There is a tide shift happening around the types of nutritional outcomes clinicians are attempting to evaluate. Momentum is growing behind studies demonstrating “resilience,” and how nutritional status can optimize the health of disease-free populations in a lasting way.

At the Council for Responsible Nutrition's (CRN) Science in Session event in Phoenix, AZ, scientists from academia and the National Institutes of Health (NIH) discussed developments in the effort to reframe the purpose of nutrition research with resilience front of mind.

A Newfound Focus at NIH

LaVerne L. Brown, PhD, chair and program director of the Trans-NIH Resilience Working Group, discussed the formation of the unit in 2019 and its overall mission. First and foremost, it has been a challenge to implement a working definition of the word “resilience” that can be used consistently in all human health studies.

So representatives from various offices of NIH developed a definition and conceptual graphic that aligns with the overall NIH mission; is applicable at both population-wide and individual levels; and broad enough to encompass diseases, stressors, and physiological processes.

The definition aims to establish consensus for researchers at NIH to harmonize the way they design studies involving resilience-related outcomes, which are defined as: “a system’s capacity to resist, recover, recover better (grow), or adapt in response to a challenge or stressor.”

NIH goes further to define exactly what is meant by “resistance,” “recovery,” “recovering better,” and “adaptation” when used as the four qualifiers.

“After developing this initial definition, NIH developed a resilience research design tool to talk about questions that should be considered in these types of studies,” Brown said. Such questions include:

• Does the study target health maintenance, the ability to thrive, or preventive/protective pathways?
• Does research design include a stressor or proxy for a stressor or challenge?
• Is an intervention identified, or are protective factors identified or sought for discovery?

“As researchers come closer to an agreed-upon definition of resilience, it bears the opportunity to better characterize resilience outcomes in study designs and reports,” Brown said. “There is an opportunity for researchers to agree upon a checklist of some sort to harmonize the science. There are still several gaps, such as how we characterize the magnitude of natural stressors”—which are much more difficult to measure outside of a clinical setting, like early childhood trauma, or environmental pollution, for example.

“Also, how do we measure the magnitude of those protective factors which are intrinsic outside of clinical settings?” Brown said. “How can we know their significance in impacting resilience outcomes? How long should the stressors be studied, and when in the life cycle do these stressors and interventions have the most influence on outcomes?”

The Importance of Biological Age

By 2030, it is estimated that one fifth of the U.S. population will be over the age of 65, burdening the healthcare system at a tremendous scale, said Emily Ho, PhD, Linus Pauling Institute chair and director.

“Of course, we need to take a proactive and prevention approach for major disorders we have in the U.S.,” she said. “But we need to move past the prevention of disease. We need to move past preventing neurodegeneration, for instance, and think about how to improve a person’s memory, how to improve focus so one can perform and be their best selves and be present every day. We need to make sure the immune system has resilience to fight off not just infections, but many, many different stressors […] These things all take place in the absence of disease, and yet these systems are failing in a way that will inevitably lead to disease.”

While there’s utility in generalized policy recommendations for the population at large, it’s important to answer questions about improving long-term outcomes for presently healthy individuals, Ho said. Different subpopulations are more or less likely to have insufficiencies in one or more nutrients, which can have a precipitous effect on health as one ages. In the absence of disease, clinically silent nutrient insufficiencies affect a variety of systems in the body.

Several factors are slowing progress, according to Ho, such as the common use of unreliable nutrient status biomarkers, or using chronological age instead of biological factors such as the epigenetic clock, mitochondrial function, or immune profiling. The U.S. is also falling short in mainstream recommendations for various nutrients because they aren’t considered relevant to human health in the Dietary Guidelines for Americans.

Nutrition researchers could look to the field of cancer research, one of the earliest adopters of personalized medicine, in order to develop strategies involving genomics—genetics, epigenetic data, and phenotypes are key in being able to distinguish responders and non-responders to nutrient interventions, according to Ho.

“We’ve become very good at measuring many new biomarkers in the past decade,” she said, “but there are some big barriers to overcome in order to integrate and interpret this type of data in clinical studies.”

Metabolism is More Than Meets the Eye

There’s potential in the field of genetics and phenotyping to isolate individuals and their needs, according to John Newman, PhD, research scientist at the USDA-ARS-Western Human Nutrition Research Center (WHNRC).

Nutritional phenotyping uses statistical analysis to integrate the ways in which genes, diet, the environment, lifelong nutritional patterns, age, and sex interact in human health outcomes. Nutritional phenotypes can often explain seemingly random variability in how resilient populations are to various stressors, Newman noted. 

“In the classic areas of inborn errors in metabolism, the study of genetic defects are well-known and there are many examples of genetic modifications that alter the nutritional needs in the population,” Newman said. “What is less understood is how subtle changes in genetic utility or functionality, interacting with the environment, can develop subpopulations or aspects of populations that may have unique metabolic needs or responses.”

“This can help to boil down who might be a responder or a non-responder, or someone who might respond more quickly or more slowly to a nutritional intervention,” Newman continued.

He noted, for instance, a WHNRC study which highlighted factors controlling baseline omega-3 status besides diet, including genetics and overall nutritional environment, particularly the intake of leafy green and orange vegetables.

“Is it a bi-nutrient interaction? Is it due to an impact on the microbiome? We just don’t know,” Newman said.

Other studies show how important it is to measure more than just the intake of a single nutrient, Newman said. Another WHNRC study concluded that 42% of the variability in Omega-3 Index responses of participants who took omega-3 supplements could be attributed specifically to upper body adiposity.

WHNRC’s Individual Metabolism and Physiology Signature (iMAPS) study (which awaits publication) and Nutritional Phenotyping study each demonstrated that phenotyping (through looking at postprandial responses rather than fasting blood states) is important to parse out previously unforeseen risks of metabolic disorders like diabetes and hypotriglyceridemia.

“There was major variability in the populations with postprandial responses, and we don’t know what that means,” Newman said. There may be a prevalent amount of undetected, sub-clinical cases of prediabetes within a given population (as was the case for around 8% of study participants), whose delayed insulin responses were only revealed through the use of testing postprandial response.

The iMAPS study found that 10% of its population had elevated triglycerides in a fasting state, while 32% of the population had elevated triglycerides after a meal over the first three hours. With fasting triglycerides failing to predict hypertriglyceridemia in such a sizeable portion of the population, it raises many more questions than answers, Newman said, but the variance indicates unknown factors are at play.

To parse out variabilities on the individual level, the field of metabolomics is used. “Metabolomics is a broad analytical approach to measure as many small molecules in a single sample as you possibly can, in order to get an overview of global biochemical events. The metabolome gets us as close as we can to integrating the genome all the way through to the phenotype, and when using it to probe metabolic outcomes, there are 500 metabolites in the fasting state, which are broken down into 87 clusters.”

In order to get a true picture of metabolomics in an interventional study, however, analyzing mono- or dizygotic twins will be crucial to providing a picture of phenotypic outcomes, Newman noted. “Using sophisticated math, you can fully segregate the effects of the genetic versus the effects of the environmental, by using two identical genetic makeups with different interventions applied.”

“Characterizing the range and nature of nutritional phenotypes in a healthy population is a means of improving the health of individuals if we can understand it,” said Newman. “There are a lot of critical questions left, but defining the connections between nutritional responses and health will help to develop strategies for health assessment and disease prevention.”