$80 million supports research into exceptional longevity

(Press-News.org) Researchers at Washington University School of Medicine in St. Louis have received an $80 million grant to continue research into the mysteries of exceptional longevity. The grant renews support for the Long Life Family Study, a long-running, international investigation of multiple generations of families with unusually high numbers of individuals who have lived much longer than statistical models predict, including some to age 100 and beyond.

The work is supported by the National Institute on Aging of the National Institutes of Health (NIH).

Launched in 2004, the Long Life Family Study has built on WashU Medicine’s long history of global leadership in genetics and genomics. One of the largest contributors to the Human Genome Project, the international effort that first sequenced the entire human genome, WashU Medicine has led the field in DNA sequencing, including in analyzing the whole genomes of all participants in the long life study to seek genetic clues to longevity. In the two decades since the study began, it has revealed important insights into features of healthy aging, notably that most long-lived families have better cardiovascular health than the average population does, including healthier blood pressures and lower rates of diabetes.

Around the world, populations are aging and with that comes an increasing number of people projected to develop chronic conditions, such as cardiovascular disease, diabetes and Alzheimer’s disease. Studies estimate that the number of people over age 50 with at least one such condition could double by 2050.

According to Michael A. Province, PhD, the Long Life Family Study’s principal investigator and a professor in the Department of Genetics at WashU Medicine, research into the genetics of families with exceptional longevity could shed light on how long-lived individuals avoid or delay the onset of common diseases of aging and guide the development of treatments and prevention strategies that could help anyone live a longer, healthier life.

“So much of medical research is focused on genetic problems that cause disease, and importantly so — we have learned a tremendous amount from that strategy,” Province said. “But I am also fascinated by the opposite question: are there genetic variants that cause good things to happen in the body? Our study suggests that there is a wide variety of genetic ways that these long-lived families could be protected from chronic diseases as they age.”

New insights into healthy aging The study has enrolled more than 5,000 participants from more than 530 families living across the U.S. and in Denmark. The oldest generation averaged 90 years of age when the study began enrolling families in 2006, and several survived beyond 110 years. Today, the children of that first generation are entering their 80s and the grandchildren are in their 50s and 60s. This study design allows the researchers to analyze inherited genetic variations that may protect multiple generations of family members from typical diseases of aging. The well-known Framingham Heart Study, which has been tracking multiple generations of families in Framingham, Mass., since 1948, serves as a comparison group.

Over the past five years, the long life study researchers have uncovered some tantalizing hints to healthy aging. Importantly, they found that the families were not uniform in terms of how they experienced unusual health, suggesting multiple potential routes to healthy aging. For instance, some families stood out as healthier than average in cognition or blood pressure, whereas others had markedly robust lung function or grip strength.

In general, though, the families tended to have lower rates of diabetes. One of the researchers’ analyses identified a genetic variant associated with lower hemoglobin A1c, a measure of average blood sugar levels that is used to diagnose diabetes.

According to Province, many families maintain unusually good cardiovascular and metabolic health, but he said there are some mysterious paradoxes in the data as well. For example, obesity is just as common among long-lived families as it is among those in the Framingham Heart Study, yet the long-lived families have only about half the cases of diabetes that would be expected.

“Something is protecting them from diseases associated with obesity,” Province said, “and we’d love to find out what that is.”

The unusually long lives of the participants also provided the opportunity to identify a novel gene associated with late-onset Alzheimer’s disease. And in an unexpected finding, the researchers uncovered a genetic variant associated with both extreme longevity and lower blood pressure but also a slightly increased risk of head and neck cancer. Although more research is needed to understand what may be causing these seemingly unrelated outcomes, the researchers said it points to a need for caution when trying to develop therapies to treat diseases caused by rare variants that may confer both positive and negative health effects.

Another new aspect of the study will be a re-analysis of whole genomes for all current and past participants using the latest “long-read” sequencing technology.  The new technology also will be used to analyze new participants’ genomes, bringing the total number of participants in the study to 7,800 individuals. The tools and techniques of whole genome sequencing have advanced dramatically over the 20 years of the study. The new long-read technology can resolve much of the so-called “dark matter” of the genome that was missed by the original short-read sequencing technology. The new analysis will allow the researchers to potentially find additional genetic clues to longevity that the older technology missed.

Because most of the oldest participants have now died, Province said, the investigators are seeking to enroll new families with very long-lived oldest generations. The goal is also to expand the genetic backgrounds of participating families, which have been largely of European descent.

“We plan to enroll more families and especially families of African ancestry,” Province said. “The larger and more diverse our dataset, the better we will be able to identify inherited genetic variants associated with longevity and then distinguish which are causing the protective effects and which are just inherited and ‘along for the ride,’ so to speak. This is a critical question as we seek possible ways to replicate these protective effects for people without the beneficial genetic variations.”

The Long Life Family Study has sites across the U.S. and internationally. As part of this grant renewal, WashU Medicine researchers are working with their collaborators at Boston University, Columbia University, the University of Pittsburgh, the University of Minnesota, Duke University, Johns Hopkins University, the University of Maryland, Tufts University, Georgia State University and the University of Southern Denmark.

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This work is supported by the NIH, grant number 2U19AG063893-06. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

About WashU Medicine

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with more than 3,000 faculty. Its National Institutes of Health (NIH) research funding portfolio is the second largest among U.S. medical schools and has grown 83% since 2016. Together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently among the top five in the country, with more than 2,000 faculty physicians practicing at 130 locations. WashU Medicine physicians exclusively staff Barnes-Jewish and St. Louis Children’s hospitals — the academic hospitals of BJC HealthCare — and Siteman Cancer Center, a partnership between BJC HealthCare and WashU Medicine and the only National Cancer Institute-designated comprehensive cancer center in Missouri. WashU Medicine physicians also treat patients at BJC’s community hospitals in our region. With a storied history in MD/PhD training, WashU Medicine recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

 

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