Washington University School of Medicine in St. Louis has received a $68 million grant to investigate and discover what contributes to extreme longevity. The researchers are studying hundreds of families — over several generations — with individuals who have had exceptionally long lives. Many of these families have unusual concentrations of people living to at least age 100.

The goal of the Long Life Family Study, funded by the National Institute on Aging of the National Institutes of Health (NIH), is to identify genetic factors that contribute to exceptional longevity. Such information could lead to new therapeutics or other health innovations to help people live longer, healthier lives.

“These families provide a unique opportunity for finding genetic links to long life spans,” said principal investigator Michael A. Province, PhD, a Washington University professor of genetics. “Remarkably, many study participants in the older generations are unusually healthy for their ages. We think we will find clues in their DNA that suggest how they might be protected from common diseases, such as diabetes or Alzheimer’s disease — or, at the very least, uncover genetic factors that might delay the onset of these health problems.”

The School of Medicine is the coordinating center for the project, which has field centers at Boston University, Columbia University, the University of Pittsburgh and the University of Southern Denmark. Province and Mary K. Wojczynski, PhD, an assistant professor of genetics at Washington University, lead the primary site and coordinate collaborations among the field sites and the University of Minnesota, where the laboratory for analyzing blood samples is located.

The study includes almost 5,000 individuals from three generations of 539 families across the United States and Denmark, first recruited from 2006 through 2009. The average age of representatives of the oldest generation in the study was 90 at that time, with some individuals exceeding 110. Those in the second generation of these families now average over 70 years of age, and the grandchildren of the oldest group are now in their 50s, on average. Studying multiple generations of families with histories of long lives presents the opportunity to study individuals who have a greater chance of reaching older ages. In particular, it provides the ability to study such individuals when they are younger and not yet obviously different from those with shorter life spans.

“When we study long-lived people, we would really like to be able to travel back in time and study them before they reach older ages — to see how they might differ from the general population when those differences might not yet be obvious,” Province said. “Our earlier findings from this study have shown that individuals in the second generation are healthier, on average, than individuals from families with more typical longevity, when measured, for example, in middle age. But these healthier traits vary by family. For example, some long-lived families might tend to have lower blood pressure while others might have better cognition into later life, and still others might have better lung function or grip strength. Across these families, there is no single factor that stands out as the main reason for the long health and life spans.”

The researchers suspect this variability may be linked to specific rare genetic variants that may protect such families from the harmful effects of aging in a variety of ways. The new funding will support whole genome sequencing of study participants in an effort to identify special protective variations in the DNA.

The researchers also will study the consequences of such differences in DNA through analyzing what effects they might have on the proteins, metabolites and other molecules that have a direct impact on the body’s biology. Such measures change with age, and the researchers are interested in comparing these with more average populations over their life spans. The comparison group is composed of participants from the well-known Framingham Heart Study, which has been tracking the health of multiple generations of families living in Framingham, Mass., since that study began in 1948. The researchers said less than 1% of families participating in the Framingham Heart Study meet the longevity criteria of the Long Life Family Study.

One genetic characteristic that stands out in some — but not all — long-lived families is the length of telomeres, or the end caps on chromosomes that protect the DNA from damage. Every time a cell divides, the telomeres get a little shorter, and shorter telomeres have been associated with chronic diseases, such as diabetes, heart disease, dementia and other disorders common among elderly people. Long-lived families seem to have longer than average telomeres.

“Telomere length might be one key component of healthy aging,” Province said. “There is evidence that healthy behaviors like exercise can protect telomere length or even extend it. But there is a genetic component to it as well. Some people just naturally have longer telomeres, or at least appear to have resilient telomeres. And that is the case in many of the families we’re studying. Based on that data, we have honed in on a gene that could be involved in telomere length, and this new grant will help us explore that possibility and other new avenues further.”