OBJECTIVE:Dysnatremia is the most common electrolyte abnormality detected during hospitalizations and outpatient visits and is associated with adverse outcomes in older adults. However, data on its prevalence and incidence in community-dwelling older individuals remain limited. This study aimed to estimate the prevalence and incidence of dysnatremia in this population across 5 European countries (Austria, France, Germany, Portugal, and Switzerland). DESIGN:Observational analysis of DO-HEALTH, a 3-year multicenter clinical trial including 2157 community-dwelling, generally healthy adults aged 70 years and older. METHODS:Sodium blood levels were collected at baseline, 12, 24, and 36 months. Dysnatremia was defined as sodium levels <135 mmol/L (hyponatremia) or >145 mmol/L (hypernatremia). Baseline prevalence and 3-year incidence were estimated overall and by predefined subgroups based on sex, age, country of residence, body mass index, prevalent chronic conditions, polypharmacy, and use of thiazide-like diuretics. RESULTS:At baseline, 2141 participants (99.3%) had available sodium data. The prevalence of dysnatremia was 3.4% (2.4% hyponatremia; 1.0% hypernatremia), with higher prevalence in participants aged ≥75 years (4.8%) and those using thiazide or thiazide-like diuretics (5.4%). Over 3 years, 150 participants (7.0%) experienced at least 1 episode of dysnatremia (3.8% hyponatremia; 3.2% hypernatremia). Higher incidence of dysnatremia was observed among participants living in Switzerland, using thiazide or thiazide-like diuretics, and with prevalent dysnatremia at baseline. CONCLUSIONS:Dysnatremia, previously linked to adverse outcomes in older adults, was observed in a non-negligible proportion of generally healthy, community-dwelling older individuals. These findings provide valuable epidemiologic data and identify subgroups that may warrant closer clinical attention.

Cancer is associated with biological aging and functional decline; however, few studies have simultaneously examined objective changes in physical function and biological aging in older adults who develop cancer. We therefore compared functional and accelerated aging in generally healthy adults with and without incident invasive cancer, using data from DO-HEALTH, a three-year, randomized controlled trial including 2152 participants (mean age: 74.9 years, 61.1% women), free of major health conditions. Functional aging was assessed by the Short Physical Performance Battery, handgrip strength, gait speed, and five-times sit-to-stand test (STS). Biological aging was measured in a subsample (n = 777) using Horvath, Hannum, GrimAge and PhenoAge clocks, and DunedinPACE. Participants with incident cancer showed a greater decline in STS (Δ adjusted means [AM]: 0.64 s [95% CI 0.06, 1.22]) and grip strength (ΔAM -1.77 kPa [-3.51, -0.03]). Furthermore, baseline biological aging was accelerated between 3.52 and 6.77 months, measured by Horvath, Hannum, and PhenoAge clocks. Findings support the geroscience hypothesis linking greater phenotypic functional decline to accelerated biological aging in older adults with incident cancer. The data for this observational analysis stem from the DO-HEALTH clinical trial, which was prospectively registered (clinicaltrials.gov; NCT01745263; registered on December 10, 2012).

In this meta-analysis of international cohorts, current smoking is confirmed as a significant BMD-independent predictor of future fracture with a stronger relationship in men than in women. A causative and reversible effect of smoking on fracture risk is suggested by past smoking having a significantly lower risk than current smoking. In this meta-analysis of international cohorts, the aim was to examine the relationship of current and past smoking with fracture risk to provide an update for future iterations of the FRAX tool. The risk of fracture associated with current and past smoking was estimated using an extended Poisson model applied separately to each of 58 prospective international cohort studies. Covariates included current time since start of follow up, current age, and in an additional model, BMD at the femoral neck. The results of the different studies were merged by using inverse-variance weighted β-coefficients. This analysis included a total of 1,691,024 participants (61.2

BACKGROUND:The ICEBERG tool was initially validated in two small pilot studies to address the lack of a comprehensive geriatric screening tool in emergency settings. The present study builds on the second pilot study and extends it to a larger, multicenter sample. METHODS:We report results from a large ICEBERG tool validation study across three emergency rooms (ERs) including 1664 patients aged 70 years and older. The tool targets 9 domains and is administered by ER physicians or specialized nurses. To assess criterion validity-the extent to which ICEBERG scores are associated with relevant clinical outcomes-we compared patients who scored below versus above the median (<10; ≥10) ICEBERG score for six key clinical outcomes: length of stay in acute care, nursing care in minutes, one-on-one nursing care, in-hospital mortality, discharge to nursing home, and readmission within 30 days. Negative binomial regression was used for the outcomes length of stay and nursing care in minutes. Logistic regression was used for the other outcomes. All analyses were adjusted for age and sex. RESULTS:Patients with ICEBERG scores of 10 or higher had significantly longer stays in acute care (8.9 vs 6.6 days), required more nursing care (56.4 vs 32.8 h), had higher odds of one-on-one nursing care (Odds Ratio, OR = 2.85), in-hospital mortality (OR = 1.89), discharge to a nursing home (OR = 3.20), or being readmitted within 30 days (OR = 1.81). CONCLUSIONS:Based on our findings, the ICEBERG tool identifies older patients with a geriatric risk profile at ERs on all key clinical outcomes tested.

The relationship between bone mineral density (BMD) at the femoral neck and fracture risk was determined in a meta-analysis of primary data of 307205 men and women from 53 cohort studies. Low BMD was an important predictor of fracture risk, particularly for hip fracture. This study aimed to quantify the relationship between DXA-measured femoral neck BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value on fracture risk, with a view to updating FRAX®. We studied 307,205 men and women from within 53 predominately population-based cohorts followed up for an average of 8.7 years and a total of 2,683,185 person-years. The association of BMD and fracture risk was examined using a Poisson model in each cohort separately by sex. Results were expressed as a gradient of risk (GR, hazard ratio/standard deviation decrease in BMD). The different studies were then merged using weighted coefficients. Most hip fractures arose in men and women with low bone mass or osteoporosis at baseline (73 = 0.12 for women and p = 0.89 for men). A significant decrease in GR for hip fracture was observed with increasing duration of follow-up, but the magnitude of the effect was modest compared with the effect of age. For other fracture outcomes, including non-hip major osteoporotic fracture, the gradient of risk was lower than for hip fracture. Femoral neck BMD is a risk factor for fracture of substantial importance, particularly for future hip fracture. The lower magnitude of association at older age is consistent with other non-skeletal factors contributing to hip fracture risk with advancing age. Its validation on an international basis supports its use in case finding strategies. Its use should, however, take account of the variations in predictive value of BMD with age, sex, length of follow-up, and BMD.

OBJECTIVE:Few studies have explored specific trajectories or patterns of falls over time in older adults, and the role of sex and self-reported risk factors for these trajectories were overlooked. This study aimed to identify sex-specific fall trajectories over 3 years and the self-reported risk factors associated with each trajectory in European older adults. DESIGN:Observational analysis of DO-HEALTH, a double-blind, randomized controlled trial. SETTING AND PARTICIPANTS:Multicenter trial conducted in 7 European centers: Zurich, Basel, Geneva (Switzerland), Berlin (Germany), Innsbruck (Austria), Toulouse (France), and Coimbra (Portugal), including 2157 community-dwelling adults aged 70 years and older without major health events in the 5 years prior to enrollment, with sufficient mobility and good cognitive status. METHODS:Falls were recorded prospectively via phone calls and in-person assessments every 3 months over 3 years of follow-up. Group-based trajectory modeling was used to identify sex-specific trajectories based on the number of falls experienced over the follow-up, and penalized logistic regression models identified the self-reported risk factors most associated with each trajectory. RESULTS:A total of 1958 participants were included in this analysis (mean age: 74.9 years, 61.7% women). We identified a "lower fall trajectory" and a "higher fall trajectory" among women and a "lower fall trajectory" and an "increasing fall trajectory" among men. In women, living alone was the only self-reported risk factor associated with the higher fall trajectory. In men, living alone (marginal), as well as reporting fatigue, pain or discomfort, mobility issues, and higher self-rated health, were significantly associated with experiencing the increasing fall trajectory. CONCLUSIONS AND IMPLICATIONS:This study provides a comprehensive assessment of falls over 3 years, highlighting differences in fall patterns and associated self-reported risk factors between men and women. These findings may offer valuable insights for developing sex-specific fall risk prediction models and targeted fall prevention strategies.

Vertebral fractures (VFs) are among the most common osteoporotic fractures. The effect of vitamin D3, omega-3s or a simple home exercise program (SHEP) on VFs is unclear. We examined whether vitamin D3, omega-3s, or SHEP, alone or in combination, over 3 years, reduce the incidence rate of VFs among European older adults. DO-HEALTH is a multi-center, 2 × 2 × 2 factorial design, randomized controlled trial, which included older adults (≥70 years) free from major health events in the 5 years prior to enrollment. The study interventions were vitamin D3 (2000IU/d), omega-3s (1 g/d), and SHEP (3 × 30 min/wk), applied alone or in combination. Quantitative and qualitative VF assessment was determined from lateral thoracolumbar DXA scans. The primary outcome for this analysis was the incidence rate (IR) of total VFs, defined as the number of any new and progressed VFs over the 3-year follow-up. Sensitivity analyses were conducted for only new VFs and only VF progressions. Negative binomial regression models were fit, adjusted for age, sex, prior fall, BMI, study site and participants' follow-up time. 1488 participants (mean age 74.9 years; 77% had low bone mass or osteoporosis; 43.8% had 25(OH)D levels <20 ng/mL) were included. There were 93 incident VFs, of which 58 were new VFs and 35 were progressions. None of the three treatments reduced the IR of total VFs overall, however, the IR was reduced with SHEP compared to the control exercise program in women (IR ratio 0.52, 95% CI 0.28, 0.98). In the sensitivity analysis for VF progressions, SHEP reduced the IR (IR ratio 0.34, 95% CI 0.16, 0.75). Among generally healthy older adults, vitamin D3 and omega-3s supplementation did not reduce the incidence rate of VFs. SHEP reduced the incidence rate of total VFs in women and of VF progressions overall. Exercise may play a role in the prevention of VFs.

In the largest meta-analysis of international cohorts to date, a family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. Parental and sibling histories of fracture carry the same significance for future fracture, including the impact of family hip fracture on future hip fracture risk. PURPOSE:We have undertaken a meta-analysis of international prospective cohorts to quantify the relationship between a family history of fracture and future fracture incidence. METHODS:The analysis dataset comprised 350,542 men and women from 42 cohorts in 29 countries followed for 2.8 million person-years. We investigated the relationship between family history of hip fracture or any fracture and the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture (MOF), and hip fracture alone using an extended Poisson model in each cohort. Models were adjusted for current age, sex, BMD, and follow-up time. RESULTS:As no difference in influence of family history of fracture was seen between genders, results are presented for men and women combined. A parental history of hip fracture was associated with a higher risk of incident fracture across all fracture outcome categories, with a stronger relationship with future hip fracture (hazard ratios (HR, 95% CI) for hip and MOF 1.37, 1.23-1.52 and 1.19, 1.12-1.27, respectively). Associations were slightly reduced but remained significant when additionally adjusted for BMD and did not vary by baseline offspring age, follow-up time, or parent affected. In a more limited analysis, parental history of any fracture or a sibling history of hip or any fracture showed similar associations to those observed with parental history of hip fracture. CONCLUSIONS:A family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. While parental hip fracture appears the strongest factor for future hip fracture, a family history of other fractures might be appropriate for inclusion in future iterations of the FRAX tool.

OBJECTIVE:To examine the association between polypharmacy and mild cognitive impairment (MCI) at baseline and over 3 years in community-dwelling older adults. DESIGN:Observational analysis of the DO-HEALTH trial. SETTING AND PARTICIPANTS:Community-dwelling adults aged ≥70 years with good cognitive function and without major diseases at baseline. METHODS:Main exposure was polypharmacy at baseline (≥5 medications). The outcome was MCI (Montreal Cognitive Assessment [MoCA] score <26), assessed at baseline and years 1, 2, and 3. Logistic regression and generalized estimating equations (GEEs) for repeated binary outcomes were used for the cross-sectional and longitudinal analysis, respectively. Minimally adjusted models included age, sex, prior fall, study site, body mass index, and education. Fully adjusted models additionally adjusted for mental health and multimorbidity. GEE models also accounted for time and DO-HEALTH treatment effects. Sensitivity analysis used a stricter MCI definition (MoCA < 24). RESULTS:A total of 2153 participants completed MoCA at baseline. Baseline MCI prevalence was higher in participants with polypharmacy compared with those with no polypharmacy (MCI < 26: 53.5% vs 46.5%; MCI < 24: 34.9% vs 17.2%). Polypharmacy was associated with greater MCI odds at baseline in the minimally adjusted models (MoCA < 26: odds ratio [OR], 1.32; 95% CI, 1.05-1.66; MoCA < 24: OR, 1.37; 95% CI, 1.06-1.79). Over 3 years, polypharmacy was associated with increased MCI odds in the minimally adjusted models (MoCA < 26: OR, 1.28; 95% CI, 1.08-1.52; MoCA < 24: OR, 1.33; 95% CI, 1.07-1.65). Notably, these associations were somewhat attenuated and nonsignificant after controlling for mental health and multimorbidity. CONCLUSION AND IMPLICATIONS:Our findings suggest that MCI is more prevalent in older adults with polypharmacy compared with those without polypharmacy. Although polypharmacy was associated with MCI at baseline and over 3 years, these associations were attenuated by mental health and multimorbidity, suggesting that mental health and multimorbidity contribute to both polypharmacy and MCI.

Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) are validated and frequently used screening tools for cognitive function. To present MMSE and MoCA scores by sex, age and education among community-dwelling older adults. This is a post-hoc observational analysis using data from the DO-HEALTH trial, which included generally healthy adults (≥ 70 years) from Switzerland, Germany, Austria, France, and Portugal who scored at least 24 points on the MMSE at baseline. We present MMSE and MoCA scores overall and by country, sex, age (70–74 years, ≥ 75 years), education (≤ and > median education years). 2151 DO-HEALTH participants (mean age 74.9 years, 57

INTRODUCTION:We have gained new insights into vitamin D. High quality studies of over 36,000 people have shown that daily vitamin D supplementation of 800 IU reduces the risk of hip fracture and falling in older adults with vitamin D deficiency and existing falling risk. We have also learnt that vitamin D supplementation in healthy middle-aged and elderly people without vitamin D deficiency and without osteoporosis offers no additional protection. Also, large intermittent bolus doses of vitamin D either show no protection against fractures or even lead to an increase in fracture risk and fall risk in vulnerable elderly people and are therefore obsolete. In recent years, however, large randomised studies on daily vitamin D supplementation with 2000 IU in healthy people without vitamin D deficiency at the age of 50 (VITAL) and at the age of 70 (DO-HEALTH) have shown a benefit on the immune system in terms of reducing advanced cancers, cancer mortality and autoimmune diseases.

The relationship between rheumatoid arthritis (RA) and fracture risk was estimated in an international meta-analysis of individual-level data from 29 prospective cohorts. RA was associated with an increased fracture risk in men and women, and these data will be used to update FRAX®. RA is a well-documented risk factor for subsequent fracture that is incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between rheumatoid arthritis and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD) with a view to updating FRAX. The resource comprised 1,909,896 men and women, aged 20–116 years, from 29 prospective cohorts in which the prevalence of RA was 3

While frailty and anemia are prevalent conditions in aging linked to adverse outcomes, their relationship remains understudied in generally healthy older adults. We conducted a post-hoc observational study among all participants of DO-HEALTH, the largest European clinical trial designed to support healthy aging. Our analysis examined whether baseline hemoglobin levels and anemia are associated with being at least pre-frail at baseline and any yearly follow-up time point over three years. Frailty status was assessed by the Fried frailty phenotype at baseline and at each annual follow-up visit. Participants were considered at least pre-frail by the presence of any frailty domain (fatigue, unintentional weight loss, slowness, weakness, low activity). For both hemoglobin levels and anemia as predictors, we used regression models based on generalized estimating equations controlling for potential confounders. In total, 2,123 of 2,157 participants had available frailty status and hemoglobin levels at baseline and were included in the analysis (mean age 74.9 years; 61.7

BACKGROUND:Although numerous cross-sectional studies have examined the relationship between anemia and cognitive impairment or dementia in older adults, data from larger longitudinal studies, especially in generally healthy older adults, are limited. OBJECTIVES:To investigate the associations between baseline hemoglobin levels, anemia, and mild cognitive impairment (MCI) over 3 y in generally healthy older adults. METHODS:This is an observational analysis of the 3-y DO-HEALTH trial, a double-blind, randomized controlled trial including 2157 European community-dwelling adults age 70+. Cognition was assessed at baseline, 12, 24, and 36 mo using the Montreal Cognitive Assessment (MoCA). MCI was defined as a MoCA score <26 at 2 consecutive time points. The exposures were the quintiles of hemoglobin levels and anemia at baseline. Logistic regression models based on generalized estimating equations controlled for age, sex, prior falls, study site, treatment allocation, body mass index, number of comorbidities, smoking status, use of iron supplements, alcohol consumption, renal function, and vitamin B12 levels. RESULTS:A total of 2150 participants were included in the analyses (mean age of 74.9 y; 61.7% females). Compared with the lowest quintile, participants in all higher quintiles had a significantly lower odds of MCI: 2nd = 34% lower odds of MCI [odds ratio (OR) = 0.66; 95% confidence interval (CI): 0.47, 0.93; P = 0.02], 3rd = 39% (OR = 0.61; 95% CI: 0.43, 0.86; P = 0.005), 4th = 44% (OR = 0.56; 95% CI: 0.39, 0.82; P = 0.003), and 5th = 36% (OR = 0.64; 95% CI: 0.43, 0.97; P = 0.03). For anemia, there was no association with the odds of MCI over time. CONCLUSIONS:Baseline hemoglobin levels >130 g/L were associated with reduced odds of MCI over 3 y. Although this study does not establish causality, it suggests further investigations in monitoring and managing hemoglobin levels, even in generally healthy older adults. This trial was registered at clinicaltrials.gov as NCT01745263.

BACKGROUND:A 2021 meta-analysis of 37 randomised controlled trials (RCTs) of vitamin D supplementation for prevention of acute respiratory infections (ARIs) revealed a statistically significant protective effect of the intervention (odds ratio [OR] 0·92 [95% CI 0·86 to 0·99]). Since then, six eligible RCTs have been completed, including one large trial (n=15 804). We aimed to re-examine the link between vitamin D supplementation and prevention of ARIs. METHODS:Updated systematic review and meta-analysis of data from RCTs of vitamin D for ARI prevention using a random effects model. Subgroup analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, dosing regimen, or age. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov between May 1, 2020 (end-date of search of our previous meta-analysis) and April 30, 2024. No language restrictions were imposed. Double-blind RCTs supplementing vitamin D for any duration, with placebo or lower-dose vitamin D control, were eligible if approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Aggregate data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. The study was registered with PROSPERO (no. CRD42024527191). FINDINGS:We identified six new RCTs (19 337 participants). Data were obtained for 16 085 (83·2%) participants in three new RCTs and combined with data from 48 488 participants in 43 RCTs identified in our previous meta-analysis. For the primary comparison of any vitamin D versus placebo, the intervention did not statistically significantly affect overall ARI risk (OR 0·94 [95% CI 0·88-1·00], p=0·057; 40 studies; 61 589 participants; I2=26·4%). Pre-specified subgroup analysis did not reveal evidence of effect modification by age, baseline vitamin D status, dosing frequency, or dose size. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0·96 [95% CI 0·90-1·04]; 38 studies; I2=0·0%). A funnel plot showed left-sided asymmetry (p=0·0020, Egger's test). INTERPRETATION:This updated meta-analysis yielded a similar point estimate for the overall effect of vitamin D supplementation on ARI risk to that obtained previously, but the 95% CI for this effect estimate now includes 1·00, indicating no statistically significant protection. FUNDING:None.

The aim of this international meta-analysis was to quantify the predictive value of BMI for incident fracture and relationship of this risk with age, sex, follow-up time, and BMD. A total of 1 667 922 men and women from 32 countries (63 cohorts), followed for a total of 16.0 million person-years were studied. 293 325 had FN BMD measured (2.2 million person-years follow-up). An extended Poisson model in each cohort was used to investigate relationships between WHO-defined BMI categories (Underweight: <18.5 kg/m2; Normal: 18.5-24.9 kg/m2; Overweight: 25.0-29.9 kg/m2; Obese I: 30.0-34.9 kg/m2; Obese II: ≥35.0 kg/m2) and risk of incident osteoporotic, major osteoporotic and hip fracture (HF). Inverse-variance weighted β-coefficients were used to merge the cohort-specific results. For the subset with BMD available, in models adjusted for age and follow-up time, the hazard ratio (95% CI) for HF comparing underweight with normal weight was 2.35 (2.10-2.60) in women and for men was 2.45 (1.90-3.17). Hip fracture risk was lower in overweight and obese categories compared to normal weight [obese II vs normal: women 0.66 (0.55-0.80); men 0.91 (0.66-1.26)]. Further adjustment for FN BMD T-score attenuated the increased risk associated with underweight [underweight vs normal: women 1.69 (1.47-1.96); men 1.46 (1.00-2.13)]. In these models, the protective effects of overweight and obesity were attenuated, and in both sexes, the direction of association reversed to higher fracture risk in Obese II category [Obese II vs Normal: women 1.24 (0.97-1.58); men 1.70 (1.06-2.75)]. Results were similar for other fracture outcomes. Underweight is a risk factor for fracture in both men and women regardless of adjustment for BMD. However, while overweight/obesity appeared protective in base models, they became risk factors after additional adjustment for FN BMD, particularly in the Obese II category. This effect in the highest BMI categories was of greater magnitude in men than women. These results will inform the second iteration of FRAX®.

Brief rationale: Limited evidence exists on calcifediol’s effect on lower extremity function in postmenopausal women with osteoporosis or osteopenia. Main result: Calcifediol (20 µg/day) showed no greater benefit than vitamin D3 (3200 IU/day) or placebo. Significance of the paper: Findings do not support high-dose vitamin D3 or calcifediol for improving lower extremity function. To test the effect of 20 µg/day of calcifediol compared with 3200 IU/day of vitamin D3 and placebo on lower extremity function in postmenopausal women with osteopenia or osteoporosis. This is a 3-arm double-blind RCT among postmenopausal women aged 50–70 years with serum 25(OH)D < 30 ng/mL, and a DXA-based diagnosis of osteopenia or osteoporosis. Participants were randomized to receive either daily 20 µg calcifediol, daily 3200 IU vitamin D3, or placebo. The primary endpoint was a composite measure of lower extremity function, assessed at baseline, 3, and 6 months, including four tests: gait speed, knee flexor and extensor strength, and repeated sit-to-stand test. The primary endpoint was the probability of success (improvement or maintenance from baseline) in any of the eight tests, four tests at 3 months and four tests at 6 months. The trial enrolled 152 women (mean age, 61.0 years; mean serum 25(OH)D level, 23.4 ng/mL), and all but one woman completed all follow-up visits. Baseline characteristics, including the four tests of lower extremity function, were balanced across the three groups. The adjusted probability of success in any of the eight tests was 53.6 https://clinicaltrials.gov/ct2/show/NCT02527668

While observational studies and small pilot trials suggest that vitamin D, omega-3 and exercise may slow biological aging, larger clinical trials testing these treatments individually or in combination are lacking. Here, we report the results of a post hoc analysis among 777 participants of the DO-HEALTH trial on the effect of vitamin D (2,000 IU per day) and/or omega-3 (1 g per day) and/or a home exercise program on four next-generation DNA methylation (DNAm) measures of biological aging (PhenoAge, GrimAge, GrimAge2 and DunedinPACE) over 3 years. Omega-3 alone slowed the DNAm clocks PhenoAge, GrimAge2 and DunedinPACE, and all three treatments had additive benefits on PhenoAge. Overall, from baseline to year 3, standardized effects ranged from 0.16 to 0.32 units (2.9–3.8 months). In summary, our trial indicates a small protective effect of omega-3 treatment on slowing biological aging over 3 years across several clocks, with an additive protective effect of omega-3, vitamin D and exercise based on PhenoAge. Applying epigenetic clocks to samples from the DO-HEALTH trial, Bischoff-Ferrari et al. report a small protective effect of omega-3 supplementation over 3 years on several clocks and an additive protective effect of omega-3, vitamin D and exercise using PhenoAge.