Frailty Influences the Relationship between the Soluble Receptor for Advanced Glycation-End Products and Mortality in Older Adults with Diabetes Mellitus.

INTRODUCTION: Frailty is prevalent among older adults with diabetes mellitus. Elevated serum levels of the soluble receptor for advanced glycation-end products (sRAGE) predict mortality in frail older adults. The evidence that sRAGE is also related to higher mortality in older adults with diabetes mellitus is inconsistent. Therefore, this study explored if frailty status influences the relationship between sRAGE and mortality in older adults with this condition. METHODS: We analysed data of 391 participants with diabetes mellitus (median age, 76 years) from four European cohorts enrolled in the FRAILOMIC project. Frailty was evaluated at baseline using Fried's criteria. Serum sRAGE was determined by ELISA. Participants were stratified by frailty status (n = 280 non-frail and 111 frail). Multivariate Cox proportional hazards regression and Kaplan-Meier survival analysis were used to assess the relationship between sRAGE and mortality. RESULTS: During 6 years of follow-up, 98 participants died (46 non-frail and 52 frail). Non-survivors had significantly higher baseline levels of sRAGE than survivors (median [IQR]: 1,392 [962-2,043] pg/mL vs. 1,212 [963-1,514], p = 0.008). High serum sRAGE (>1,617 pg/mL) was associated with increased mortality in the whole diabetes sample after adjustment for relevant confounders (HR 2.06, 95% CI: 1.36-3.11, p < 0.001), and there was an interaction between sRAGE and frailty (p = 0.006). Accordingly, the association between sRAGE and mortality was stronger in the frail group compared to the non-frail group (HR 2.52, 95% CI: 1.30-4.90, p = 0.006 vs. HR 1.71, 95% CI: 0.91-3.23, p = 0.099, respectively). Likewise, Kaplan-Meier curves showed a significant difference in survival rates between frail participants with high sRAGE and those with low sRAGE (p = 0.001), whereas no survival difference was seen in the non-frail group (p = 0.09). CONCLUSIONS: Frailty status influences the relationship between sRAGE and mortality in older adults with diabetes mellitus. Determination of sRAGE in this population could be a useful tool for risk stratification.

Lack of Immune Resilience Negatively Affects Physical Resilience: Results From the InCHIANTI Follow-Up Study.

There is consistent evidence that immune response declines with aging, with wide interindividual variability and a still unclear relationship with the development of frailty. To address this question, we assessed the role of immune resilience (capacity to restore immune functions), operationalized as the neutrophil-to-lymphocytes ratio (NL-ratio) and monocytes-to-lymphocytes ratio (ML-ratio), in the pathway that from robust status shifts to pre-frailty and frailty, and finally to death. The InCHIANTI study enrolled representative samples from the registry lists of 2 towns in Tuscany, Italy. Baseline data were collected in 1998, with follow-up visits every 3 years. The 1 453 participants enrolled were assessed and followed for lifestyle, clinical condition, physical performance, clinical, and physiological measures. For the purpose of this analysis, we used only 1 022 subjects aged 65 or older at baseline. Participants in the 3 highest deciles of distribution for NL-ratio (>2.44) were more likely to experience a transition from robust to pre-frail, and to overt frailty status. Moreover, NL-ratio (tenth decile > 3.53) and ML-ratio (tenth decile > 2.02) were both predictors of mortality. These results were independent of chronological age, sex, comorbidities, and chronic low-grade inflammation assessed by high sensitivity C-reactive protein measurement. The 2 leucocytes-derived ratios, NL-ratio and ML-ratio, represent markers of immune resilience and predict changes in physical resilience and mortality. These biomarkers are inexpensive because they are based on data routinely collected in clinical practice and can be used to assess the risk of frailty progression and mortality. Clinical Trials Registration Number: NCT01331512.

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Neutrophil, lymphocyte count, and neutrophil to lymphocyte ratio predict multimorbidity and mortality-results from the Baltimore Longitudinal Study on Aging follow-up study.

Immunosenescence is the age-related changes in the immune system, namely, progressively higher levels of circulating inflammatory markers, characteristics changes of circulating immune subset cells and altered immune function. The neutrophil to lymphocyte ratio (NL ratio) has been identified as a prognostic indicator for neoplastic disease progression, in predicting chronic degenerative diseases, and as a potential indirect marker of healthy aging. This study aims to examine the longitudinal association of neutrophil, lymphocyte absolute count, and their ratio with longitudinal risk for multimorbidity and mortality. The Baltimore Longitudinal Study of Aging (BLSA) is an open observational cohort study of community-dwelling volunteers that are followed every 1-4 years depending on their age. The sample considered in the study consists of 1769 participants (5090 follow-ups) with completed data for physical examination, health history assessment, and donated a blood sample. The NL ratio increased with age and was associated with a higher risk of mortality, while a lower NL ratio was inversely correlated with multimorbidity. Neutrophils increased with aging and an increase in their absolute number predicted mortality risk. However, the absolute number of lymphocytes was associated with age only in a cross-sectional analysis. In conclusion, this study supports the importance of the NL ratio and absolute neutrophil count as markers of aging health status, and as significant predictors of all-cause mortality and multimorbidity in aging individuals. It remains to be demonstrated whether interventions contrasting these trends in circulating cells may result in improved health outcomes.

Physiological Dysregulation Proceeds and Predicts Health Outcomes Similarly in Chinese and Western Populations.

BACKGROUND: A decade ago, we proposed an index of physiological dysregulation based on Mahalanobis distance (DM) that measures how far from the norm an individual biomarker profile is. While extensive validation has been performed, focus was mostly on Western populations with little comparison to developing countries, particularly at a physiological system level. The degree to which the approach would work in other sociocultural contexts and the similarity of dysregulation signatures across diverse populations are still open questions. METHODS: Using 2 data sets from China and 3 from Western countries (United States, United Kingdom, and Italy), we calculated DM globally and per physiological system. We assessed pairwise correlations among systems, difference with age, prediction of mortality and age-related diseases, and sensitivity to interchanging data sets with one another as the reference in DM calculation. RESULTS: Overall, results were comparable across all data sets. Different physiological systems showed distinct dysregulation processes. Association with age was moderate and often nonlinear, similarly for all populations. Mahalanobis distance predicted most health outcomes, although differently by physiological system. Using a Chinese population as the reference when calculating DM for Western populations, or vice versa, led to similar associations with health outcomes, with a few exceptions. CONCLUSIONS: While small differences were noticeable, they did not systematically emerge between Chinese and Western populations, but rather diffusively across all data sets. These findings suggest that DM presents similar properties, notwithstanding sociocultural backgrounds, and that it is equally effective in capturing the loss of homeostasis that occurs during aging in diverse industrial human populations.

Muscle quality, physical performance, and comorbidity are predicted by circulating procollagen type III N-terminal peptide (P3NP): the InCHIANTI follow-up study.

Sarcopenia is characterized by skeletal muscle quantitative and qualitative alterations. A marker of collagen turnover, procollagen type III N-terminal peptide (P3NP), seems to be related to those conditions. This study aims to assess the predictive role of P3NP in muscle density and physical performance changes. In the InCHIANTI study, a representative sample from the registry lists of two towns in Tuscany, Italy, was recruited. Baseline data was collected in 1998, and follow-up visits were conducted every 3 years. Out of the 1453 participants enrolled at baseline, this study includes 1052 participants. According to P3NP median levels, population was clustered in two groups; 544 (51.7%) of the 1052 subjects included were classified in the low median levels (LM-P3NP); at the baseline, they were younger, had higher muscle density, and performed better at the Short Physical Performance Battery (SPPB), compared to the high-median group (HM-P3NP).LM-P3NP cases showed a lower risk to develop liver chronic diseases, CHF, myocardial infarction, and osteoarthritis. HM-P3NP levels were associated with a longitudinal reduction of muscle density, and this effect was potentiated by the interaction between P3NP and leptin. Moreover, variation in physical performance was inversely associated with high level of P3NP, and directly associated with high fat mass, and with the interaction between P3NP and muscle density. Our data indicate that P3NP is associated with the aging process, affecting body composition, physical performance, and clinical manifestations of chronic degenerative age-related diseases.

OVCH1 Antisense RNA 1 is differentially expressed between non-frail and frail old adults.

While some old adults stay healthy and non-frail up to late in life, others experience multimorbidity and frailty often accompanied by a pro-inflammatory state. The underlying molecular mechanisms for those differences are still obscure. Here, we used gene expression analysis to understand the molecular underpinning between non-frail and frail individuals in old age. Twenty-four adults (50% non-frail and 50% frail) from InCHIANTI study were included. Total RNA extracted from whole blood was analyzed by Cap Analysis of Gene Expression (CAGE). CAGE identified transcription start site (TSS) and active enhancer regions. We identified a set of differentially expressed (DE) TSS and enhancer between non-frail and frail and male and female participants. Several DE TSSs were annotated as lncRNA (XIST and TTTY14) and antisense RNAs (ZFX-AS1 and OVCH1 Antisense RNA 1). The promoter region chr6:366,786,54-366,787,97;+ was DE and overlapping the longevity CDKN1A gene. GWAS-LD enrichment analysis identifies overlapping LD-blocks with the DE regions with reported traits in GWAS catalog (isovolumetric relaxation time and urinary tract infection frequency). Furthermore, we used weighted gene co-expression network analysis (WGCNA) to identify changes of gene expression associated with clinical traits and identify key gene modules. We performed functional enrichment analysis of the gene modules with significant trait/module correlation. One gene module is showing a very distinct pattern in hub genes. Glycogen Phosphorylase L (PYGL) was the top ranked hub gene between non-frail and frail. We predicted transcription factor binding sites (TFBS) and motif activity. TF involved in age-related pathways (e.g., FOXO3 and MYC) shows different expression patterns between non-frail and frail participants. Expanding the study of OVCH1 Antisense RNA 1 and PYGL may help understand the mechanisms leading to loss of homeostasis that ultimately causes frailty.

Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies.

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium. METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction. RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P=0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions. CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

Real-World Balance Assessment While Standing for Fall Prediction in Older Adults.

OBJECTIVE: Postural control naturally declines with age, leading to an increased risk of falling. Within clinical settings, the deployment of balance assessments has become commonplace, facilitating the identification of postural instability and targeted interventions to forestall falls among older adults. Some studies have ventured beyond the controlled laboratory, leaving, however, a gap in our understanding of balance in real-world scenarios. METHODS: Previously reported algorithms were used to build a finite-state machine (FSM) with four states: walking, turning, sitting, and standing. The FSM was validated against video annotations (gold standard) in an independent dataset with data collected on 20 older adults. Later, the FSM was applied to data from 168 community-dwelling older people in the InCHIANTI cohort who were evaluated both in the laboratory and then remotely in real-world conditions for a week. A 70/30 data split with recursive feature selection and resampling techniques was used to train and test four machine-learning models. RESULTS: In identifying fallers, duration, distance, and mean frequency computed during standing in real-world settings revealed significant relationships with fall risk. Also, the best-performing model (Lasso Regression) built on real-world balance features had a higher area under the curve (AUC, 0.76) than one built on lab-based assessments (0.57). CONCLUSION: Real-world balance features differ considerably from laboratory balance assessments (Romberg test) and have a higher predictive capacity for identifying patients at high risk of falling. SIGNIFICANCE: These findings highlight the need to move beyond traditional laboratory-based balance measures and develop more sensitive and accurate methods for predicting falls.

Beyond Inflammaging: The Impact of Immune System Aging on Age-Related Muscle Decline, Results From the InCHIANTI Study.

Aging is characterized by chronic low-level inflammation and is associated with geriatric syndromes such as sarcopenia and frailty. Our aim was to evaluate the longitudinal variation of muscle area, muscle quality, and muscle strength, relative to the variation of leukocyte-derived markers, and to assess the presence of a pathway of associations among derived leukocyte ratios, and the components of muscle health. The InCHIANTI is a longitudinal cohort study of aging that began in 1998 with follow-up visits every 3 years. Out of the 1 453 participants enrolled at baseline, this study includes 1 179 participants with complete data. Muscle strength was assessed by hand grip strength test, whereas muscle density and fat area were considered as indirect markers of muscle quality, derived from peripheral quantitative computed tomography of the calf. Muscle area was associated with neutrophil-to-lymphocyte ratio (NL-ratio), age, gender, comorbidities, and body mass index (BMI). Muscle density variation over time was inversely associated with age, comorbidities, and BMI, while being positively associated with monocyte-to-lymphocyte ratio (ML-ratio) and male gender. Fat area was inversely associated with age, interleukine-6 (IL-6), male gender, and NL-ratio, while being positively associated with ML-ratio, comorbidities, and BMI. Handgrip strength decreased with age, IL-6 levels, comorbidities, and NL-ratio, but increased with ML-ratio, being male, and having a higher BMI. In a path-analysis model, ML-ratio positively correlates with muscle mass, density, and strength, while NL-ratio only correlates inversely with muscle mass and density. NL-ratio and ML-ratio are associated with aging and may be implicated in age-related mechanisms that affect body composition and muscle strength. These ratios may represent a link between aging of the immune system and decline of muscle health with aging. However, further studies are needed to identify their usefulness for early detection of sarcopenia, myosteatosis, and frailty in the older adult.

Proteomic Analysis of the Senescence-Associated Secretory Phenotype: GDF-15, IGFBP-2, and Cystatin-C Are Associated With Multiple Aging Traits.

Cellular senescence, a hallmark of aging, results in a senescence-associated secretory phenotype (SASP) with an increased production of proinflammatory cytokines, growth factors, and proteases. Evidence from nonhuman models demonstrates that SASP contributes to tissue dysfunction and pathological effects of aging. However, there are relatively few human studies on the relationship between SASP and aging-related health outcomes. Proteins from the SASP Atlas were measured in plasma using aptamer-based proteomics (SomaLogic). Regression models were used to identify SASP protein associations with aging-related traits representing multiple aspects of physiology in 1 201 participants from 2 human cohort studies (BLSA/GESTALT and InCHIANTI). Traits examined were fasting glucose, C-reactive protein, interleukin-6, alkaline phosphatase, blood urea nitrogen, albumin, red blood cell distribution width, waist circumference, systolic and diastolic blood pressure, gait speed, and grip strength. Study results were combined with a fixed-effect inverse-variance weighted meta-analysis. In the meta-analysis, 28 of 77 SASP proteins were significantly associated with age. Of the 28 age-associated SASP proteins, 18 were significantly associated with 1 or more clinical traits, and 7 SASP proteins were significantly associated with 3 or more traits. Growth/differentiation factor 15, Insulin-like growth factor-binding protein 2, and Cystatin-C showed significant associations with inflammatory markers and measures of physical function (grip strength or gait speed). These results support the relevance of SASP proteins to human aging, identify specific traits that are potentially affected by SASP, and prioritize specific SASP proteins for their utility as biomarkers of human aging.

Temporal trends, sex differences, and age-related disease influence in Neutrophil, Lymphocyte count and Neutrophil to Lymphocyte-ratio: results from InCHIANTI follow-up study.

BACKGROUND: Neutrophils and lymphocytes represent the larger percentage of all white blood cells, they vary with age, with a progressive increase of the ratio in the first years of life, and then tend to remain at similar levels in steady state condition during adult age. Neutrophils to lymphocytes-ratio (NL-ratio) was proposed as an effective and low-cost marker to monitor and predict the evolution of several clinical conditions. The main objective of the study is to analyze its temporal trend variation, over twenty years' follow-up, according to age, sex, and main clinical diagnosis, in a large representative Italian population. METHODS: The InCHIANTI study enrolled representative samples from the registry list of two towns in Tuscany, Italy. Baseline data were collected in 1998, and last follow-up visits were made in 2015-18. 1343 out of the 1453 participants enrolled were included, and consented to donate a blood sample. All subjects were assessed and followed for life-style, clinical condition, physical performance, and underwent an instrumental diagnostic session. RESULTS: The NL-ratio showed a statistically significant interaction between birth-cohort and time of the study (p-value = 0.005). A gender dimorphism was recognized in the neutrophils absolute count and in the NL-ratio. Moreover, in female participants only, those who reported CHF had lower neutrophil-count and NL-ratio; whereas an increase in creatinine clearance was directly associated with NL-ratio. In male subjects, an increase of BMI was inversely associated with both NL-ratio and neutrophils-count during the follow-up; a similar association but in the opposite direction was observed in female participants. CONCLUSION: NL-ratio is a more reliable predictor of healthy aging than absolute lymphocytes and/or neutrophils counts. It is associated with the changes induced by disease, lifestyle, and environmental challenges in the immune system. NL-ratio confirms the gender dimorphism in the occurrence of inflammation-driven diseases, thus providing additional evidence for the necessity of tailored sex-specific measures to prevent and treat such diseases.

Temporal trends, sex differences, and age-related disease influence in Neutrophil, Lymphocyte count and Neutrophil to Lymphocyte-ratio. Results from InCHIANTI follow-up study.

Background Neutrophils and lymphocytes represent the larger percentage of all white bloodcells, they vary with age, with a progressive increase of the ratio in the first years of life, and then tend to remain at similar levels in steady state condition during adult age. Neutrophils to lymphocytes-ratio (NL-ratio) was proposed as an effective and low-cost marker to monitor and predict the evolution of severalclinical conditions. The main objective of the study is to analyze its temporal trend variation, over twenty years' follow-up, according to age, sex, and main clinical diagnosis, in a large representative Italian population. Methods The InCHIANTI study enrolled representative samples from the registry list of two towns in Tuscany, Italy. Baseline data were collected in 1998, and last follow-up visits were made in 2015-18. 1343 out of the 1453 participants enrolled were included, and consented to donate a blood sample. All subjects were assessed and followed for life-style, clinical condition, physical performance, and underwent an instrumental diagnostic session. Results The NL-ratio showed a statistically significant interaction between birth-cohort and time of the study (p-value=0.005). A gender dimorphism was recognized in the neutrophils absolute count and in the NL-ratio. Moreover, in female participants only, those who reported CHF had lower neutrophil-count and NL-ratio; whereas an increase in creatinine clearance was directly associated with NL-ratio. In male subjects, an increase of BMI was inversely associated with both NL-ratio and neutrophils-count during the follow-up; a similar association but in the opposite direction was observed in female participants. Conclusion NL-ratio is a more reliable predictor of healthy aging than absolute lymphocytes and/or neutrophils counts. It is associated with the changes induced by disease, lifestyle, and environmental challenges in the immune system. NL-ratio confirms the gender dimorphism in the occurrence of inflammation-driven diseases, thus providing additional evidence for the necessity of tailored sex-specific measures to prevent and treat such diseases.

Proteomic Mediators of Overall Cardiovascular Health on All-Cause Mortality.

Measures of cardiovascular health (CVH) assessed by a combination of behavioral and biological factors has shown protective associations with all-cause mortality. The mechanisms underlying these associations have not been fully elucidated. In this study, we characterized the plasma proteomics profile of CVH and tested whether specific proteins mediated the associations between CVH and all-cause mortality in participants of the InCHIANTI study. Of the 1301 proteins tested, 92 proteins were associated with CVH (22 positively, 70 negatively). Proteins most strongly associated with CVH included leptin (LEP), fatty acid binding protein 3 (FABP3), Angiopoietin-2 (ANGPT2), and growth-differential factor 15 (GDF15). Of the 92 CVH-associated proteins, 33 proteins significantly mediated the associations between CVH and all-cause mortality, with percent mediation ranging from 5 to 30%. The most significant mediating proteins were GDF15 and insulin-like growth factor 2 (IGFBP2). Proteins associated with better CVH were enriched for proteins that reflect the suppression of the complement coagulation and GH/IGF pathways.

Metabolomic markers mediate erythrocyte anisocytosis in older adults: Results from three independent aging cohorts.

BACKGROUND: Anisocytosis reflects unequal-sized red blood cells and is quantified using red blood cell distribution width (RDW). RDW increases with age and has been consistently associated with adverse health outcomes, such as cardiovascular disease and mortality. Why RDW increases with age is not understood. We aimed to identify plasma metabolomic markers mediating anisocytosis with aging. METHODS: We performed mediation analyses of plasma metabolomics on the association between age and RDW using resampling techniques after covariate adjustment. We analyzed data from adults aged 70 or older from the main discovery cohort of the Baltimore Longitudinal Study of Aging (BLSA, n = 477, 46% women) and validation cohorts of the Health, Aging and Body Composition Study (Health ABC, n = 620, 52% women) and Invecchiare in Chianti, Aging in the Chianti Area (InCHIANTI) study (n = 735, 57% women). Plasma metabolomics was assayed using the Biocrates MxP Quant 500 kit in BLSA and Health ABC and liquid chromatography with tandem mass spectrometry in InCHIANTI. RESULTS: In all three cohorts, symmetric dimethylarginine (SDMA) significantly mediated the association between age and RDW. Asymmetric dimethylarginine (ADMA) and 1-methylhistidine were also significant mediators in the discovery cohort and one validation cohort. In the discovery cohort, we also found choline, homoarginine, and several long-chain triglycerides significantly mediated the association between age and RDW. CONCLUSIONS AND RELEVANCE: This metabolomics study of three independent aging cohorts identified a specific set of metabolites mediating anisocytosis with aging. Whether SDMA, ADMA, and 1-methylhistidine are released by the damaged erythrocytes with high RDW or they affect the physiology of erythrocytes causing high RDW should be further investigated.

Apolipoprotein E gene variants shape the association between dietary fibre intake and cognitive decline risk in community-dwelling older adults.

BACKGROUND: healthy dietary patterns have been associated with lower risk for age-related cognitive decline. However, little is known about the specific role of dietary fibre on cognitive decline in older adults. OBJECTIVE: this study aimed to examine the association between dietary fibre and cognitive decline in older adults and to assess the influence of genetic, lifestyle and clinical characteristics in this association. DESIGN AND PARTICIPANTS: the Invecchiare in Chianti, aging in the Chianti area study is a cohort study of community-dwelling older adults from Italy. Cognitive function, dietary and clinical data were collected at baseline and years 3, 6, 9 and 15. Our study comprised 848 participants aged ≥ 65 years (56% female) with 2,038 observations. MAIN OUTCOME AND MEASURES: cognitive decline was defined as a decrease ≥3 units in the Mini-Mental State Examination score during consecutive visits. Hazard ratios for cognitive decline were estimated using time-dependent Cox regression models. RESULTS: energy-adjusted fibre intake was not associated with cognitive decline during the 15-years follow-up (P > 0.05). However, fibre intake showed a significant interaction with Apolipoprotein E (APOE) haplotype for cognitive decline (P = 0.02). In participants with APOE-ɛ4 haplotype, an increase in 5 g/d of fibre intake was significantly associated with a 30% lower risk for cognitive decline. No association was observed in participants with APOE-ɛ2 and APOE-ɛ3 haplotypes. CONCLUSIONS AND RELEVANCE: dietary fibre intake was not associated with cognitive decline amongst older adults for 15 years of follow-up. Nonetheless, older subjects with APOE-ɛ4 haplotype may benefit from higher fibre intakes based on the reduced risk for cognitive decline in this high-risk group.

Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts.

OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). DESIGN: Pooled analysis. DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020. STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m2. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m2 and <75% of baseline rate. RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I2=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I2=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I2=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 v <60 years), estimated glomerular filtration rate (60-89 v ≥90 mL/min/1.73 m2), hypertension, diabetes, and coronary heart disease at baseline. CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.

Predicting risk of declining functional ability in community-dwelling older people.

OBJECTIVE: The frailty phenotype (FP) proposed by Fried and colleagues has been shown to be strongly associated with incident disability, but its discriminative capacities remain suboptimal, with good specificity but a sensitivity of only 10-20%. The objective of the present study was to evaluate whether the addition to the FP of other biological and social variables may improve the prediction of declining functional ability in community-dwelling older people. DESIGN: Prospective observational study. SETTING AND PARTICIPANTS: Community-dwelling older subjects. METHODS: We used data from the InChianti (N 897) and the SHARE (N 444) studies to derive and validate a scoring system consisting of FP components along with age, perceived health status and markers of socio-economic disadvantage. Backward stepwise logistic regressions were used to obtain a parsimonious model, able to predict the loss of ability to perform instrumental or basic activities of daily living over time. RESULTS: A scoring system derived from a model only including age, low physical activity level, exhaustion and perceived health status had an area under the receiver operating characteristic curve (AUROC) of 0.846 in the training cohort (InChianti), and 0.745 in the testing cohort (SHARE). By applying the cut-off of 33 and 25 in the InChianti and SHARE, respectively, sensitivity raised to 0.70 and 0.62 with specificity of 0.83 and 0.70, respectively. CONCLUSIONS AND IMPLICATIONS: A simple score based on anamnestic variables may be more sensitive than the FP towards worsening functional ability, while retaining good specificity. Further studies are needed to confirm its performance.

DNA methylation GrimAge version 2.

We previously described a DNA methylation (DNAm) based biomarker of human mortality risk DNAm GrimAge. Here we describe version 2 of GrimAge (trained on individuals aged between 40 and 92) which leverages two new DNAm based estimators of (log transformed) plasma proteins: high sensitivity C-reactive protein (logCRP) and hemoglobin A1C (logA1C). We evaluate GrimAge2 in 13,399 blood samples across nine study cohorts. After adjustment for age and sex, GrimAge2 outperforms GrimAge in predicting mortality across multiple racial/ethnic groups (meta P=3.6x10-167 versus P=2.6x10-144) and in terms of associations with age related conditions such as coronary heart disease, lung function measurement FEV1 (correlation= -0.31, P=1.1x10-136), computed tomography based measurements of fatty liver disease. We present evidence that GrimAge version 2 also applies to younger individuals and to saliva samples where it tracks markers of metabolic syndrome. DNAm logCRP is positively correlated with morbidity count (P=1.3x10-54). DNAm logA1C is highly associated with type 2 diabetes (P=5.8x10-155). DNAm PAI-1 outperforms the other age-adjusted DNAm biomarkers including GrimAge2 in correlating with triglyceride (cor=0.34, P=9.6x10-267) and visceral fat (cor=0.41, P=4.7x10-41). Overall, we demonstrate that GrimAge version 2 is an attractive epigenetic biomarker of human mortality and morbidity risk.

Urinary and Daily Assumption of Polyphenols and Hip-Fracture Risk: Results from the InCHIANTI Study.

A high polyphenol intake has been associated with higher bone-mineral density. In contrast, we recently demonstrated that the urinary levels of these micronutrients were associated with the long-term accelerated deterioration of the bone. To expand on the health consequences of these findings, we assessed the association between urinary level and dietary intake of polyphenols and the 9-year risk of hip fractures in the InCHIANTI study cohort. The InCHIANTI study enrolled representative samples from two towns in Tuscany, Italy. Baseline data were collected in 1998 and at follow-up visits in 2001, 2004, and 2007. Of the 1453 participants enrolled at baseline, we included 817 participants in this study who were 65 years or older at baseline, donated a 24 hour urine sample, and underwent a quantitative computerized tomography (pQCT) of the tibia. Fracture events were ascertained by self-report over 9 years of follow-up. Thirty-six hip fractures were reported over the 9-year follow-up. The participants who developed a hip fracture were slightly older, more frequently women, had a higher dietary intake of polyphenols, had higher 24-hour urinary polyphenols excretion, and had a lower fat area, muscle density, and cortical volumetric Bone Mineral Density (vBMD) in the pQCT of the tibia. In logistic regression analyses, the baseline urinary excretion of total polyphenols, expressed in mg as a gallic acid equivalent, was associated with a higher risk of developing a hip fracture. Dietary intake of polyphenols was not associated with a differential risk of fracture. In light of our findings, the recommendation of an increase in dietary polyphenols for osteoporosis prevention should be considered with caution.