're stuck with the family trees that the research community is fortunate enough to identify - but one nonetheless has to wish for more individuals, in order to obtain a more reliable confirmation, when an effect of this size is reported. It means taking a step back to revisit questions we've asked ourselves about the odds of finding significant longevity-enhancing mutations in our species, based upon the absence of results for the past twenty years of searching.
This is also a finding that can and probably should be taken as support for current work on elimination of senescent cells as a potential rejuvenation therapy. PAI-1 isn't a gene pulled from thin air in this context. It is well studied for its influence on aging, and appears to be one of the driving regulators of the harmful effects of cellular senescence. Lingering senescent cells accumulate with age, and secrete a mix of damaging signal molecules that produce chronic inflammation, damage tissue structure, and alter the behavior of nearby cells for the worse. This is known as the senescence-associated secretory phenotype (SASP), and PAI-1 is involved in both the SASP and in some of the processes by which cells become senescent. Studies show that inhibition or loss of PAI-1 reduces some of the harms now known to be associated with senescent cell presence, and in doing so slows measures of aging.
There is all sorts of past research into PAI-1 and senescent cells that we might choose to draw lines between. To pick one example, PAI-1 inhibition can slow atherosclerosis, just as can removal of senescent foam cells in atherosclerotic plaque. There are no doubt overlapping mechanisms here, though it seems clear that reducing PAI-1 levels has a variety of other effects as well. Those effects can't be all that terrible given the existence of a lineage of thriving human mutants lacking PAI-1, something that is always a good demonstration to have in hand. There are a few other beneficial mutations with a small human population to examine, such as those related to reduced blood lipids; we may see many of these lines of research result in therapies in the years ahead. And yet! While there will no doubt be an avalanche of funding into bringing PAI-1 inhibitors to the clinic, ask yourself this: if tinkering with a fraction of the harmful secretions of senescent cells is this beneficial, how much better will it be to remove these damaging cells entirely via senolytic therapies? All of those involved in this field should spend more time than they do on work with a higher expectation value, I believe.
The first genetic mutation that appears to protect against multiple aspects of biological aging in humans has been discovered in an extended family of Old Order Amish. 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. Indiana Amish kindred (immediate family and relatives) with the mutation live more than 10 percent longer and have 10 percent longer telomeres (a protective cap at the end of our chromosomes that is a biological marker of aging) compared to Amish kindred members who don't have the mutation.
Amish with this mutation also have significantly less diabetes and lower fasting insulin levels. A composite measure that reflects vascular age also is lower - indicative of retained flexibility in blood vessels in the carriers of the mutation - than those who don't have the mutation. These Amish individuals have very low levels of PAI-1 (plasminogen activator inhibitor,) a protein that comprises part of a "molecular fingerprint" related to aging or senescence of cells. It was previously known that PAI-1 was related to aging in animals but unclear how it affected aging in humans.
"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. 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.'"
The researchers have partnered with another group 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. The team will apply for FDA approval to start an early phase trial in the U.S., possibly to begin within the next six months. The proposed 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.
Aging remains one of the most challenging biological processes to unravel, with coordinated and interrelated molecular and cellular changes. Humans exhibit clear differential trajectories of age-related decline on a cellular level with telomere attrition across various somatic tissues and on a physiological level across multiple organ systems. In addition to telomere length, researchers have proposed several molecular drivers of aging, including genomic instability, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Despite knowledge of these potential molecular causes of aging, no targeted interventions currently exist to delay the aging process and to promote healthy longevity.
In the United States, cardiometabolic disease influences life span as a leading cause of death and disability in adult men and women. Cardiometabolic disease is associated with a shorter leukocyte telomere length (LTL). Telomere shortening, which results from replication of somatic cells in vitro and in vivo, may cause replicative senescence. Senescent cells and tissues exhibit a distinctive pattern of protein expression, including increased plasminogen activator inhibitor-1 (PAI-1) as a part of the senescence-associated secretory phenotype (SASP).
PAI-1, which is encoded by the SERPINE1 gene, is the primary inhibitor of endogenous plasminogen activators and is synthesized in the liver and fat tissue. In addition to its role in regulating fibrinolysis, PAI-1 also contributes directly to cellular senescence in vitro. Genetic absence or pharmacologic inhibition of PAI-1 in murine models of accelerated aging provides protection from aging-like pathology, prevents telomere shortening, and prolongs life span. Cross-sectional human studies have demonstrated an association of plasma levels of PAI-1 with insulin resistance. Large genome-wide association studies (GWAS) provide an additional supportive evidence for a casual effect of PAI-1 on insulin resistance and coronary heart disease.
The role of the SASP, in general, and specifically PAI-1 in longevity in humans is uncertain. We have previously reported the identification of a rare frameshift mutation in the SERPINE1 gene in the Old Order Amish (OOA), living in relative geographic and genetic isolation; this mutation results in a lifelong reduction in PAI-1 levels. Therefore, we tested the association of carrier status for the null SERPINE1 mutation with LTL as the prespecified primary end point in the only known cohort with a SERPINE1 null mutation. The central findings of our study are that heterozygosity for the null SERPINE1 gene encoding PAI-1, which is associated with a lifelong reduction in PAI-1, is associated with longer LTL, a healthier metabolic profile with lower prevalence of diabetes, and a longer life span. The Amish kindred provide an unprecedented opportunity to study the biological effects of a private loss-of-function mutation with a large effect on circulating PAI-1 on longevity in humans.
The current study builds upon the available cellular and animal evidence supporting the role of PAI-1, the product of SERPINE1, as an important contributor to aging. PAI-1 expression is increased in senescent cells and tissues and is a fundamental component of the SASP. There is a compelling evidence that senescent cells accumulate in the tissues and contribute to the aging process. In addition to contributing to the molecular fingerprint of senescence, PAI-1 is necessary and sufficient for the induction of replicative senescence in vitro and is a critical downstream target of the tumor suppressor p53. The contribution of PAI-1 to cellular senescence is broadly relevant in the organism as a whole.