Going forward, as researchers across various scientific domains and sectors come closer to a unified definition of resilience and perhaps agree to the use of a standard checklist for designing and reporting on resilience studies, there is greater opportunity to harmonize the science and develop more empirical evidence of resilience outcomes.Optimizing performance also includes building resilience in order to enhance the ability to perform tasks and ensuring resilience in order to prevent illness, injury, and disease. Within the US Department of Defense, researchers are able to study different models of physical and psychological stress and the application of different nutritional interventions with Service Members throughout their careers. Various models of stress are introduced, including initial military training , advanced military training courses , service academies , and extreme environments , along with examples of various interventions and outcome measures collected to date. The importance of nutrition on readiness and resilience was identified in military populations more than a decade ago and continues to be of interest. Two specific examples are provided to further explore nutrition interventions aimed at optimizing performance in the Department of Defense. The first, a completed double-blind, randomized, placebo-controlled trial, used a calcium and vitamin D fortified food product to optimize bone health during initial military training of Marine Corps recruits. Using a supplement or food intervention for calcium and vitamin D, participants received 2000-mg calcium and 1000-IU vitamin D per day. The primary outcomes of the study showed that bone markers and vitamin D status improve, but the supplementation did not affect skeletal parameters. A second,bato bucket forth coming study aims to evaluate the effectiveness of adding spices and herbs to increase vegetable intake among junior-enlisted Service Members.

Their current research is focused on the stressors and challenges to enhance resilience. Using a cycle of basic science/discovery that advances to clinical trials with various review steps helps move the field of nutrition science forward in a “total force fitness” approach. Total force fitness was introduced as a framework to help Service Members, their families, and military units reach and sustain optimal, holistic health, and performance in a way that aligns with their mission, culture, and identity. Other examples of frameworks focused on a holistic approach to research include Whole Person Health proposed by the National Center for Complementary and Integrative Health, Whole Health developed by the Department of Veterans Affairs, and a recent consensus study report by the National Academies entitled Achieving Whole Health. A focus on improving resilience as a model outcome highlights the opportunities and complexities of conducting optimal health and nutrition research in this space.As the number and proportion of older adults in the population increase, the prevalence of age-related deficits in mobility and cognition also increases. Such deficits may be because of normal aging or to pathologic processes. For instance, cognitive impairments like declines in memory and speed of processing may result from normal brain aging or neurodegenerative diseases like dementia. When considering hallmarks of optimal nutrition and health, improving resilience from cognitive decline has strong promise and impact. Although the etiology of age-related mobility and cognitive changes is multifactorial, it is well established that vulnerability to oxidative stress and inflammation increases as we age. Strategies that target oxidative stress and inflammation may improve resilience to processes that lead to cognitive decline. For example, a healthy diet may help combat both oxidative stress and inflammation in the body, but a diet rich in bio-active polyphenolics from fruit, vegetables, walnuts, and coffee may be especially important in improving resilience and health outcomes. Polyphenols have antioxidant and anti-inflammatory activities, so consuming them could slow or prevent age-related changes.

As previously shown, foods high in polyphenols, e.g., dark-colored berry fruits, prevent age-related neuronal and behavioral deficits in animal models of aging. In particular, studies from animal models of aging have found that polyphenolic compounds from walnuts and berries hold promise in slowing—and perhaps even reversing—age-related motor and cognitive declines. These polyphenolics possess antioxidant and anti-inflammatory properties and may also influence the brain directly through various mechanisms, including altered cell signaling and increased neurogenesis, arborization of dendrites, and autophagy in the brain. In recent randomized, double-blind, placebo-controlled pilot studies in healthy older adults , blueberry or strawberry supplementation was able to improve some aspects of cognitive performance, but not gait or balance. In a randomized, double-blind, placebo-controlled trial in 44 healthy older adults , supplementation with freeze-dried blueberry powder for 3 months improved 1 measure of executive function and 1 measure of learning and memory. In a similarly designed trial, supplementation of freeze-dried strawberry powder in 39 healthy older adults for 3 months improved 2 measures of learning and memory compared with placebo but had no effect on executive function. Both trials found that berry powder supplementation did not affect mobility, including measures of balance and gait, likely because the study subjects had no mobility detriments at baseline. Berry supplementation did not decrease serum levels of inflammatory biomarkers compared with placebo, but when serum from berry-supplemented subjects was applied directly to cultured microglia cells, there was a reduction in LPS-induced inflammatory markers relative to placebo-treated subjects. Interestingly, the serum was protective when taken during fasting as well as post prandially. Although these studies are preliminary, they add to the evidence that berry supplementation may help protect against age-related cognitive declines. In addition to single nutrients, healthy dietary patterns have been shown to slow the rate of cognitive decline. In particular, the Mediterranean-DASH diet intervention for neurodegenerative delay diet, which highlights increased intake of plant-based foods, such as berries and green leafy vegetables, is associated with lower risk of cognitive impairment in older adults.

Further investigations examined mechanisms and other factors involved in the beneficial effects of berry fruits. For example, changes in circulating levels of specific phenolic compounds were correlated with changes in cognition. Furthermore, cognitive performance and inflammation were related, as serum collected from berry-supplemented animals reduced LPS-induced inflammatory-stress-mediated signals in stressed highly aggressively proliferating immortalized microglia in vitro relative to serum from placebo-fed controls, and nitrite levels following supplementation were positively correlated with cognitive performance. Therefore, the inclusion of additional servings of polyphenolic-rich foods, such as nuts and berries, in the diet may be one strategy to forestall age-related neuronal deficits, perhaps via decreases in inflammation and suppression of microglial activation, to help increase cognitive resilience and preserve cognitive function. Other non-nutritive natural compounds derived from plants should also be considered as bio-active compounds that contribute to optimal health and improving resilience. The BENFRA Botanical Dietary Supplements Research Center at Oregon Health & Science University studies Botanicals Enhancing Neurological and Functional Resilience in Aging. Two botanicals of interest are Centella asiatica and Withania somnifera . The Center has considerable experience with Centella asiatica, which is used in Ayurvedic medicine to improve memory. It is a popular dietary supplement for “brain health” and shows potential to be developed as a FDA approved “botanical drug” for the treatment of Alzheimer’s disease. The rational use of botanicals, whether as dietary supplements or botanical drugs, requires their evaluation through optimized clinical trials. These trials must be based on sound preclinical studies providing evidence for functional effects, mechanisms of action, and active compounds. The use of preclinical models is critical to inform the optimal design and implementation of future nutrient or botanical clinical intervention trials in healthy older adults and in patients with neurologic diseases, such as Alzheimer’s disease. However, due to the limitations of preclinical models in representing human health, disease, and responses, evaluation of the efficacy of an intervention through clinical trials in humans is essential. Research needs to focus on product authentication, identification of the biologically active compounds and their mechanisms of action, and detection of relevant biomarkers that translate to humans. Preclinical studies also need to address efficacy and safety of the botanical to advance translational research in cognitive resilience. Preclinical studies at Oregon Health & Science University have confirmed the cognitive effects of Centella asiatica in aged mice and that the antioxidant response gene Nrf2 is a molecular target of this herb. Triterpenes and caffeoylquinic acids have been identified as active compounds in C. asiatica and may account for its neuroprotection.

A phase I clinical trial examining the pharmacokinetics of Centella asiatica compounds in older adults with mild cognitive impairment was recently published. A recently initiated clinical trial will examine safety of C. asiatica and also characterize the biologic signatures of its cognitive effects in a population of cognitively impaired older adults. In the case of Ashwagandha, work at the BENFRA Center has focused on water and hydroethanolic extracts of the root,dutch bucket hydroponic as these preparations are commonly used in dietary supplements and in previously reported scientific studies. In one study, the effects of aqueous and hydroethanolic extracts of Ashwagandha root were compared in Drosophila melanogaster models of sleep, cognition, locomotion , and stress-induced depression. Treatment with the hydroethanolic extract improved age-related sleep fragmentation in male flies. Surprisingly, Ashwagandha root aqueous extract showed stronger effects than the hydroethanolic extract in Drosophila melanogaster models of cognition and locomotion and a model of stress-induced depression. Treatment with the aqueous extract of W. somnifera improved age-related locomotor declines in females at lower doses than the hydroethanolic extract. The aqueous extract also provided some resilience against stress-induced depression both when given prophylactically and continuously in a Drosophila model of depression. By contrast, the hydroethanolic extract was only effective when given continuously. The withanolides, commonly regarded as Ashwagandha’s active compounds, are present in greater amounts in the hydroethanolic than aqueous extracts. Together, this suggests that different Ashwangandha compounds may modulate the botanical’s effects on cognition, mood, and sleep and that compounds other than the well-known with anolides may be involved in some of its biologic effects. Studies are underway to explore these unknown active compounds in resilience to age-related cognitive decline and stress. Knowledge of the bioactive compounds associated with each potential clinical use of Ashwangandha will be important in optimizing products for clinical trials of Ashwangandha for those conditions. In summary, as we pivot to emphasize the promotion of optimal health, we need alternative indices of health besides disease outcomes. An individual’s ability to be resilient, including the ability to respond to stressors and to thrive and retain functionality while maintaining a high quality of life, should be considered. Moreover, both essential nutrients as well as other nonessential bioactive compounds should be considered as key factors that promote optimal health.As we define optimal health, it is clear that the potential solutions will vary depending on many individual and environmental factors. Nutritional interventions in healthy adults are known to produce a variety of responses, and work is underway to identify and characterize the different phenotypes that result in unique metabolic needs, with the goal to design personalized dietary approaches to maximize individual health. Although reasonable skepticism regarding the consumer readiness for precision and personalized nutrition exists, efforts to better illuminate the goals and challenges to this emerging technology are being openly discussed in the research community. For instance, in August of 2021, the National Academy of Science, Engineering, and Medicine held a public workshop titled “Challenges and Opportunities for Precision and Personalized Nutrition”. At this workshop, participants raised important perspectives on current opportunities and information gaps in our understanding and approaches to variability in nutritional responses, the shift in the personalized nutrition industry, and numerous studies demonstrating the potential utility for research in this area to aid in our understanding of variable nutritional responses as well as how in certain circumstances they may be beneficial in tooling both dietary guidance for glucose control and therapeutic interventions for weight loss. Addressing these knowledge gaps and refining our expectations and applications for individualized nutrition will be critical to realizing the full potential of this knowledge as another tool in our arsenal to improve human health. In 2020, the NIH also launched a new strategic plan for nutrition that emphasizes Precision Nutrition. In 2022, the NIH invested $170M in a new Precision Health program that leverages the All of Us research program and will allow unprecedented opportunities to combine metabolism, microbiome, diet assessment methods, and data sciences together to provide new insights in precision nutrition. Instead of a one-size-fits-all, we can envision a time where a person’s unique characteristics will be effectively used in a proactive approach to health promotion and disease prevention, and importantly, allowing personalized strategies based on these characteristics.