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Elevated homocysteine levels and low vitamin B12 and folate levels have been associated with deteriorated bone health. This systematic literature review with dose-response meta-analyses summarizes the available scientific evidence on associations of vitamin B12, folate, and homocysteine status with fractures and bone mineral density (BMD). Twenty-seven eligible cross-sectional (n = 14) and prospective (n = 13) observational studies and one RCT were identified. Meta-analysis on four prospective studies including 7475 people showed a modest decrease in fracture risk of 4% per 50 pmol/L increase in vitamin B12 levels, which was borderline significant (RR = 0.96, 95% CI = 0.92 to 1.00).Meta-analysis of eight studies including 11511 people showed an increased fracture risk of 4% per μmol/L increase in homocysteine concentration (RR = 1.04, 95% CI = 1.02 to 1.07). We could not draw a conclusion regarding folate levels and fracture risk, as too few studies investigated this association.Meta-analyses regarding vitamin B12, folate and homocysteine levels, and BMD were possible in female populations only and showed no associations. Results from studies regarding BMD that could not be included in the meta-analyses were not univocal. [ABSTRACT FROM AUTHOR]

Calculation of the heat flow through the air cavities in the EN ISO 10077-2:2017 standard for the determination of the thermal transmittance of window profiles uses models based on the equivalent thermal conductivity method. The method takes into account the radiative heat exchange in a simplified or accurate manner. In the first case, the heat exchange depends on the average temperature in cavity, in the second case - it is determined accurately by the ray tracing method. It is also of importance to differentiate emissivity of surfaces due to aging or painting what influences calculation time. In this work, the impact of the calculation method and the impact of simplifications in modelling of the untreated surfaces on the value of the thermal transmittance of aluminium profiles was analysed on the example of a real series of products. Comparing the simplified and accurate method of determining the radiation exchange in cavities, the differences in the thermal transmittances of window profiles were up to 22%. The differences between the most simplified and the most accurate modelling of the surfaces emissivity reached 23%.

Background: There are several mechanisms via which increased protein intake might maintain or improve bone mineral density (BMD), but current evidence for an association or effect is inconclusive. The objectives of this study were to investigate the association between dietary protein intake (total, plant and animal) with BMD (spine and total body) and the effects of protein supplementation on BMD., Methods: Individual data from four trials that included either (pre-)frail, undernourished or healthy older adults (aged ≥65 years) were combined. Dietary intake was assessed with food records (2, 3 or 7 days) and BMD with dual-energy X-ray absorptiometry (DXA). Associations and effects were assessed by adjusted linear mixed models., Results: A total of 1570 participants [57% women, median (inter-quartile range): age 71 (68-75) years] for which at least total protein intake and total body BMD were known were included in cross-sectional analyses. In fully adjusted models, total protein intake was associated with higher total body and spine BMD [beta (95% confidence interval): 0.0011 (0.0006-0.0015) and 0.0015 (0.0007-0.0023) g/cm 2 , respectively]. Animal protein intake was associated with higher total body and spine BMD as well [0.0011 (0.0007-0.0016) and 0.0017 (0.0010-0.0024) g/cm 2 , respectively]. Plant protein intake was associated with a lower total body and spine BMD [-0.0010 (-0.0020 to -0.0001) and -0.0019 (-0.0034 to -0.0004) g/cm 2 , respectively]. Associations were similar between sexes. Participants with a high ratio of animal to plant protein intake had higher BMD. In participants with an adequate calcium intake and sufficient serum 25(OH)D concentrations, the association between total protein intake with total body and spine BMD became stronger. Likewise, the association between animal protein intake with total body BMD was stronger. In the longitudinal analyses, 340 participants [58% women, median (inter-quartile range): age 75 (70-81) years] were included. Interventions of 12 or 24 weeks with protein supplementation or protein supplementation combined with resistance exercise did not lead to significant improvements in BMD., Conclusions: An association between total and animal protein intake with higher BMD was found. In contrast, plant protein intake was associated with lower BMD. Research is warranted to further investigate the added value of dietary protein alongside calcium and vitamin D for BMD improvement, especially in osteopenic or osteoporotic individuals. Moreover, more research on the impact of a plant-based diet on bone health is needed., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Low diet quality among the elderly may be correlated with some diseases, including Frailty Syndrome (FS). This decline in function restricts the activity of older people, resulting in higher assistance costs. The aim of this study was to increase knowledge of diet quality predictors. Dietary intake was assessed among 196 individuals aged 60+ years using the three-day record method and FS by Fried's criteria. Based on the compliance with the intake recommendation (% of EAR/AI), we distinguished three clusters that were homogeneous in terms of the nutritional quality of the diet, using Kohonen's neural networks. The prevalence of frailty in the entire group was 3.1%, pre-frailty 38.8%, and non-frailty 58.1%. Cluster 1 (91 people with the lowest diet quality) was composed of a statistically significant higher number of the elderly attending day care centers (20.7%), frail (6.9%), pre-frail (51.7%), very low vitamin D intake (23.8% of AI), using sun cream during the summer months (always 19.8% or often 39.6%), having diabetes (20.7%), having leg pain when walking (43.1%), and deteriorating health during the last year (53.5%). The study suggests the need to take initiatives leading to the improvement of the diet of the elderly, especially in day care senior centers, where there are more frail individuals, including nutritional education for the elderly and their caregivers.

The article aims to determine the effect of cement addition on the water vapour resistance factor of stabilized rammed earth. Literature analysis indicates that different earthen materials show large differences in water vapour resistance factor values. The high diffusion resistance of concrete concerning other construction materials suggests that cement will be one of the factors significantly affecting these values. The paper presents water vapour resistance factor test results of rammed earth with various soil particle sizes and cement contents. The obtained results showed that an increase of cement addition increases the diffusion resistance of the material. However, the diffusion resistance of cement stabilized rammed earth is still low compared to concrete.

Aims: The aim of this study was to investigate the effect of iron or/and zinc supplementation and termination of this treatment on the antioxidant defence of the male reproductive system and sperm viability in rats., Methods: The study consisted of 3 stages: I) 4-week adaptation to the diets (C-control or D-iron deficient); II) 4-week iron and/or zinc supplementation (10-times more than in the C diet of iron: CSFe, DSFe; zinc: CSZn, DSZn; or iron and zinc: CSFeZn, DSFeZn; and III) 2-week post-supplementation period (the same diets as during stage I). Parameters of antioxidant status (total antioxidant capacity and SOD, GPx, and CAT activiy), oxidative damage (lipid and protein peroxidation), and sperm viability were measured., Results: Simultaneous iron and zinc supplementation compared to iron supplementation (CSFeZn vs CSFe) increased SOD activity in the testes and decreased the level of malondialdehyde in the epididymis after stage II, and increased the percentage of live sperm after stage III. After discontinuation of the iron and zinc supplementation and a return to the control diet, the following was observed a decrease of SOD activity in the testes and GPx activity in the epididymis, and a increase malondialdehyde concentration in prostates. After stage III, in DSFeZn vs DSFe rats, an increase of SOD and CAT activity in the epididymis was found., Conclusion: Zinc supplementation simultaneous with iron may protect the male reproductive system against oxidative damage induced by high doses of iron and may have a beneficial effect on sperm viability. The effect of this supplementation was observed even two weeks after the termination of the intervention., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Dietary fat subtypes may play an important role in the regulation of muscle mass and function during ageing. The aim of the present study was to determine the impact of isocaloric macronutrient substitutions, including different fat subtypes, on sarcopenia risk in older men and women, while accounting for physical activity (PA) and metabolic risk. A total of 986 participants, aged 65-79 years, completed a 7-day food record and wore an accelerometer for a week. A continuous sex-specific sarcopenia risk score (SRS), including skeletal muscle mass assessed by dual-energy X-ray absorptiometry (DXA) and handgrip strength, was derived. The impact of the isocaloric replacement of saturated fatty acids (SFAs) by either mono- (MUFAs) or poly-unsaturated (PUFAs) fatty acids on SRS was determined using regression analysis based on the whole sample and stratified by adherence to a recommended protein intake (1.1 g/BW). Isocaloric reduction of SFAs for the benefit of PUFAs was associated with a lower SRS in the whole population, and in those with a protein intake below 1.1 g/BW, after accounting for age, smoking habits, metabolic disturbances, and adherence to PA guidelines. The present study highlighted the potential of promoting healthy diets with optimised fat subtype distribution in the prevention of sarcopenia in older adults.

Background: The key issue is whether voluntarily fortified foods and vitamin/mineral supplements available on the market serve public health needs. The study aim was to estimate nutrient intakes from voluntarily fortified foods and vitamin/mineral supplements in relation to the Dietary Reference Intake (DRI) in adolescents ( n = 759) aged 13-19 who attended public secondary schools in Central-Eastern Poland. Methods: Data on the consumption of voluntarily fortified foods were collected using a semi-quantitative food frequency questionnaire containing 58 food items. Data on the use of dietary supplements were assessed via an open-ended question. The content of nutrients was estimated using the producer's labeling declaration. The distribution of nutrient intakes according to the percentage of DRI categories (<20%, 20-39.9%, 40-59.9%, 60-79.9%, 80-99.9%, 100-119%, or >120%) was estimated. Results: Consumption of voluntarily fortified foods was a common behavior in adolescents (86.7% of participants), while vitamin/mineral supplements were used by less than one-fifth of them (17.7%). The amounts of nutrient intakes from fortified foods and/or supplements were at different levels: (I) vitamins A, D, calcium, magnesium (>50% of adolescents did not exceed 20% of DRI); (II) vitamins E, B 12 , iron (>50% of respondents consumed at least 20% of DRI); (III) niacin and pantothenic acid (>50% of respondents consumed at least 40% of DRI); IV) vitamins C, B 1 , B 2 , B 6 , folate, biotin (>50% of participants consumed at least 60% of DRI). In a subgroup of respondents who used fortified foods and supplements simultaneously ( n = 126), some nutrients (i.e., vitamins C, B 1 , B 2 , B 6 , niacin, and biotin) were consumed in amounts ≥150% of DRI. Intake above the Tolerable Upper Intake Levels was observed for niacin, vitamin A, B 6 and folic acid in individual cases (up to 1.1% of respondents); a higher risk of overconsumption was associated with using vitamin/mineral supplements than voluntarily fortified foods. Conclusion: Adolescents should be educated on how to reasonably use fortified foods and dietary supplements to help to overcome the potential deficiency of nutrients without causing excessive consumption., (Copyright © 2020 Sicińska, Pietruszka, Januszko, Jakubowski, Kielak-Biskupska, Rolf and Kaluza.)

Objective: Ageing is accompanied by deterioration of multiple bodily functions and inflammation, which collectively contribute to frailty. We and others have shown that frailty co-varies with alterations in the gut microbiota in a manner accelerated by consumption of a restricted diversity diet. The Mediterranean diet (MedDiet) is associated with health. In the NU-AGE project, we investigated if a 1-year MedDiet intervention could alter the gut microbiota and reduce frailty., Design: We profiled the gut microbiota in 612 non-frail or pre-frail subjects across five European countries (UK, France, Netherlands, Italy and Poland) before and after the administration of a 12-month long MedDiet intervention tailored to elderly subjects (NU-AGE diet)., Results: Adherence to the diet was associated with specific microbiome alterations. Taxa enriched by adherence to the diet were positively associated with several markers of lower frailty and improved cognitive function, and negatively associated with inflammatory markers including C-reactive protein and interleukin-17. Analysis of the inferred microbial metabolite profiles indicated that the diet-modulated microbiome change was associated with an increase in short/branch chained fatty acid production and lower production of secondary bile acids, p-cresols, ethanol and carbon dioxide. Microbiome ecosystem network analysis showed that the bacterial taxa that responded positively to the MedDiet intervention occupy keystone interaction positions, whereas frailty-associated taxa are peripheral in the networks., Conclusion: Collectively, our findings support the feasibility of improving the habitual diet to modulate the gut microbiota which in turn has the potential to promote healthier ageing., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sarcopenia is characterised by a progressive loss of skeletal muscle mass and physical function as well as related metabolic disturbances. While fibre-rich diets can influence metabolic health outcomes, the impact on skeletal muscle mass and function is yet to be determined, and the moderating effects by physical activity (PA) need to be considered. The aim of the present study was to examine links between fibre intake, skeletal muscle mass and physical function in a cohort of older adults from the NU-AGE study. In 981 older adults (71 ± 4 years, 58% female), physical function was assessed using the short-physical performance battery test and handgrip strength. Skeletal muscle mass index (SMI) was derived using dual-energy X-ray absorptiometry (DXA). Dietary fibre intake (FI) was assessed by 7-day food record and PA was objectively determined by accelerometery. General linear models accounting for covariates including PA level, protein intake and metabolic syndrome (MetS) were used. Women above the median FI had significantly higher SMI compared to those below, which remained in fully adjusted models (24.7 ± 0.2% vs. 24.2 ± 0.1%, p = 0.011, η 2 p = 0.012). In men, the same association was only evident in those without MetS (above median FI: 32.4 ± 0.3% vs. below median FI: 31.3 ± 0.3%, p = 0.005, η 2 p = 0.035). There was no significant impact of FI on physical function outcomes. The findings from this study suggest a beneficial impact of FI on skeletal muscle mass in older adults. Importantly, this impact is independent of adherence to guidelines for protein intake and PA, which further strengthens the potential role of dietary fibre in preventing sarcopenia. Further experimental work is warranted in order to elucidate the mechanisms underpinning the action of dietary fibre on the regulation of muscle mass.

Mediterranean diet has been proposed to promote healthy aging, but its effects on aging biomarkers have been poorly investigated. We evaluated the impact of a 1-year Mediterranean-like diet in a pilot study including 120 elderly healthy subjects from the NU-AGE study (60 Italians, 60 Poles) by measuring the changes in their epigenetic age, assessed by Horvath's clock. We observed a trend towards epigenetic rejuvenation of participants after nutritional intervention. The effect was statistically significant in the group of Polish females and in subjects who were epigenetically older at baseline. A genome-wide association study of epigenetic age changes after the intervention did not return significant (adjusted p value < 0.05) loci. However, we identified small-effect alleles (nominal p value < 10-4), mapping in genes enriched in pathways related to energy metabolism, regulation of cell cycle, and of immune functions. Together, these findings suggest that Mediterranean diet can promote epigenetic rejuvenation but with country-, sex-, and individual-specific effects, thus highlighting the need for a personalized approach to nutritional interventions.

Background: Mediterranean diets limit red meat consumption and increase intakes of high-phytate foods, a combination that could reduce iron status. Conversely, higher intakes of fish, a good source of selenium, could increase selenium status., Objectives: A 1-y randomized controlled trial [New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe (NU-AGE)] was carried out in older Europeans to investigate the effects of consuming a Mediterranean-style diet on indices of inflammation and changes in nutritional status., Methods: Selenium and iron intakes and status biomarkers were measured at baseline and after 1 y in 1294 people aged 65-79 y from 5 European countries (France, Italy, the Netherlands, Poland, and the United Kingdom) who had been randomly allocated either to a Mediterranean-style diet or to remain on their habitual, Western diet., Results: Estimated selenium intakes increased significantly with the intervention group (P < 0.01), but were not accompanied by changes in serum selenium concentrations. Iron intakes also increased (P < 0.001), but there was no change in iron status. However, when stratified by study center, there were positive effects of the intervention on iron status for serum ferritin for participants in Italy (P = 0.04) and France (P = 0.04) and on soluble transferrin receptor (sTfR) for participants in Poland (P < 0.01). Meat intake decreased and fish intake increased to a greater degree in the intervention group, relative to the controls (P < 0.01 for both), but the overall effects of the intervention on meat and fish intakes were mainly driven by data from Poland and France. Changes in serum selenium in the intervention group were associated with greater changes in serum ferritin (P = 0.01) and body iron (P = 0.01), but not sTfR (P = 0.73); there were no study center × selenium status interactions for the iron biomarkers., Conclusions: Consuming a Mediterranean-style diet for 1 y had no overall effect on iron or selenium status, although there were positive effects on biomarkers of iron status in some countries. The NU-AGE trial was registered at clinicaltrials.gov as NCT01754012., (Copyright © American Society for Nutrition 2019.)

Background: Ageing is inevitably associated with a progressive cognitive decline. With the rising percentage of the elderly in society, the number of people with dementia and cognitive impairment increases. Water is a vital ingredient that must be included in the diet. The impact of hydration status on cognitive performance has been studied only a little so far., Aims: The objective of the study was to investigate the relation between the hydration status and the cognitive function., Methods: The study was conducted among 60 free-living volunteers, aged 60-93 years. Data on water consumption were gathered based on 3-day records. The hydration status was assessed in morning urine samples by evaluating urine specific gravity. The cognitive function was tested using the Mini Mental State Examination (MMSE), the Babcock Story Recall Test and the Trail Making Test. Information about depression was gathered by the Geriatric Depression Scale., Results: The mean daily total water intake was 2441 ± 622 ml, and 70% of respondents met the reference values for an adequate intake. The mean urine specific gravity (1.013 g/cm 3 , range of 1.004-1.025 g/cm 3 ) indicated that most of the individuals were in a good hydration state. The average result of MMSE was 27.8, which is connected with mild cognitive impairment. There was no significant relationship between the hydration status and the results of the cognitive function test in the studied population., Discussion/conclusion: As the elderly volunteers had a good hydration status, there was no significant relationship between cognitive performance and urine specific gravity. It is necessary to replicate the findings of this study with a larger and more diverse sample of older adults.

Vitamin/mineral supplement (VMS) use has become increasingly popular in children and adolescents; however, different predictors may be associated with their usage. Therefore, the aim of this study was to compare determinants of VMS use in 1578 children and adolescents. Data was collected among parents of children (≤12 years old) and among adolescents (>12 years old) who attended public schools by a self-administered questionnaire. Multivariate-adjusted logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for determining the predictors of VMS use. In children, the following determinants of VMS use were indicated: socioeconomic status (average vs. very good/good; OR: 1.69, 95% CI: 1.16⁻2.48), physical activity (1⁻5 vs. <1 h/week; OR: 1.44, 95% CI: 1.02⁻2.04), BMI (≥25 vs. 18.5⁻24.9 kg/m²; OR: 0.67, 95% CI: 0.46⁻0.98), and presence of chronic diseases (yes vs. no; OR: 2.32, 95% CI: 1.46⁻3.69). In adolescents, gender (male vs. female; OR: 0.56, 95% CI: 0.37⁻0.87), residential area (rural vs. urban; OR: 0.63, 95% CI: 0.40⁻0.99), BMI (<18.5 vs. 18.5⁻24.9 kg/m²; OR: 0.35, 95% CI: 0.17⁻0.73), and health status (average/poor vs. at least good; OR: 1.96, 95% CI: 1.13⁻3.39) were factors of VMS use. In both groups, the mother's higher educational level, fortified food consumption and diet modification towards better food choices were predictors of VMS use. In conclusion, most of the predictors of VMS use were different in children and adolescents., Competing Interests: The authors declare no conflicts of interest.

In this work we present a novel statistical approach to improve the assessment of the adherence to a 1-year nutritional intervention within the framework of the NU-AGE project. This was measured with a single adherence score based on 7-days food records, under limitations on the number of observations per subject and time frame of intervention. The results of the NU-AGE dietary intervention were summarized by variations of the NU-AGE index as described in the NU-AGE protocol. Food and nutrient intake of all participants was assessed by means of 7-days food records at recruitment and after 10 to 14 months of intervention (depending on the subject availability). Sixteen food groups and supplementations covering the dietary goals of the NU-AGE diet have been used to estimate the NU-AGE index before and after the intervention. The 7-days food record is a reliable tool to register food intakes, however, as with other tools used to assess lifestyle dietary compliance, it is affected by uncertainty in this estimation due to the possibility that the observed week is not fully representative of the entire intervention period. Also, due to logistic limitations, the effects of seasonality can never be completely removed. These variabilities, if not accounted for in the index estimation, will reduce the statistical power of the analyses. In this work we discuss a method to assess these uncertainties and thus improve the resulting NU-AGE index. The proposed method is based on Hierarchical Bayesian Models. This model explicitly includes country-specific averages of the NU-AGE index, index variation induced by the dietary intervention, and country based seasonality. This information is used to evaluate the NU-AGE index uncertainty and thus to estimate the "real" NU-AGE index for each subject, both before and after the intervention. These corrections reduce the possibility of misinterpreting measurement variability as real information, improving the power of the statistical tests that are performed with the resulting index. The results suggest that this method is able to reduce the short term and seasonal variability of the measured index in the context of multicenter dietary intervention trials. Using this method to estimate seasonality and variability would allow one to obtain better measurements from the subjects of a study, and be able to simplify the scheduling of diet assessments. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01754012.

We aimed to determine the effect of a Mediterranean-style diet, tailored to meet dietary recommendations for older adults, on blood pressure and arterial stiffness. In 12 months, randomized controlled trial (NU-AGE [New Dietary Strategies Addressing the Specific Needs of Elderly Population for Healthy Aging in Europe]), blood pressure was measured in 1294 healthy participants, aged 65 to 79 years, recruited from 5 European centers, and arterial stiffness in a subset of 225 participants. The intervention group received individually tailored standardized dietary advice and commercially available foods to increase adherence to a Mediterranean diet. The control group continued on their habitual diet and was provided with current national dietary guidance. In the 1142 participants who completed the trial (88.2%), after 1 year the intervention resulted in a significant reduction in systolic blood pressure (-5.5 mm Hg; 95% CI, -10.7 to -0.4; P=0.03), which was evident in males (-9.2 mm Hg, P=0.02) but not females (-3.1 mm Hg, P=0.37). The -1.7 mm Hg (95% CI, -4.3 to 0.9) decrease in diastolic pressure after intervention did not reach statistical significance. In a subset (n=225), augmentation index, a measure of arterial stiffness, was improved following intervention (-12.4; 95% CI, -24.4 to -0.5; P=0.04) with no change in pulse wave velocity. The intervention also resulted in an increase in 24-hour urinary potassium (8.8 mmol/L; 95% CI, 0.7-16.9; P=0.03) and in male participants (52%) a reduction in pulse pressure (-6.1 mm Hg; 95% CI, -12.0 to -0.2; P=0.04) and 24-hour urinary sodium (-27.1 mmol/L; 95% CI, -53.3 to -1.0; P=0.04). In conclusion, a Mediterranean-style diet is effective in improving cardiovascular health with clinically relevant reductions in blood pressure and arterial stiffness. Clinical Trial Registration- URL: http://www.clinicialtrials.gov . Unique identifier: NCT01754012.

Aging is a dynamic process depending on intrinsic and extrinsic factors and its evolution is a continuum of transitions, involving multifaceted processes at multiple levels. It is recognized that frailty and sarcopenia are shared by the major age-related diseases thus contributing to elderly morbidity and mortality. Pre-frailty is still not well understood but it has been associated with global imbalance in several physiological systems, including inflammation, and in nutrition. Due to the complex phenotypes and underlying pathophysiology, the need for robust and multidimensional biomarkers is essential to move toward more personalized care. The objective of the present study was to better characterize the complexity of pre-frailty phenotype using untargeted metabolomics, in order to identify specific biomarkers, and study their stability over time. The approach was based on the NU-AGE project (clinicaltrials.gov, NCT01754012) that regrouped 1,250 free-living elderly people (65-79 y.o., men and women), free of major diseases, recruited within five European centers. Half of the volunteers were randomly assigned to an intervention group (1-year Mediterranean type diet). Presence of frailty was assessed by the criteria proposed by Fried et al. (2001). In this study, a sub-cohort consisting in 212 subjects (pre-frail and non-frail) from the Italian and Polish centers were selected for untargeted serum metabolomics at T0 (baseline) and T1 (follow-up). Univariate statistical analyses were performed to identify discriminant metabolites regarding pre-frailty status. Predictive models were then built using linear logistic regression and ROC curve analyses were used to evaluate multivariate models. Metabolomics enabled to discriminate sub-phenotypes of pre-frailty both at the gender level and depending on the pre-frailty progression and reversibility. The best resulting models included four different metabolites for each gender. They showed very good prediction capacity with AUCs of 0.93 (95% CI = 0.87-1) and 0.94 (95% CI = 0.87-1) for men and women, respectively. Additionally, early and/or predictive markers of pre-frailty were identified for both genders and the gender specific models showed also good performance (three metabolites; AUC = 0.82; 95% CI = 0.72-0.93) for men and very good for women (three metabolites; AUC = 0.92; 95% CI = 0.86-0.99). These results open the door, through multivariate strategies, to a possibility of monitoring the disease progression over time at a very early stage.