Protein intake and cancer: an umbrella review of systematic reviews for the evidence-based guideline of the German Nutrition Society.

PURPOSE: It has been proposed that a higher habitual protein intake may increase cancer risk, possibly via upregulated insulin-like growth factor signalling. Since a systematic evaluation of human studies on protein intake and cancer risk based on a standardised assessment of systematic reviews (SRs) is lacking, we carried out an umbrella review of SRs on protein intake in relation to risks of different types of cancer. METHODS: Following a pre-specified protocol (PROSPERO: CRD42018082395), we retrieved SRs on protein intake and cancer risk published before January 22th 2024, and assessed the methodological quality and outcome-specific certainty of the evidence using a modified version of AMSTAR 2 and NutriGrade, respectively. The overall certainty of evidence was rated according to predefined criteria. RESULTS: Ten SRs were identified, of which eight included meta-analyses. Higher total protein intake was not associated with risks of breast, prostate, colorectal, ovarian, or pancreatic cancer incidence. The methodological quality of the included SRs ranged from critically low (kidney cancer), low (pancreatic, ovarian and prostate cancer) and moderate (breast and prostate cancer) to high (colorectal cancer). The outcome-specific certainty of the evidence underlying the reported findings on protein intake and cancer risk ranged from very low (pancreatic, ovarian and prostate cancer) to low (colorectal, ovarian, prostate, and breast cancer). Animal and plant protein intakes were not associated with cancer risks either at a low (breast and prostate cancer) or very low (pancreatic and prostate cancer) outcome-specific certainty of the evidence. Overall, the evidence for the lack of an association between protein intake and (i) colorectal cancer risk and (ii) breast cancer risk was rated as possible. By contrast, the evidence underlying the other reported results was rated as insufficient. CONCLUSION: The present findings suggest that higher total protein intake may not be associated with the risk of colorectal and breast cancer, while conclusions on protein intake in relation to risks of other types of cancer are restricted due to insufficient evidence.

Dietary protein and blood pressure: an umbrella review of systematic reviews and evaluation of the evidence.

INTRODUCTION: This umbrella review aimed to investigate the evidence of an effect of dietary intake of total protein, animal and plant protein on blood pressure (BP), and hypertension (PROSPERO: CRD42018082395). METHODS: PubMed, Embase and Cochrane Database were systematically searched for systematic reviews (SRs) of prospective studies with or without meta-analysis published between 05/2007 and 10/2022. The methodological quality and outcome-specific certainty of evidence were assessed by the AMSTAR 2 and NutriGrade tools, followed by an assessment of the overall certainty of evidence. SRs investigating specific protein sources are described in this review, but not included in the assessment of the overall certainty of evidence. RESULTS: Sixteen SRs were considered eligible for the umbrella review. Ten of the SRs investigated total protein intake, six animal protein, six plant protein and four animal vs. plant protein. The majority of the SRs reported no associations or effects of total, animal and plant protein on BP (all "possible" evidence), whereby the uncertainty regarding the effects on BP was particularly high for plant protein. Two SRs addressing milk-derived protein showed a reduction in BP; in contrast, SRs investigating soy protein found no effect on BP. The outcome-specific certainty of evidence of the SRs was mostly rated as low. DISCUSSION/CONCLUSION: This umbrella review showed uncertainties whether there are any effects on BP from the intake of total protein, or animal or plant proteins, specifically. Based on data from two SRs with milk protein, it cannot be excluded that certain types of protein could favourably influence BP.

Protein intake and type 2 diabetes mellitus: an umbrella review of systematic reviews for the evidence-based guideline for protein intake of the German Nutrition Society.

PURPOSE: Protein-rich foods show heterogeneous associations with the risk of type 2 diabetes (T2D) and it remains unclear whether habitual protein intake is related to T2D risk. We carried out an umbrella review of systematic reviews (SR) of randomised trials and/or cohort studies on protein intake in relation to risks of T2D. METHODS: Following a pre-specified protocol (PROSPERO: CRD42018082395), we retrieved SRs on protein intake and T2D risk published between July 1st 2009 and May 22nd 2022, and assessed the methodological quality and outcome-specific certainty of the evidence using a modified version of AMSTAR 2 and NutriGrade, respectively. The overall certainty of evidence was rated according to predefined criteria. RESULTS: Eight SRs were identified of which six contained meta-analyses. The majority of SRs on total protein intake had moderate or high methodological quality and moderate outcome-specific certainty of evidence according to NutriGrade, however, the latter was low for the majority of SRs on animal and plant protein. Six of the eight SRs reported risk increases with both total and animal protein. According to one SR, total protein intake in studies was ~ 21 energy percentage (%E) in the highest intake category and 15%E in the lowest intake category. Relative Risks comparing high versus low intake in most recent SRs ranged from 1.09 (two SRs, 95% CIs 1.02-1.15 and 1.06-1.13) to 1.11 (1.05-1.16) for total protein (between 8 and 12 cohort studies included) and from 1.13 (1.08-1.19) to 1.19 (two SRs, 1.11-1.28 and 1.11-1.28) (8-9 cohort studies) for animal protein. However, SRs on RCTs examining major glycaemic traits (HbA1c, fasting glucose, fasting insulin) do not support a clear biological link with T2D risk. For plant protein, some recent SRs pointed towards risk decreases and non-linear associations, however, the majority did not support an association with T2D risk. CONCLUSION: Higher total protein intake was possibly associated with higher T2D risk, while there is insufficient evidence for a risk increase with higher intakes of animal protein and a risk decrease with plant protein intake. Given that most SRs on plant protein did not indicate an association, there is possibly a lack of an effect.

Protein intake and body weight, fat mass and waist circumference: an umbrella review of systematic reviews for the evidence-based guideline on protein intake of the German Nutrition Society.

PURPOSE: This umbrella review aimed to assess whether dietary protein intake with regard to quantitative (higher vs. lower dietary protein intake) and qualitative considerations (total, plant-based or animal-based protein intake) affects body weight (BW), fat mass (FM) and waist circumference (WC). METHODS: A systematic literature search was conducted in PubMed, Embase and Cochrane Database of Systematic Reviews for systematic reviews (SRs) with and without meta-analyses of prospective studies published between 04 October 2007 and 04 January 2022. Methodological quality and outcome-specific certainty of evidence of the retrieved SRs were assessed by using AMSTAR 2 and NutriGrade, respectively, in order to rate the overall certainty of evidence using predefined criteria. RESULTS: Thirty-three SRs were included in this umbrella review; 29 were based on randomised controlled trials, a few included cohort studies. In studies without energy restriction, a high-protein diet did not modulate BW, FM and WC in adults in general (all "possible" evidence); for older adults, overall certainty of evidence was "insufficient" for all parameters. Under hypoenergetic diets, a high-protein diet mostly decreased BW and FM, but evidence was "insufficient" due to low methodological quality. Evidence regarding an influence of the protein type on BW, FM and WC was "insufficient". CONCLUSION: "Possible" evidence exists that the amount of protein does not affect BW, FM and WC in adults under isoenergetic conditions. Its impact on the reduction in BW and FM under hypoenergetic conditions remains unclear; evidence for an influence of protein type on BW, FM and WC is "insufficient".

A new statistical workflow (R-packages based) to investigate associations between one variable of interest and the metabolome.

INTRODUCTION: In metabolomics, the investigation of associations between the metabolome and one trait of interest is a key research question. However, statistical analyses of such associations are often challenging. Statistical tools enabling resilient verification and clear presentation are therefore highly desired. OBJECTIVES: Our aim is to provide a contribution for statistical analysis of metabolomics data, offering a widely applicable open-source statistical workflow, which considers the intrinsic complexity of metabolomics data. METHODS: We combined selected R packages tailored for all properties of heterogeneous metabolomics datasets, where metabolite parameters typically (i) are analyzed in different matrices, (ii) are measured on different analytical platforms with different precision, (iii) are analyzed by targeted as well as non-targeted methods, (iv) are scaled variously, (v) reveal heterogeneous variances, (vi) may be correlated, (vii) may have only few values or values below a detection limit, or (viii) may be incomplete. RESULTS: The code is shared entirely and freely available. The workflow output is a table of metabolites associated with a trait of interest and a compact plot for high-quality results visualization. The workflow output and its utility are presented by applying it to two previously published datasets: one dataset from our own lab and another dataset taken from the repository MetaboLights. CONCLUSION: Robustness and benefits of the statistical workflow were clearly demonstrated, and everyone can directly re-use it for analysis of own data.

Perspective: A Conceptual Framework for Adaptive Personalized Nutrition Advice Systems (APNASs).

Nearly all approaches to personalized nutrition (PN) use information such as the gene variants of individuals to deliver advice that is more beneficial than a generic "1-size-fits-all" recommendation. Despite great enthusiasm and the increased availability of commercial services, thus far, scientific studies have only revealed small to negligible effects on the efficacy and effectiveness of personalized dietary recommendations, even when using genetic or other individual information. In addition, from a public health perspective, scholars are critical of PN because it primarily targets socially privileged groups rather than the general population, thereby potentially widening health inequality. Therefore, in this perspective, we propose to extend current PN approaches by creating adaptive personalized nutrition advice systems (APNASs) that are tailored to the type and timing of personalized advice for individual needs, capacities, and receptivity in real-life food environments. These systems encompass a broadening of current PN goals (i.e., what should be achieved) to incorporate "individual goal preferences" beyond currently advocated biomedical targets (e.g., making sustainable food choices). Moreover, they cover the "personalization processes of behavior change" by providing in situ, "just-in-time" information in real-life environments (how and when to change), which accounts for individual capacities and constraints (e.g., economic resources). Finally, they are concerned with a "participatory dialog between individuals and experts" (e.g., actual or virtual dieticians, nutritionists, and advisors) when setting goals and deriving measures of adaption. Within this framework, emerging digital nutrition ecosystems enable continuous, real-time monitoring, advice, and support in food environments from exposure to consumption. We present this vision of a novel PN framework along with scenarios and arguments that describe its potential to efficiently address individual and population needs and target groups that would benefit most from its implementation.

Protein intake and bone health: an umbrella review of systematic reviews for the evidence-based guideline of the German Nutrition Society.

This umbrella review aimed at assessing whether a protein intake exceeding the current recommendation for younger (0.8 g/kg body weight [BW]/day) and older (1.0 g/kg BW/day) adults affects bone mineral density and fracture risk. Moreover, the effect of animal or plant protein was evaluated. A systematic literature search was conducted in PubMed, Embase, and Cochrane Database of Systematic Reviews for systematic reviews (SRs) with or without meta-analysis of prospective studies published between 11/2008 and 08/2021. Methodological quality, outcome-specific certainty of evidence, and overall certainty of evidence of the retrieved SRs were assessed using established tools and predefined criteria. Eleven SRs of randomized controlled trials (RCTs) and/or cohort studies were included. In SRs of cohort studies and RCTs, protein intake/kg BW/day ranged between 0.21-0.95 g (low intake) and > 1.24 g (high intake), respectively, and between 0.67-1.1 g (control groups) and 1.01-1.69 g (intervention groups), respectively. The vast majority of outcome-specific certainty of evidence was rated "low" or "very low." The overall certainty of evidence for an association (cohort studies) or effect (RCTs) of total, animal or plant protein intake on each of the investigated outcomes was rated "insufficient," with the exception of possible evidence for a reduced hip fracture risk by high vs. low protein intake. Since protein intakes in low/control and high/intervention groups were very heterogeneous and with low certainty of evidence, it remains unclear whether a dose above the current recommendation or type of protein intake (animal or plant protein) affects bone health overall. However, there is possible evidence for reduced hip fracture risk with high versus low protein intake.

Microbial Metabolism of the Soy Isoflavones Daidzein and Genistein in Postmenopausal Women: Human Intervention Study Reveals New Metabotypes.

BACKGROUND: Soy isoflavones belong to the group of phytoestrogens and are associated with beneficial health effects but are also discussed to have adverse effects. Isoflavones are intensively metabolized by the gut microbiota leading to metabolites with altered estrogenic potency. The population is classified into different isoflavone metabotypes based on individual metabolite profiles. So far, this classification was based on the capacity to metabolize daidzein and did not reflect genistein metabolism. We investigated the microbial metabolite profile of isoflavones considering daidzein and genistein. METHODS: Isoflavones and metabolites were quantified in the urine of postmenopausal women receiving a soy isoflavone extract for 12 weeks. Based on these data, women were clustered in different isoflavone metabotypes. Further, the estrogenic potency of these metabotypes was estimated. RESULTS: Based on the excreted urinary amounts of isoflavones and metabolites, the metabolite profiles could be calculated, resulting in 5 metabotypes applying a hierarchical cluster analysis. The metabotypes differed in part strongly regarding their metabolite profile and their estimated estrogenic potency.

Protein intake and risk of urolithiasis and kidney diseases: an umbrella review of systematic reviews for the evidence-based guideline of the German Nutrition Society.

PURPOSE: Changes in dietary protein intake metabolically affect kidney functions. However, knowledge on potential adverse consequences of long-term higher protein intake (HPI) for kidney health is lacking. To summarise and evaluate the available evidence for a relation between HPI and kidney diseases, an umbrella review of systematic reviews (SR) was conducted. METHODS: PubMed, Embase and Cochrane Database of SRs published until 12/2022 were searched for the respective SRs with and without meta-analyses (MA) of randomised controlled trials or cohort studies. For assessments of methodological quality and of outcome-specific certainty of evidence, a modified version of AMSTAR 2 and the NutriGrade scoring tool were used, respectively. The overall certainty of evidence was assessed according to predefined criteria. RESULTS: Six SRs with MA and three SRs without MA on various kidney-related outcomes were identified. Outcomes were chronic kidney disease, kidney stones and kidney function-related parameters: albuminuria, glomerular filtration rate, serum urea, urinary pH and urinary calcium excretion. Overall certainty of evidence was graded as 'possible' for stone risk not to be associated with HPI and albuminuria not to be elevated through HPI (above recommendations (> 0.8 g/kg body weight/day)) and graded as 'probable' or 'possible' for most other kidney function-related parameters to be physiologically increased with HPI. CONCLUSION: Changes of the assessed outcomes may have reflected mostly physiological (regulatory), but not pathometabolic responses to higher protein loads. For none of the outcomes, evidence was found that HPI does specifically trigger kidney stones or diseases. However, for potential recommendations long-term data, also over decades, are required.

Assessment of Energy and Nutrient Intake and the Intestinal Microbiome (ErNst Study): Protocol and Methods of a Cross-sectional Human Observational Study.

BACKGROUND: On the national level, nutritional monitoring requires the assessment of reliable representative dietary intake data. To achieve this, standardized tools need to be developed, validated, and kept up-to-date with recent developments in food products and the nutritional behavior of the population. Recently, the human intestinal microbiome has been identified as an essential mediator between nutrition and host health. Despite growing interest in this connection, only a few associations between the microbiome, nutrition, and health have been clearly established. Available studies paint an inconsistent picture, partly due to a lack of standardization. OBJECTIVE: First, we aim to verify if food consumption, as well as energy and nutrient intake of the German population, can be recorded validly by means of the dietary recall software GloboDiet, which will be applied in the German National Nutrition Monitoring. Second, we aim to obtain high-quality data using standard methods on the microbiome, combined with dietary intake data and additional fecal sample material, and to also assess the functional activity of the microbiome by measuring microbial metabolites. METHODS: Healthy female and male participants aged between 18 and 79 years were recruited. Anthropometric measurements included body height and weight, BMI, and bioelectrical impedance analysis. For validation of the GloboDiet software, current food consumption was assessed with a 24-hour recall. Nitrogen and potassium concentrations were measured from 24-hour urine collections to enable comparison with the intake of protein and potassium estimated by the GloboDiet software. Physical activity was measured over at least 24 hours using a wearable accelerometer to validate the estimated energy intake. Stool samples were collected in duplicate for a single time point and used for DNA isolation and subsequent amplification and sequencing of the 16S rRNA gene to determine microbiome composition. For the identification of associations between nutrition and the microbiome, the habitual diet was determined using a food frequency questionnaire covering 30 days. RESULTS: In total, 117 participants met the inclusion criteria. The study population was equally distributed between the sexes and 3 age groups (18-39, 40-59, and 60-79 years). Stool samples accompanying habitual diet data (30-day food frequency questionnaire) are available for 106 participants. Current diet data and 24-hour urine samples for the validation of GloboDiet are available for 109 participants, of which 82 cases also include physical activity data. CONCLUSIONS: We completed the recruitment and sample collection of the ErNst study with a high degree of standardization. Samples and data will be used to validate the GloboDiet software for the German National Nutrition Monitoring and to compare microbiome composition and nutritional patterns. TRIAL REGISTRATION: German Register of Clinical Studies DRKS00015216; https://drks.de/search/de/trial/DRKS00015216. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42529.

First review on the selenium status in Germany covering the last 50 years and on the selenium content of selected food items.

INTRODUCTION: Selenium is important for human health. However, the selenium status and selenium intake of the German population has not been recorded in a representative study so far. MATERIAL AND METHODS: Thus, literature from the last 50 years was screened in a systematic way and the results of various studies were pulled together to shed light on the selenium status of the German population. Moreover, the selenium content of selected food items that were either found on the German market or grown in Germany was researched and evaluated. RESULTS: Of 3542 articles identified, 37 studies met the inclusion criteria. These 37 studies comprised a total of 8,010 healthy adults living in Germany with a weighted arithmetic mean of 82 µg/l selenium in plasma or serum. The results will form a basis for interpreting upcoming results from national food consumption surveys. Furthermore, 363 selenium values for 199 food items were identified out of 20 data sources-published or analysed between 2002 and 2019. An estimation of the selenium intake of the German population will be possible with this data in future nutrition surveys.

Revised D-A-CH reference values for the intake of biotin.

PURPOSE: The reference values for biotin intake for Germany, Austria and Switzerland lead back to a report in 2000. Following a timely update process, they were revised in 2020. METHODS: For infants aged 0 to < 4 months, adequate biotin supply via human milk was assumed and in consequence the reference value reflects the amount of biotin delivered by human milk. For infants aged 4 to < 12 months, biotin intake was extrapolated from the reference value for younger infants. Due to missing data on average requirement, the reference values for biotin intake for children, adolescents and adults were derived based on observed intake levels. The reference value for lactating women considered in addition biotin losses via human milk. RESULTS: The reference value for biotin intake for infants aged 0 to < 4 months was set at 4 µg/day and for infants aged 4 to < 12 months at 6 µg/day. In children and adolescents, the reference values for biotin intake ranged from 20 µg/day in children 1 to < 4 years to 40 µg/day in youths 15 to < 19 years. For adults including pregnant women, 40 µg/day was derived as reference value for biotin intake. For lactating women, this value was set at 45 µg/day. CONCLUSIONS: As deficiency symptoms of biotin do not occur with a usual mixed diet and the average requirement cannot be determined, reference values for an adequate biotin intake for populations from Germany, Austria and Switzerland were derived from biotin intake levels assessed in population-based nutrition surveys.

Dietary protein intake and health-related outcomes: a methodological protocol for the evidence evaluation and the outline of an evidence to decision framework underlying the evidence-based guideline of the German Nutrition Society.

PURPOSE: The present work aimed to delineate (i) a revised protocol according to recent methodological developments in evidence generation, to (ii) describe its interpretation, the assessment of the overall certainty of evidence and to (iii) outline an Evidence to Decision framework for deriving an evidence-based guideline on quantitative and qualitative aspects of dietary protein intake. METHODS: A methodological protocol to systematically investigate the association between dietary protein intake and several health outcomes and for deriving dietary protein intake recommendations for the primary prevention of various non-communicable diseases in the general adult population was developed. RESULTS: The developed methodological protocol relies on umbrella reviews including systematic reviews with or without meta-analyses. Systematic literature searches in three databases will be performed for each health-related outcome. The methodological quality of all selected systematic reviews will be evaluated using a modified version of AMSTAR 2, and the outcome-specific certainty of evidence for systematic reviews with or without meta-analysis will be assessed with NutriGrade. The general outline of the Evidence to Decision framework foresees that recommendations in the derived guideline will be given based on the overall certainty of evidence as well as on additional criteria such as sustainability. CONCLUSION: The methodological protocol permits a systematic evaluation of published systematic reviews on dietary protein intake and its association with selected health-related outcomes. An Evidence to Decision framework will be the basis for the overall conclusions and the resulting recommendations for dietary protein intake.

Human health risk-benefit assessment of fish and other seafood: a scoping review.

Fish and other seafood are important sources of nutrients, but they are also sources of chemical contaminants that may cause adverse health effects. This article aimed to identify existing risk-benefit assessments (RBA) of fish, shellfish, and other seafood, compare methodologies, discuss differences and commonalities in findings, and identify limitations and ways forward for future studies. We conducted a scoping review of the scientific literature of studies in all languages published from 2000 through April 2019. We identified 106 RBA of fish and other seafood across Europe, Asia, North America, Africa, and at the global level. Studies were heterogeneous in terms of types of fish and other seafood considered, beneficial and adverse compounds assessed, and overall methodology. Collected data showed that a diet consisting of a variety of lean and fatty fish and other seafood is recommended for the overall population and that women of childbearing age and children should limit the consumption of fish and other seafood types that have a high likelihood of contamination. Our review emphasizes the need for evidence-based, up-to-date, and harmonized approaches in RBA in general.

What is the promise of personalised nutrition?

Personalised nutrition (PN) is an emerging field that bears great promise. Several definitions of PN have been proposed and different modelling approaches have been used to claim PN effects. We tentatively propose to group these approaches into two categories, which we term outcome-based and population reference approaches, respectively. Understanding the fundamental differences between these two types of modelling approaches may allow a more realistic appreciation of what to expect from PN interventions presently and may be helpful for designing and planning future studies investigating PN interventions.

Integration of various dimensions in food-based dietary guidelines via mathematical approaches: report of a DGE/FENS Workshop in Bonn, Germany, 23-24 September 2019.

In the past, food-based dietary guidelines (FBDGs) were derived nearly exclusively by using systematic reviews on diet-health relationships and translating dietary reference values for nutrient intake into foods. This approach neglects many other implications that dietary recommendations have on society, the economy and environment. In view of pressing challenges, such as climate change and the rising burden of diet-related diseases, the simultaneous integration of evidence-based findings from different dimensions into FBDGs is required. Consequently, mathematical methods and data processing are evolving as powerful tools in nutritional sciences. The possibilities and reasons for the derivation of FBDGs via mathematical approaches were the subject of a joint workshop hosted by the German Nutrition Society (DGE) and the Federation of European Nutrition Societies (FENS) in September 2019 in Bonn, Germany. European scientists were invited to discuss and exchange on the topics of mathematical optimisation for the development of FBDGs and different approaches to integrate various dimensions into FBDGs. We concluded that mathematical optimisation is a suitable tool to formulate FBDGs finding trade-offs between conflicting goals and taking several dimensions into account. We identified a lack of evidence for the extent to which constraints and weights for different dimensions are set and the challenge to compile diverse data that suit the demands of optimisation models. We also found that individualisation via mathematical optimisation is one perspective of FBDGs to increase consumer acceptance, but the application of mathematical optimisation for population-based and individual FBDGs requires more experience and evaluation for further improvements.

Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial.

Importance: The benefits of vitamin D, omega-3 fatty acids, and exercise in disease prevention remain unclear. Objective: To test whether vitamin D, omega-3s, and a strength-training exercise program, alone or in combination, improved 6 health outcomes among older adults. Design, Setting, and Participants: Double-blind, placebo-controlled, 2 × 2 × 2 factorial randomized clinical trial among 2157 adults aged 70 years or older who had no major health events in the 5 years prior to enrollment and had sufficient mobility and good cognitive status. Patients were recruited between December 2012 and November 2014, and final follow-up was in November 2017. Interventions: Participants were randomized to 3 years of intervention in 1 of the following 8 groups: 2000 IU/d of vitamin D3, 1 g/d of omega-3s, and a strength-training exercise program (n = 264); vitamin D3 and omega-3s (n = 265); vitamin D3 and exercise (n = 275); vitamin D3 alone (n = 272); omega-3s and exercise (n = 275); omega-3s alone (n = 269); exercise alone (n = 267); or placebo (n = 270). Main Outcomes and Measures: The 6 primary outcomes were change in systolic and diastolic blood pressure (BP), Short Physical Performance Battery (SPPB), Montreal Cognitive Assessment (MoCA), and incidence rates (IRs) of nonvertebral fractures and infections over 3 years. Based on multiple comparisons of 6 primary end points, 99% confidence intervals are presented and P < .01 was required for statistical significance. Results: Among 2157 randomized participants (mean age, 74.9 years; 61.7% women), 1900 (88%) completed the study. Median follow-up was 2.99 years. Overall, there were no statistically significant benefits of any intervention individually or in combination for the 6 end points at 3 years. For instance, the differences in mean change in systolic BP with vitamin D vs no vitamin D and with omega-3s vs no omega-3s were both -0.8 (99% CI, -2.1 to 0.5) mm Hg, with P < .13 and P < .11, respectively; the difference in mean change in diastolic BP with omega-3s vs no omega-3s was -0.5 (99% CI, -1.2 to 0.2) mm Hg; P = .06); and the difference in mean change in IR of infections with omega-3s vs no omega-3s was -0.13 (99% CI, -0.23 to -0.03), with an IR ratio of 0.89 (99% CI, 0.78-1.01; P = .02). No effects were found on the outcomes of SPPB, MoCA, and incidence of nonvertebral fractures). A total of 25 deaths were reported, with similar numbers in all treatment groups. Conclusions and Relevance: Among adults without major comorbidities aged 70 years or older, treatment with vitamin D3, omega-3s, or a strength-training exercise program did not result in statistically significant differences in improvement in systolic or diastolic blood pressure, nonvertebral fractures, physical performance, infection rates, or cognitive function. These findings do not support the effectiveness of these 3 interventions for these clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT01745263.