Nutrition's role in extending healthspan: CRN-international symposium report

Abstract

The annual CRN-International symposium, “Food Is Medicine: The Role of Nutrition in Extending Healthspan” sought to address the profound impact of dietary habits on health and healthy lifespan, as judicious nutritional choices can serve as a powerful tool for health promotion. A key question to consider with the “Food is Medicine (FIM)” movement is to what degree diet and nutrition regimes play a role in FIM efforts beyond treatment for morbidity and disease by contributing to resilience and extension of years people are healthy. A paradigm shift in healthcare policy and practice is necessary, recognizing nutrition and dietary interventions as foundational components of health care. Geography, cultural, and socioeconomic factors must be examined as integral parts of interventions that are sustainable and accessible to all, thereby democratizing health. Nutrition, including food, beverages, and dietary/food supplements, serves as a cornerstone of preventive medicine. Integration of nutritional strategies into the healthcare system is urgently needed so they are considered alongside medications, procedures, and tests, particularly for prevention and health promotion. There is a need for increased awareness and education about healthy dietary habits combined with policy changes that encourage such habits, contributing to an improved healthspan and quality of life.

Introduction

The importance of nutrition has evolved far beyond the traditional understanding of simply fueling the body or preventing overt nutrient deficiency. Today, optimal nutrition is increasingly recognized as a cornerstone of health, wellness, health promotion, and disease prevention. The World Health Organization (WHO) has focused public and scientific attention on the importance of a holistic strategy of encouraging healthful activities and discouraging socioenvironmental insults that undermine longevity [1]. Within this paradigm is nutritional optimization, a role for choiceful nutrition that builds resiliency and prevents or minimizes the detrimental outcomes associated with diseases, especially later in life. The philosophy of "Food is Medicine (FIM)" or Food First strategies encapsulate this paradigm shift, reflecting the concept that the food we consume has the power to not only sustain life but also to heal, protect, and enhance our physical and mental well-being prior to the need for allopathic medicinal intervention [2]. This aligns with a growing body of scientific research on resiliency underscores the profound impact of diet on a wide range of health outcomes, from chronic disease management to cognitive function and immune support. Well-intentioned socioeconomic or geopolitical constructs have often pitted nutrition and modern medicine against one another to extend our healthy lifespan, when evidence for the two working in harmony is clear. These proceedings capture recent advances highlighting the interwoven role played by nutrition in maintaining optimal longevity while underscoring the value that sound nutrition plays in rebounding from injury. Utilizing single ingredients as case examples, good nutrition is critical to support the functionality of musculoskeletal, hematopoietic, and immune systems, primary keys to extending quality of life, and warding off harm.

A crucial aspect of optimal nutrition is ensuring adequate protein intake. Protein is vital for muscle repair but also immune function, enzyme production, and hormone regulation. Inadequate protein intake can lead to a variety of health issues, including muscle wasting, weakened immunity, and slower recovery from illness or injury. It is particularly important as we age when the body’s ability to digest, absorb and synthesize protein decreases, leading to an increased need for dietary protein [3]. Less known, protein plays a significant role in stabilizing blood sugar levels and maintaining satiety, which helps prevent overeating and reduces the risk of obesity-related diseases [4]. Another vital nutrient that plays an essential role in maintaining optimal health is vitamin D, primarily synthesized by the body through exposure to sunlight but supplementation is often critical in situations where sunlight is limited. Adequate vitamin D intake is crucial for calcium utilization and bone health, a healthy immune response and vitamin D deficiency is linked to a range of health problems including an increased risk of chronic diseases such as cardiovascular disease, diabetes, and autoimmune conditions [5]. In addition to macronutrients and vitamins, botanicals and phytochemicals also play a significant role in promoting health. Phytochemicals—bioactive compounds found in plants—can be powerful antioxidants, anti-inflammatory agents, and immune modulators [6, 7]. Integrating these botanicals into daily nutrition provides an additional layer of support for the body’s natural defenses, highlighting the powerful synergy between plant-based nutrients and management of overall health.

The idea of FIM goes beyond preventing malnutrition or addressing dietary insufficiencies. It suggests that the strategic use of foods can assist conventional medicine with its aim of preventing, treating, and even reversing certain health conditions. As more individuals turn to diet as a proactive approach to health, medical professionals, researchers, and policymakers are increasingly advocating for nutrition as an essential tool in both chronic disease management and preventive healthcare.

This manuscript summarizes the outcome of the 2024 CRN-I symposium “Food is Medicine: The Role of Nutrition in Extending Healthspan”, exploring the intersection of optimal nutrition and the emerging concept of FIM. By examining scientific evidence and real-world applications, this symposium sought to provide a comprehensive understanding of how nutrition can serve as a powerful, accessible tool in promoting health and preventing illness. The authors highlight robust scientific evidence for the benefits of healthy nutrition on resilience and quality of life. The growing body of peer-reviewed FIM literature attests to the veracity of the claims without the need for traditional clinical trials as required for synthetic or iatrogenic compounds. As we continue to uncover the remarkable benefits of food, it becomes clear that optimal nutrition is not just a lifestyle choice but a vital component of modern healthcare.

Food is medicine: the role of nutrition in extending healthspan—OVERVIEW

Initially a philosophy acknowledging the connection between food and well-being, FIM has evolved into a set of programs and initiatives aimed at shaping public policy and the environment to improve the accessibility to, and sustainability of, nutritious foods. The concept that food—in all its forms—can effectively maintain health, prevent, manage, and/or treat specific conditions—is in accord with the modern and holistic view of nutrition. No longer exclusively applied for the prevention of overt nutrient deficiency, the field of nutrition has expanded to impact chronic disease risk, resilience and healthspan. Evidence continues to emerge demonstrating how various nutrition interventions, including dietary patterns, such as the Mediterranean diet, replete with micronutrients and bioactive substances, can impact the body’s ability to cope with physiological stress, slow the pace of acing and delay the onset of age-related functional decline.

According to the World Health Organization (WHO), health promotion, “…is the process of enabling people to increase control over, and to improve their health” [8]. The manner in which diet and nutrition promote health can be measured or demonstrated through intrinsic capacity (IC) or resilience. IC is defined by the WHO as, “…all the mental and physical capacities that a person can draw on and includes their ability to walk, think, see, hear and remember” [9], while the National Institutes of Health (NIH) defines resilience as, “…a system's capacity to recover, grow, adapt, or resist perturbation from a challenge or stressor…”[10]. The terms are somewhat synonymous; both are measurable, and both determine a person’s (or population’s) functional trajectory over time. In the context of healthspan, the greater the IC (or resilience), the longer the healthspan—the amount of time a person is healthy, free from chronic disease and disability, and enjoying a good quality of life.

It can be argued that the modern purpose of diet and nutrition is to equip the body to be more resilient, or enhance IC, and extend healthspan (and avoid disease in the process). The various domains of IC (Cognition, Locomotion, Psychological, Vitality, Sensory) [11] can all be impacted through nutrition and/or lifestyle interventions. The ability to maintain IC or resilience with age is in turn impacted by exposure to various common physiologic, metabolic, environmental, psycho/social, and dietary stressors (Table 1). The degree, frequency, duration, etc. of exposure to common stressors, including smoking (oxidative stress), sun exposure, alcohol consumption, being sedentary, infection, sleep deprivation, and others, negatively impacts organ and tissue function [12]. Nutrition interventions may exacerbate or protect against stress-induced cellular, tissue, and organ damage, ultimately impacting function in the form of IC or resilience outcomes.

Table 1.

Examples of nutrition intervention studies with resilience outcomes*

Intervention	Stressor	Outcome(s)	Reference
Nicotinamide riboside supplementation	Inflammaging	Reduction in proinflammatory markers vs. Placebo	Elhassan et al. 2019
Lutein supplementation	Computer monitor (blue light) exposure	Improved visual acuity & contrast sensitivity vs. Placebo	Ma et al. 2009
β-alanine supplementation	24 h simulated Sustained Military Operations	Maintenance of performance indicators (physical, reaction time, subjective soreness & fatigue) vs. Placebo	Varanoske et al. 2018
Vitamin D supplementation	Psychological stress procedure	Normal recovery from stress in the winter months vs. Placebo	Hansen et al. 2020

*The studies listed are intended to be examples of how resilience outcomes can be incorporated into study designs to assess the impact of nutrition interventions on healthspan; the studies themselves are small and can only be considered as pilot data. Further research in larger clinical trials are needed to confirm both efficacy and safety of these interventions

Examples of nutrition interventions improving resilience

Various examples exist in literature demonstrating a positive effect of a nutritional intervention on resilience in the face of a stressor. The following examples are intended to be illustrative of how resilience outcomes may be incorporated into intervention study designs to assess the impact of nutrition interventions on healthspan. While promising, these studies are relatively small in size and duration, limiting the generalizability of the findings. Larger clinical trials including diverse populations are necessary to validate these initial findings. Such trials tend to be both time and resource intensive, and thus ideally are the purview of governments (e.g. NIH, UKRI, EU) to fund. With the present situation for government funding of biomedical research in peril in the US, more creative and diverse approaches for funding may need to be considered going forward.

A classic example relates to the essential coenzyme, nicotinamide adenine dinucleotide (NAD). Known mostly for its role in electron transport and ATP production, the oxidized form, NAD + is also involved in a range of cellular and DNA repair processes. Both aging and exposure to metabolic stress disrupts NAD + metabolism and depresses NAD + cell and tissue levels. This has been demonstrated in animal models to result in increased oxidative stress, inflammation, and tissue dysfunction. In humans, it is linked to a range of mitochondrial disorders, including several neurodegenerative diseases [13]. Lifestyle modifications, including calorie restriction [14], moderate exercise [15], and supplementation with NAD + precursors (forms of vitamin B3) [16] can prevent or even reverse this metabolic stress-induced NAD + decline. Daily supplementation with 1000 mg of the NAD + precursor nicotinamide riboside (NR) for 21 days in a group of older men (70–80 yrs; BMI 20–30 kg/m²) resulted in a significant increase in whole blood NAD + levels and a reduction in age-associated inflammation (n = 6 for NR, n = 6 for Placebo) [17]. Similar findings of NR supplementation and reduction in proinflammatory factors are supported in several very small and short-term human trials with less than 50 participants [18–22]. As a next step large-scale and longer-term clinical trials are needed to establish clinical efficacy and safety to advance application of NAD + at the clinical and public health level.

Lutein is a xanthophyll carotenoid naturally present in yellow and green leafy vegetables and in high concentrations in the macula, the part of the retina responsible for the central field of vision. Both epidemiological and intervention studies have long demonstrated a role for dietary and supplemental lutein in the reduction of ocular disease risk, including age-related macular degeneration and cataract [23]. Its ability to absorb high-energy blue light and scavenge free radicals may explain lutein’s beneficial effects. More recent studies suggest that short-term supplementation with lutein may enhance resilience following ocular stress. In one such study, 37 young adults exposed to daily computer monitor use of more than 10 h per day over the previous two years were supplemented with lutein (lutein at (6 (n = 12) or 12 (n = 12) mg/day, respectively) or placebo (n = 12). Computer screens are known to emit light wavelengths between 400 and 490 nm—the same as high-energy blue light. The lutein groups experienced improvements in visual acuity and contrast sensitivity compared to the placebo group [24]. Results of this study suggest that raising lutein status via supplementation may help improve visual resilience when faced with the ocular stress of high-energy blue light in younger adults.

Carnosine (β-alanyl-l-histidine) is a histidine-containing dipeptide naturally present in mammalian skeletal muscle and is suggested to play a role in the regulation of anaerobic exercise by acting as an intracellular pH buffer, modulating energy metabolism, quenching free radicals and impacting calcium ion signaling [25]. Supplementation with the carnosine precursor β-alanine is known to elevate muscle carnosine levels or status. A recent study by Varanoske et al. [26] investigated the impact of b-alanine supplementation on resilience in 19 military soldiers. Male soldiers were supplemented with 12 g/day of β-alanine (n = 10) or placebo (n = 9) for two weeks prior to an intense 24 h Sustained Military Operations exercise. At three time points (0 h, 12 h, and 24 h), soldiers’ physical performance, visual reaction time, subjective feelings of soreness and fatigue, and inflammatory and endocrine markers were assessed. The placebo group reported significantly higher subjective feelings of soreness and fatigue (at 12 h), slower visual reaction time (at 24 h), more errors on reaction time testing and a longer 1 km run time vs. the β-alanine group. These findings of one small clinical trial suggest that β-alanine supplementation prior to the onset of a substantial physical stress may improve the resilience of the soldiers, rendering them better equipped to cope with the stress.

Vitamin D is known to exert health effects beyond bone, with both geographic and seasonal variation in sun exposure impacting status. In a recent study, investigators examined the effect of vitamin D supplementation on stress resilience in 86 adult patients from an inpatient treatment facility [27]. Before and after supplementation with 1600 IU/day vitamin D (n = 39) or placebo (n = 43) for 6 months, patients were subjected to an experimental psychological stress procedure (involving completion of cognitive tasks during exposure to aversive noise). Psychophysiological activity was measured at baseline, during stress exposure, and during recovery. Prior to supplementation, both groups’ baseline, stress, and recovery activity were the same. However, following supplementation, the vitamin D group recovered normally with improved vitamin D status, while the placebo group did not, with no change in vitamin D status. Interestingly, the pre-supplementation stress assessment was conducted in the spring months while the post-supplementation assessment was conducted in the winter months. The findings of this small clinical trial suggest that improving vitamin D status, particularly in the winter months when status tends to decline, may enhance the ability to cope with, in this case, psychological stress. Larger clinical trials are needed to validate these initial findings.

Incorporating supplements into the FIM discussion

The examples provided (See Table 1 for summary) suggest that nutrition interventions with micronutrients and bioactive compounds may positively impact resilience or IC. This fundamental notion that nutritional interventions may enhance resilience, promote health, and extend healthspan is a foundational aspect of FIM. To date, FIM initiatives and programs have been discussed and implemented in the context of foods—access to nutritious and health promoting whole foods and prepared foods. Yet, food components, including essential micronutrients and bioactive compounds, in addition to whole foods, can impact health. Thus, in so much as the above examples utilized dietary supplements as the intervention, it begs the question of whether dietary/food/health supplements should be part of the FIM dialogue, provided the necessary trials are conducted to validate these outcomes. However, it must be acknowledged that supplements—as the name indicates—are supplementary to, not a substitute for, a healthy diet. Whole food-based diets include components, bioactives and phytonutrients, many of which have yet to be identified in combinations and ratios unlikely to be replicated by supplement products. To the extent supplements have a part in the FIM dialogue, it’s one that is complimentary in nature. Indeed, of the markets worldwide that have established a formal legal framework for dietary/food/health supplements, the overwhelming majority consider them a category of food [28]. Furthermore, in established markets like the US, roughly 75% of the population reports using dietary supplements [29]. According to the US National Health and Nutrition Examination Survey (NHANES), the top two reasons Americans cite for using supplements is to improve overall health and maintain health [30]. With recent advances in nutrition science, policy, and food and supplement regulation, now is the time to consider whether and how supplements can be part of the FIM movement.

Food is medicine: past, present, and future

Past

FIM is an ancient concept that has been an important part of many traditions and cultures across the globe. The Papyrus Ebers from ancient Egypt, one of the oldest surviving medical documents, contains many references to the medicinal properties of food [31]. In the Americas, for indigenous populations, the connection of food to the earth imbued it with both spiritual and healing properties [32, 33]. For example, the “three sisters” staple foods (corn, beans, and squash), found in many areas across the continent, were thought to have medicinal properties beyond their role in basic sustenance [34, 35]. In the Indian subcontinent, ayurvedic medicine emerged, with food as a critical part. Ayurvedic medicine uses foods therapeutically to balance the three doshas, which are energies or life forces (vata, pitta, kapha) [36, 37]. Ayurvedic medicine also emphasizes diet as prevention [37].

The concept of FIM was prevalent in later periods as well. In the fifth century B.C., the ancient Greeks’ understanding is revealed by the famous quote by Hippocrates of Cos, considered the father of Western medicine: “Let food be thy medicine and medicine be thy food.” During this time in Greece and Rome, the belief was that optimal body function relied on four main fluids, or humors: blood, yellow bile (choler), black bile, and phlegm [38]. Similar to the Ayurvedic doshas, balance was vital. An imbalance in the humors was considered a cause of illness, and patients were advised to eat different foods to treat illness [38, 39]. Also, during this general timeframe (third century B.C.), the Chinese medical book Huang Di Nei Jing (The Yellow Emperor’s Book of Medicine) was created, which is considered a foundational source for traditional Chinese medicine. Like the Greco-Roman humors and the Ayurvedic doshas, this text emphasized the concept of balance, in this case between yin and yang, with five elements as central to health and well-being [40]. To maintain health, it specified that grains, meat, vegetables, and fruit should be consumed in the right proportions [40].

Present

Current FIM efforts reaffirm the ancient connection between food and health while incorporating modern scientific evidence. The concept is especially relevant given an aging population—the number of people aged 65 and older is expected to double by 2050 [41]. Although life expectancy is increasing, a significant number of those years are impacted by diet-related chronic diseases such as heart disease and diabetes. Thus, while lifespan (the number of years people live) has increased, healthspan (how many of those years people remain healthy and disease-free) has not [42]. FIM can be key in treating and preventing chronic disease as people age.

FIM programs are defined as the provision of healthy food resources to prevent, manage, or treat specific clinical conditions in coordination with the healthcare sector [43]. There are several different types of FIM programs, and although they have common elements, each is unique in terms of history, priority population served, and operationalization. Produce prescription programs are one type of program in which patients are referred by healthcare providers and receive economic incentives, usually in the form of electronic cards or paper vouchers, to redeem for fruits and vegetables at retail food outlets (grocery stores, farmers markets, mobile markets) [44]. There is some evidence, mainly from pre-post studies, that these programs can reduce HbA1c, BMI, and blood pressure [44]. Additional studies, including randomized controlled and comparative effectiveness trials are needed to fully assess the impact of these programs on health outcomes. Produce prescription programs are suitable for preventing disease among at-risk patients who can shop and prepare food independently. Medically tailored groceries are a prescribed selection of foods designed to address a specific diet-related diagnosis [44]. Some programs provide home delivery of the groceries to help improve access among patients with barriers to shopping; however, the patient must be capable of preparing food at home. Medically tailored meals are fully prepared meals delivered to a patient’s home, and a registered dietitian designs them to meet the specific dietary requirements of a patient living with one or more health conditions [44]. They can benefit patients who have difficulty shopping or preparing meals for themselves. All types of FIM programs typically include some form of nutrition education, such as one-on-one counseling or classes. Although research is ongoing, for all types of programs, the evidence is mounting for the effectiveness in improving food security, diet quality, health outcomes, and healthcare utilization and costs (reviewed in Mozaffarian et al. [44]).

Future

As FIM programs continue to grow and develop, especially as new policies are enacted to support them, it will be critical to ensure that they are feasibly and sustainably integrated into healthcare systems and fully accessible to patients who are most in need. To that end, there has been an increasing number of studies examining the implementation of these programs [45–50]. More is being learned about best practices for integrating them into a clinical workflow so that they do not overburden staff. Research to date suggests the importance of offering up-front support for clinics adopting these programs, standardizing some aspects of the programs but allowing some flexibility to integrate them into clinical workflows, and identifying policy opportunities to ensure the sustainability of the programs since clinics are unable to bear the costs [45–47, 49]. Implementation studies can also help document the barriers to participation that patients may face, which is critical to adapting the program design so that programs can better include patients with fewer resources and looser ties to healthcare systems. These studies will help ensure efficient, equitable, and sustainable implementation as we move forward into the future of FIM programs.

Meals that move you: the importance of protein-rich food for muscle mass and function with age

Maintaining an adequate quantity and quality of skeletal muscle is vital for metabolic health and functional independence with advancing age. This important tissue is constantly ‘turning over’ through the targeted degradation of old/damaged protein into its constituent amino acids, with new functional proteins synthesized in their place. Through its ability to stimulate muscle protein synthesis, which can be compromised with advancing age and/or inactivity [51], dietary protein represents an important nutritional factor to help mitigate the risk or severity of sarcopenia, which is defined as the loss of muscle mass and strength/function. For example, older adults consuming > / = 1.2 g/kg/d, which exceeds the current recommended dietary allowance (RDA) of 0.8 g/kg/d, was associated with a ~ 44% attenuation in lean body mass (including muscle) decline over 3 years compared to those consuming at or below the RDA [52]. Furthermore, a well-controlled prospective study demonstrated that older adults consuming the RDA experienced ~ 1.5% loss of thigh muscle cross-sectional area in just 3 months [53] which is equivalent to the expected 3-year loss reported by some [54]. Observational data have also revealed greater indices of upper and lower body strength as well as muscle quality (i.e., strength normalized to muscle CSA [cross-sectional area]) in older adults consuming > 1.2 g/kg/d protein as compared to those consuming below this level [55]. The impact of protein on functional strength measurements such as grip strength may be greater at older ages (i.e., > 65 years for women and > 75 years for men) [56]. Collectively, these observations have contributed to the growing call for increasing the recommended daily intake of protein for older adults to help mitigate age-related loss of muscle mass and function [57–59]. Despite recommendations that older adults should target ~ 1.0–1.2 g/kg/d, many community dwelling older adults consume below this level with up to ~ 57% not meeting a minimum of 1.0 g/kg/d in some cohorts [60].

While targeting a daily protein intake may be useful for older adults, physiologically, the muscle responds to the nutrients consumed within a 4-6 h postprandial period. It is clear that meal protein ingestion stimulates the synthesis of muscle proteins (including the force-generating myofibrillar proteins) in both young and older adults [61]. However, older adults require a greater meal protein intake to obtain a similar benefit as their younger counterparts (~ 0.4 g/kg vs ~ 0.25 g/kg, respectively) [62]. However, indiscriminately increasing meal size (i.e., both protein and energy) may not be advisable for all adults given the growing incidence of sarcopenic obesity [63], which itself can be counterproductive via its association with anabolic resistance to protein and exercise [64, 65]. Thus, when evaluating the typical daily protein distribution that is skewed towards the greatest meal protein in the evening [66], the first meal of the day after an overnight fast (i.e., negative muscle protein balance) may represent an ideal opportunity for protein supplementation or advocating older adults consume greater protein-containing foods. To this point, foods that have a higher protein:energy density arguably should be prioritized for older adults to ensure adequate intake of the anabolic essential amino acids (EAA) [67]. Importantly, the EAA leucine is known to be particularly anabolic for skeletal muscle due to its robust ability to activate the mechanistic target of rapamycin canonical signaling pathway, a process that is attenuated with age but can be reversed with higher dietary leucine intake [68–71].Thus, the general recommendations to optimize postprandial muscle protein synthesis are to consume an adequate quantity and quality of dietary protein at each meal of the day to counter any age-related anabolic resistance to help mitigate the risk of sarcopenia. Further, in addition to government recommendations (e.g. U.S. Department of Agriculture MyPlate) to consumed nutrient dense, lower fat foods, it has been argued that the density and bioavailability of EAA in food as well as factors related to processing (e.g. heat treatment) should be considered when identifying optimal food protein options to stimulate muscle anabolism with age [72]. While a focus on higher daily protein, especially from animal sources such as red meat, has been suggested to increase the risk of mortality from cancer or cardiovascular disease (CVD) [73, 74], recent analysis of the NHANES data do not support that usual protein intake per se or that of animal-origin specifically impact the risk for CVD or cancer [75]. Nevertheless, in addition to optimizing the anabolic potential of dietary protein (as discussed below), physical activity should be viewed as paramount to reducing the risk of CVD, cancer, and all-cause mortality and disease in addition to (or irrespective of) diet quality [76].

Skeletal muscle is a plastic tissue that is able to respond to physical stimuli or lack thereof. During muscle disuse (e.g. bed rest, limb immobilization) there is a characteristic loss of muscle mass, independent of age, that is underpinned by inactivity-induced anabolic resistance [77]. However, even more ‘benign’ forms of disuse, such as a low daily step count, are associated with an attenuated muscle protein synthetic response to dietary protein ingestion, which may underpin or exacerbate age-related anabolic resistance and muscle loss [78, 79]. It is therefore concerning that average daily step counts may decrease with age [80] and be associated with low muscle mass and function in older adults [81, 82]. However, lighter load but high effort resistance exercise is a potent countermeasure to low daily step counts that can completely offset inactivity-induced muscle loss and improve the muscle protein synthetic response to dietary protein [83]. This highlights the established role of resistance exercise to increase the utilization of dietary amino acids for new muscle protein synthesis regardless of age [84]. Moreover, merely performing a moderate intensity evening walk (~ 3500 extra steps per day) can increase the delivery of dietary amino acids to and muscle protein synthetic response of older skeletal muscle the following morning [85, 86], highlighting that even a suboptimal daily protein distribution may be improved by increased physical activity. Finally, we have recently demonstrated that reducing daily sedentary time through the utilization of exercise breaks (2 min of moderate walking or 15 sit-to-stand chair rises) every 30 min increases the utilization of dietary amino acids to build new muscle in otherwise healthy adults [87]. Thus, moving more and sitting less during the postprandial period may represent a feasible, cost-effective, and accessible lifestyle approach that improves the anabolic potential of any/all food (potentially irrespective of protein quality) to support optimal muscle mass and function across the life span (Fig. 1).

Fig. 1.

Dietary protein and physical activity recommendations to maintain optimal muscle mass and quality with age. RDA, recommended dietary allowance. Figure created with BioRender (Toronto, Canada)

The potential for dietary phytochemicals to boost healthspan: a critical evaluation

Healthspan

Healthspan is the period of life characterized by the absence of poor health (i.e., no type 2 diabetes, cardiovascular issues, chronic inflammation, impaired cognition, nor digestive problems) along with adept metabolic responses to meal challenges, resilience to stress, high vitality, and a healthy gut microbiota. Obesity, consumption of a poor diet, lack of exercise, and environmental factors lead to chronic conditions that can all shorten the healthspan. Healthy diets that are high in phytochemicals can help lower the risk of an early onset of chronic conditions. Research and advice in this area must be based on evidence, including human intervention studies, mechanistic studies, and epidemiology, but current advice is fragmented, and most countries do not have recommendations for phytochemical intake.

Classification, nomenclature, and amounts of dietary phytochemicals in foods

A description of the differences between phytochemicals, phytonutrients, bioactives, and (poly)phenols has been reported [88]. The latter includes phenolic acids, stilbenoids, isoflavones, flavonoids, and tannins. Other phytochemicals include carotenoids, phytosterols, alkaloids, and organosulfur compounds. Typical contents of phytochemicals in the diet of a person consuming 5 portions of fruit and vegetables per day with coffee and tea are 600–1000 mg (poly)phenols and 4–20 mg carotenoids based on composition data of raw foods. However, many phytochemicals are lost during processing. Indeed, almost all are absent from ultra-processed foods [89], and over-consumption of ultra-processed foods is a major dietary cause of adverse health outcomes, including negative effects on metabolic health [90]. After consumption of phytochemicals, metabolites appear in the blood with defined kinetics depending on the chemical structure of the parent compound. The gut microbiota plays an important role in the metabolism of many phytochemicals and often leads to the production of further bioactive compounds.

What are the mechanisms and evidence for the action of phytochemicals on healthspan?

Firstly, it is important to note that the property of being a chemical antioxidant does not imply any health effects. Although various tests have been reported in the literature, they are only useful for showing the total content of some phytochemicals in foods and beverages [91]. In addition, effects are likely to be subtle but important as they are exerted over a lifetime, since food is consumed every day. Multiple effects of phytochemicals have been proposed, but here we focus on the reported actions to lower the risk of type 2 diabetes, vascular dysfunction, and chronic inflammation, important parameters related to healthspan.

Effects of phytochemicals on blood sugar and insulin related to type 2 diabetes risk

Good metabolic health is characterized by well-regulated fasting blood glucose and insulin, low triglycerides and branched chain amino acids, insulin-responsive muscle, and a strong flow-mediated dilation (FMD) response. With a diet high in calories and ultra-processed foods, metabolic inflexibility develops, leading to increased ectopic fat, increased fasting blood glucose, lowered insulin sensitivity, elevated triglycerides and branched chain amino acids, together with an impaired FMD response. Phytochemicals can affect multiple steps in this progression, including inhibition of α-amylases [92] and of α-glucosidases [93] to lower postprandial blood glucose. The importance of this effect in lowering the risk of developing metabolic dysfunction is shown by acarbose, a drug that inhibits these enzymes but is not absorbed. Chronic acarbose administration decreased the incidence of diabetes by 36%, improved FMD, and lowered cardiovascular disease events [94]. Are phytochemical-containing supplements as effective as foods? Using the example of orange juice, several studies have examined the effects of whole orange juice or hesperidin supplements on metabolic outcomes in overweight volunteers or with metabolic syndrome in randomized controlled studies. Over 12 weeks, 500 ml of orange juice per day containing 120–160 mg hesperidin lowered HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) and fasting blood glucose [95, 96], whereas 250 ml did not [97]. A larger dose of hesperidin (1000 mg per day) alone also lowered HOMA-IR and fasting blood glucose [98]. Tea and coffee both contain high levels of phytochemicals. There is a dose-dependent reduction in risk of developing type 2 diabetes with both tea and coffee consumption in epidemiological studies [99–101], which is mostly not due to caffeine [102, 103]. A meta-analysis, with a total of ~ 200,000 participants, concluded that 4 cups of coffee per day gave a 35% reduction in the risk of type 2 diabetes [104]. Another meta-analysis, with a total of ~ 500,000 participants, demonstrated that the effect was dose-dependent, where each cup of coffee per day gave ~ 7% reduction in type 2 diabetes risk [105].

Effects of phytochemicals on vascular dysfunction related to lowered cardiovascular disease risk

Endothelial dysfunction is an early stage of cardiovascular disease, assessed by FMD. Many phytochemicals have been shown to have an effect on FMD and cardiovascular risk. As an example, a systematic review and meta-analysis of nine relevant studies on about 300 volunteers showed a strong chronic protective effect of anthocyanin-rich foods or extracts on fasting FMD [106]. The largest human intervention study to date on phytochemicals was on cocoa flavanols and cardiovascular risk. It involved > 21,000 healthy male and female volunteers (> 60 years old) given cocoa flavanols for 5 years in a randomized, placebo-controlled, double-blinded study. In compliant participants, there was a significant reduction of 15% in the total count of all cardiovascular events and a 39% reduction in deaths from cardiovascular disease [107].

Conclusions on phytochemicals and healthspan

Phytochemicals are absorbed from food, beverages, and supplements into the blood, often requiring the action of gut microbiota, and act by multiple mechanisms against conditions that lower healthspan. By targeting sugar spikes, energy metabolism, and nitric oxide signaling in the blood vessel walls, specific phytochemicals at sufficient doses in foods or supplements protect against the development of type 2 diabetes, vascular dysfunction, and chronic inflammation based on evidence from epidemiology, human interventions, and mechanistic studies when consumed habitually. Recommendations on individual phytochemicals are difficult to make, as epidemiological studies and most intervention studies are on phytochemical-rich foods and not on individual compounds. Often a higher dose of the pure compound is required to obtain the equivalent effect of a food in an intervention study, presumably because the presence of other phytochemicals and nutrients in the food leads to interactions and synergy between components.

Vitamin D: What did we learn from recent mega-trials, VITAL and DO-HEALTH?

Vitamin D deficiency remains prevalent in the population as a whole. Data suggest that children and younger adults present with vitamin D deficiency in about 50% of cases (25-hydroxyvitamin D [25(OH)D] levels < 20 ng/ml or < 50 nmol/l) [108]. The highest vitamin D deficiency prevalence, however, has been documented in older hip fracture patients, with about 80% being affected [109]. This is in part explained by the fact that ageing reduces skin production of vitamin D four-fold compared with younger adults [110]. An important role of vitamin D in overall health is supported by the presence of the specific vitamin D receptor in many organs, including the intestine, muscle, bone, brain, and the immune system [111].

While vitamin D plays an important role in bone health at any age [112], at older age, vitamin D deficiency contributes to the risk of sustaining fractures in two ways: (1) it impairs calcium metabolism causes secondary hyperparathyroidism and bone loss [112], (2) it causes muscle weakness and thereby promotes the risk of falling [113]. Consistently, daily vitamin D supplementation with 800 to 1000 IU was found to reduce fall [114] and fracture risk [115] in vulnerable older adults at risk of vitamin D deficiency. However, such benefits have not been confirmed in generally healthy and largely vitamin D replete middle-aged [116, 117] (VITAL) and older adults [118] (DO-HEALTH). Further, detrimental effects with an increase in falls and fractures were found with intermittent bolus dosing of vitamin D in monthly to yearly intervals (60,000 to 100,000 IU monthly, or 300,000 to 500,000 yearly) in vulnerable older adults [119]. The detrimental effects of vitamin D with intermittent bolus dosing have in part been explained by its triggering of countervailing factors that induce the degradation of vitamin D [119].

Two recent large clinical trials provide new insight on the effects of daily vitamin D supplementation in a dose of 2000 IU vitamin D on the immune system in generally healthy and largely not vitamin D deficient adults age 50 and older in the VITAL trial and age 70 and older in the DO-HEALTH trial. The European DO-HEALTH trial enrolled 2157 adults age 70 [118] and the US VITAL trial enrolled 25,871 adults [120]. Both trials were designed as partner trials. In VITAL among adults age 50 and older and over a 5-year treatment period, vitamin D supplementation reduced serum hs-CRP levels by 19% [121], reduced incidence of autoimmune diseases by 22% (31% if combined with omega-3 supplementation) [122], reduced incidence of advanced metastatic or fatal cancers by 17% [123] and reduced cancer mortality by 25% [120]. In DO-HEALTH among adults age 70 and older and over a 3-year intervention, findings showed an additive effect of vitamin D with omega-3 and a simple strength exercise program tested in an 8-arm study design to document individual and combined benefits of the interventions. The trial found that individuals who received a combination of 2000 IU/day of vitamin D3, 1 g of omega-3 s, and exercise (3*30 min a week) reduced their cancer risk by 61% [124], reduce their pre-frailty risk by 39% [125] and slowed their biological aging by on average 3 months [126].

Conclusion

The CRN-International Scientific Symposium explored the evolution of the FIM paradigm and examined current initiatives aimed at medical treatment, disease prevention, and health promotion. The potential of diet and nutrition to extend healthspan as part of FIM efforts is promising but for several nutrients lack evidence and safety data from large-scale clinical trials is missing. However, larger clinical trials exist for dietary regimes, including fruits and vegetables, protein, omega-3 and vitamin D. The distinguished expert presenters further considered the integration of specific dietary regimes and supplementation focused on health promotion and prevention into FIM programs and health policies for strategies that have been proven to be effective and safe in larger clinical trials,

Evidence-based solutions are of paramount importance for any FIM program, from a public health policy perspective, fortification and supplementation in low- and middle-income countries are currently crucial tools at the population level, particularly for specific life stages and vulnerable populations. However, data on dietary intake is often poor or non-existent, making it challenging to tailor interventions effectively. There is potential for "precision nutrition" in medically tailored meals, where dietary plans are customized to individual needs, potentially including supplementation. While evidence-based dietary supplements are already prescribed by healthcare professionals, they are typically excluded from healthcare coverage policies and should be considered for reimbursement, similar to medically tailored meals.

There is a need to reframe health promotion with a more comprehensive definition, incorporating the concept of resilience and using resilience-based study designs to demonstrate the effectiveness of interventions. Micronutrient deficiencies remain prevalent even in high-income countries and may be exacerbated by dietary transitions. FIM approaches should therefore include systematic monitoring and mitigation of micronutrient gaps alongside efforts to optimize overall dietary quality and food patterns. Additionally, there is a need for updated dietary guidelines, school meal programs with nutrition education, and a shift from a purely clinical focus to a broader, societal approach that emphasizes the social and cultural aspects of food. Family-based interventions should be considered as healthy habits are often learned within this context. Efforts should focus on making healthy eating fun and engaging, particularly for children, and on leveraging social media as an educational tool.

Integrating FIM principles into health policy requires a multi-faceted approach that addresses evidence-based supplementation, early intervention, health promotion, and social and cultural aspects of food. There is a need for continued research, particularly in the areas of food processing, health promotion, and the development of effective interventions that resonate with diverse populations.

Data availability

No new data were generated or analyzed in support of this symposium report. Data sharing is not applicable to this article.

Declarations

Conflict of interest

The event was organized and supported by the Council for Responsible Nutrition-International (CRN-I), an association representing dietary supplement and functional food manufacturers and ingredient suppliers. CRN receives support primarily from its industry membership. H. Bischoff-Ferrari, S Folta, D Moore, A Shao, G Williamson, and JC Griffiths had their travel expenses reimbursed by CRN-I. A Shao is an employee of ChromaDex, a CRN board member, and a former CRN employee. L Huber is an employee of CRN. D Marsman is a former chair of the board of directors for CRN-I. M Stout is an employee of Amway/Nutrilite and a CRN board member. JC Griffiths is a former employee of CRN. None of the authors declares any conflict of interest in providing their solely scientific opinion for this review.