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, plastic pot 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, 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. 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 bio-active 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 lifte, should be considered. Moreover, both essential nutrients as well as other nonessential bio-active 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. Significant strides in science and technology made over the past decade will be instrumental in our efforts to understand precision nutrition. In this next section, we discuss contributors to individual variability and precision nutrition, including the role of metabolism, genotypes, and the gut microbiome.Variability in responses to nutritional interventions in healthy humans is well-known and suggests that individuals may benefit from more personalized dietary regimens to improve or maintain health. Although the physiologic/genetic underpinnings of these phenotypes and their responsiveness to changes in nutritional status largely remain to be explored, tools to efficiently identify nutritionally responsive phenotypes are emerging. Variable responses to dietary omega-3 FAs are one of the better characterized nutritionally responsive phenotypes, and this research highlights the complexity and nuance needed to fully appreciate physiologically relevant responses. For instance, in a secondary analysis of a randomized, double-blind, placebo-controlled trial of short-term fish oil supplementation in 83 individuals of African ancestry, a two-thirds by one-third split in ‘high responders’ compared with ‘low responders’ was reported with respect to intervention effect on red blood cell long-chain ω-3 FA enrichment, reduction in plasma triglyceride concentrations, and stimulated monocyte inflammatory responses. Although an individual’s adiposity, baseline ω-3 FA status, consumed dose, grow bag and the ingested ω-3 form contribute to the ω-3 response, this variance may also be influenced by an individual’s background diet. In particular, the consumption of less than one-third cup of dark-green and orange vegetables and legumes—and the health effects of their accompanying nutrients—was associated with the low response in a secondary analysis of the aforementioned intervention study. Another experimental approach to examine inter individual variability to a nutritional intervention is the mixed meal/ macronutrient challenge test. Analogous to oral glucose tolerance tests, in which the metabolic response to a standardized carbohydrate challenge is investigated, a mixed macronutrient challenge can be used to probe the metabolic response to a complex meal. Using standard clinical measurements, such a challenge can be used to simultaneously assess insulin sensitivity and fat tolerance. However, by expanding the experimental end points to include both physiologic and broad metabolic responses using modern metabolomic technologies, the potential for phenotypic profiling of an individual’s response to such a standardized meal is extraordinary. For instance, an individual’s metabolic flexibility , their metabolic health, and the potential for their response to interventions can all be assessed. Another powerful application of metabolomic phenotyping in nutritional research is the application to twin studies. By employing sets of both dizygotic and monozygotic twins, these approaches have demonstrated the power to segregate and quantify the genetic and environmental factors driving covariance between physiologic and metabolic traits and health outcomes. In summary, characterizing the range and nature of both fasting and postprandial nutritional phenotypes based on differences in metabolism in healthy populations offers novel approaches to identify individuals that may benefit from more individualized nutritional guidance to improve and/or maintain their health.
Moreover, tools exist today to begin this task. The application of these tools in well-designed clinical trials will be critical to effectively demonstrate their value in aligning nutritional guidance and/or interventions with metabolic phenotypes.Gene-by-diet interactions have the potential to have a tremendous impact on human health. Throughout history, humans evolutionarily adapted to their local environments to move across the globe, including to their changing diets. However, transitions to the modern Western diet in the last 75 y have resulted in maladaptations leading to a high prevalence of various chronic diseases, including obesity, cancer, and cardiometabolic diseases that disproportionately affect certain populations and create ethnic health disparities. For example, the adoption of the Western diet brought about a dramatic increase in the intake of PUFAs, specifically dietary ω-6 PUFAs. This shift was initiated by an American Heart Association recommendation in 1961 to replace dietary SFAs with PUFAs. Evidence supporting the recommendation included randomized controlled trials and cohort studies conducted in non-Hispanic White populations showing benefits of increasing ω-6 PUFAs on levels of serum lipids and lipoproteins . It was also assumed that only a small proportion of these ω-6 PUFAs could be converted to proinflammatory/prothrombotic long-chain ω-6 PUFAs, such as arachidonic acid, so adding 5%–10% energy as ω-6 PUFAs would have limited detrimental inflammatory/thrombotic effects due to saturation of the biosynthetic pathway. However, studies began to emerge a decade ago that showed genetic ancestry plays a critical role in determining the metabolic capacity of the long-chain ω-6 PUFA biosynthetic pathway. Specifically, several studies revealed that populations with African ancestry have much higher frequencies of genetic variants in the FA desaturase cluster on chromosome 11 that markedly enhance the conversion of dietary ω-6 PUFAs to the long-chain ω-6, arachidonic acid and proin- flammatory/prothrombotic oxylipins , and endocannabinoids metabolites. This underlying pathogenetic mechanism potentially results in a higher risk of chronic disease in those of African ancestry compared with those with European ancestry.With few exceptions, ω-6 long-chain PUFAs, such as arachidonic acid are proinflammatory/prothrombotic, and ω-3 longchain PUFAs, such as EPA and DHA are anti-inflammatory/ antithrombotic. Given the fact that a much higher proportion of populations of African ancestry has the capacity to form higher levels of arachidonic acid and its metabolites from dietary ω-6 PUFAs, it might be expected that ω-3 long-chain PUFAs would have a greater capacity to balance the impact of high dietary ω-6 PUFAs in these populations. Among clinical trials carried out to date, the VITamin D and omegA-3 TriaL is of particular interest when considering African ancestry, as it included n ¼ 5106 African-American participants out of n ¼ 25,871 total participants. Overall, supplementation with marine ω-3 long-chain PUFAs failed to prevent CVD or cancer events among healthy middle-aged men and women over 5 y of follow-up. Although ω-3 long-chain PUFA supplementation failed to prevent CVD in the full group analysis, in a follow-up subgroup analysis, Manson et al.demonstrated robust risk reductions in AfAm . Similarly, subgroup reanalysis of the VITAL study data based on the FADS framework compared the Kaplan–Meier curves for the MI end point, faceted by fish consumption and the number of CVD risk factors, for both European American and AfAm participants. This reanalysis revealed a marked ~80% reduction in MI associated with ω-3 long-chain PUFA supplementation in AfAm participants with baseline CVD risk who did not consume fish.