Researchers Conduct Comprehensive Analysis to Try and Determine Why Some Families Live Longer

The Long Life Family Study (LLFS) is a unique, international project designed to reveal why some people live until a very old age and why some families maintain their health far longer than others. There are four locations participating in the study — three in the United States and one in Denmark — with the University of Minnesota Medical School serving as the central laboratory that coordinates biospecimen collection and conducts laboratory analyses. 

Bharat Thyagarajan, MD, PhD, MPH, associate professor in the Department of Laboratory Medicine and Pathology, received a five-year clinical research grant worth $4.2 million to continue the study, which is now in its third iteration. Dr. Thyagarajan joined the LLFS as a junior faculty member and has since become one of the principal investigators of this study. 

Research began in the early 2000s when roughly 4,500 people from 400 different eligible families were recruited to participate. The LLFS is a family-based study consisting of a very select group of families. To be an eligible participant, two generations of family members must have lived past the age of 90. In addition, researchers recruited the spouses for the control group.

The original idea of the study was to try and identify the genetic determinants of longevity, but the work has steadily expanded to include other areas of research. 

“We are looking at data at each level of regulation (genomics, transcriptomics, epigenetics, metabolomics and proteomics) and also across all different levels to identify determinants of longevity. We haven’t found a smoking gun for longevity, but what we have found is that different families are exceptional in different ways,” Dr. Thyagarajan said.

Analyzing families gives researchers an advantage since they can find trends by looking at segregation patterns and transmission across generations. But, collecting and analyzing the data isn’t a straightforward process. A good example is HbA1c, a hemoglobin measurement used to assess risk for diabetes. When looking at HbA1c levels, there is a specific region of the genome (known as a linkage peak) that’s associated with risk of diabetes, but after analyzing the data more closely, only 10 or 12 families among the overall 400 contributed significantly towards this result.

“When doing the genetic analysis, we were thinking there would be some common genomic region, or we might find a few pathways that would explain variance across all of these exceptionally successful families. Instead, what we’re finding is that each family has its own set of variance within HbA1c linkage peaks, which seems to explain why they have exceptional levels. So, that has been very unexpected. It’s these variants that are private to each family that are driving these linkage peaks and associations,” Dr. Thyagarajan said.

Data shows that many families are exceptional, meaning they possess better biomarker levels or phenotype traits as compared to controls with similar age and sex distribution, in one trait, yet very few families are exceptional in multiple traits. Some families have outstanding glucose control, while for others it's their cholesterol levels, lung functioning or cognition. 

“It seems to be different pathways through which each family becomes an exceptional survivor. Over the last 10 to 15 years, we’ve found that there are many different pathways through which someone can get longevity. Through our molecular analysis, we’re trying to find if there are some commonalities that allow people to be exceptional in various pathways,” Dr. Thyagarajan said.

Unfortunately, recognizing that every family is unique doesn’t immediately influence public health or clinical care, but the mountains of data and subsequent analysis will inform future decisions. 

“By looking at the genomics and the ultimate phenotype, we are seeing that there are common biological processes identified across all of these families that can become a marker for risk or even diagnosis. It’s something that we can implement on a more broad population scale,” Dr. Thyagarajan said.

Long-term cohort studies often prove invaluable over time as they give physicians evidence and justification for their choices. They are the informational foundation for many best practices.

“The hope is that, in routine clinical care, you won’t need to sequence entire genomes or do all of this extensive work that we’re doing from a discovery standpoint. After doing this work, we will have identified a more targeted group that can be easily measured within a clinical setting. If people want to screen who’s at risk for diabetes, they would screen maybe 10 markers that can all be combined into a single assay. Physicians would use these kinds of assays instead of the broad, general screening assays that are very expensive,” Dr. Thyagarajan said.

In the next phase of the LLFS, researchers plan to look at the different genetic variants and see how they coalesce into a biological pathway that is altered and gives rise to exceptional outcomes. They are already recruiting the third generation of participants, which are the grandchildren of the study’s original group. They’ve also found that the great-grandchildren of the original cohort actually have a lower infant mortality rate and less incidence of childhood infection, leading them to wonder what else they could learn. 

“We have to see what the findings of this study are going to be in the near future. Whatever is being transmitted seems to have this broad effect that transcends multiple generations. We started off as an aging study, but I believe with time, that the study will expand and include early-life determinants of longevity as well that will allow us to study aging over the entire life course,” Dr. Thyagarajan said.

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