Biomarker signatures associated with ageing free of major chronic diseases: results from a population-based sample of the EPIC-Potsdam cohort.

BACKGROUND: A number of biomarkers denoting various pathophysiological pathways have been implicated in the aetiology and risk of age-related diseases. Hence, the combined impact of multiple biomarkers in relation to ageing free of major chronic diseases, such as cancer, cardiovascular disease and type 2 diabetes, has not been sufficiently explored. METHODS: We measured concentrations of 13 biomarkers in a random subcohort of 2,500 participants in the European Prospective Investigation into Cancer and Nutrition Potsdam study. Chronic disease-free ageing was defined as reaching the age of 70 years within study follow-up without major chronic diseases, including cardiovascular disease, type 2 diabetes or cancer. Using a novel machine-learning technique, we aimed to identify biomarker clusters and explore their association with chronic disease-free ageing in multivariable-adjusted logistic regression analysis taking socio-demographic, lifestyle and anthropometric factors into account. RESULTS: Of the participants who reached the age of 70 years, 321 met our criteria for chronic-disease free ageing. Machine learning analysis identified three distinct biomarker clusters, among which a signature characterised by high concentrations of high-density lipoprotein cholesterol, adiponectin and insulin-like growth factor-binding protein 2 and low concentrations of triglycerides was associated with highest odds for ageing free of major chronic diseases. After multivariable adjustment, the association was attenuated by socio-demographic, lifestyle and adiposity indicators, pointing to the relative importance of these factors as determinants of healthy ageing. CONCLUSION: These data underline the importance of exploring combinations of biomarkers rather than single molecules in understanding complex biological pathways underpinning healthy ageing.

Assessment of Plasma Phospholipid Very-Long-Chain Saturated Fatty Acid Levels and Healthy Aging.

Importance: Identifying novel factors that protect against age-related diseases and promote healthy aging is critical to public health. Higher levels of circulating very-long-chain saturated fatty acids (VLSFAs) are integrated biomarkers of diet and metabolism shown to have beneficial associations in cardiovascular disease and total mortality, but whether they are associated with overall healthy aging is unknown. Objective: To examine the association of circulating levels of 3 VLSFAs with unhealthy aging events, including incident chronic disease (cardiovascular disease, cancer, lung disease or severe kidney disease), physical dysfunction, and cognitive decline. Design, Setting, and Participants: This cohort study used 1992 to 2014 data from the Cardiovascular Health Study (CHS). The CHS is a multicenter, population-based study of cardiovascular disease among older adults. Among the 4559 CHS participants with available fatty acid data, 1879 participants who had an age-related event before their first measurement were excluded. Data analysis was performed in 2020. Main Outcomes and Measures: Plasma phospholipid VLSFA levels were measured by thin-layer chromatography followed by gas chromatography. The main outcome was the hazard ratio (HR) of an incident unhealthy aging event associated with serial measures of plasma arachidic acid, behenic acid, and lignoceric acid. Results: Among the 2680 study participants (976 men [36.4%]), the mean (SD) age was 74.7 (4.8) years old at entry. During a median (interquartile range) of 6.4 (2.9-12.9) years of follow-up, 2484 participants experienced an unhealthy event. Compared with the lowest quintile, levels of behenic acid in the highest quintile of the fatty acid distribution were associated with 15% lower risk of an unhealthy event (HR, 0.85; 95% CI, 0.74-0.97; P for trend = .01) after adjustment for demographic characteristics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of lignoceric acid were similarly associated with 16% lower risk of an unhealthy event (HR, 0.84; 95% CI, 0.73-0.95; P for trend = .001). Conclusions and Relevance: These findings suggest that higher levels of circulating behenic acid and lignoceric acid are associated with lower risk of unhealthy aging events. These results highlight the need to explore determinants of circulating VLSFAs for potential novel efforts to promote healthy aging.

Association between GDF15, poverty and mortality in urban middle-aged African American and white adults.

Mortality disparities are influenced by race and poverty. There is limited information about whether poverty influences biologic markers of mortality risk. Emerging data suggests that growth differentiation factor 15 (GDF15) is associated with mortality; however, the interplay between GDF15, sociodemographic factors and mortality is not known. We sought to evaluate the interactions between GDF15 and sex, race and poverty status on mortality. Serum GDF15 was measured in 1036 African American and white middle-aged men and women above and below 125% of the Federal poverty status from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Multivariable adjusted Cox regression models were used to assess the association between log-transformed GDF15 (logGDF15) and 12-year mortality outcomes (all-cause, cardiovascular- and cancer-specific outcomes) and interactions with sex, race and poverty status. Likelihood ratio tests were used to assess significance of the interaction terms. Median GDF15 was 655.2 pg/mL (IQR = 575.1). During 12.2 years of follow-up, 331 died of which 94 cardiovascular- and 87 were cancer-specific deaths. One unit of increase in logGDF15 was associated with a hazard ratio for all-cause mortality, cardiovascular- and cancer-specific mortality of 2.26 (95% confidence interval [CI], 1.94-2.64), 2.74 (95%CI, 2.06-3.63) and 1.41 (95%CI, 1.00-2.00), respectively. There was an interaction between logGDF15 and poverty status on all-cause mortality (p<0.05). The GDF15×poverty status interaction term improved model calibration for all-cause mortality. Our study provides the first evidence that the effect of elevated GDF15 on all-cause mortality is modified by poverty status.

Clinical Assessment of the NADome as Biomarkers for Healthy Aging.

Nicotinamide adenine dinucleotide (NAD+) and its related metabolites (NADome) are important endogenous analytes that are thought to play important roles in cellular metabolism, inflammation, oxidative stress, cancer, neurodegeneration, and aging in mammals. However, these analytes are unstable during the collection of biological fluids, which is a major limiting factor for their quantitation. Herein, we describe a highly robust and quantitative method using liquid chromatography coupled to tandem mass spectrometry to quantify the NADome in whole blood, plasma, mononuclear cells, platelets, cerebrospinal fluid (CSF), and urine. This methodology represents a "gold standard" of measure for understanding biological pathways and developing targeted pharmacological interventions to modulate NAD+ biosynthesis and NAD-dependent mediators in health and disease.

Changing from a Western to a Mediterranean-style diet does not affect iron or selenium status: results of the New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe (NU-AGE) 1-year randomized clinical trial in elderly Europeans.

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.

Associations between inflammatory and neurological markers with quality of life and well-being in older adults.

OBJECTIVES: Stressful experiences, poor self-rated health, and negative emotional states have been implicated with higher levels of inflammatory markers and lower levels of neurotrophic factors in some healthy adults and clinical populations, but these relationships are unclear in the elderly. This study aimed to identify the associations between systemic inflammatory and neurological markers with well-being and health-related quality of life (HR-QoL) in independently living elderly people. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: A total of 268 men and women aged ≥65 years living independently in retirement communities in Melbourne, Australia. MEASURES: Questionnaires were used to assess HR-QoL [Short Form (SF)-36 version 2] and well-being (Personal Wellbeing Index). Serum inflammatory cytokines [interleukin (IL)-4, IL-6, IL-1ß, IL-8, IL-10, tumor necrosis factor (TNF)-α, and high sensitive C-reactive protein (hs-CRP)] were standardised to Z-scores and used to calculate pro- and anti-inflammatory composite score and an overall composite inflammatory index. Plasma levels of the neurological markers amyloid ß (1-40) and amyloid ß (1-42), brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF), were also assessed. RESULTS: No significant associations were found between any inflammatory or neurological marker with HR-OoL or well-being, with the exception that lower perceptions of the HR-QoL vitality subscale were associated with higher levels of hs-CRP [unstandardized beta-coefficient (ß): -1.50; 95% CI: -2.53, -0.46; P = 0.004] and Z-scores in the pro-inflammatory composite score (ß = -2.06; 95% CI: -3.49, -0.62; P = 0.005). CONCLUSIONS/IMPLICATIONS: In elderly people residing in independent living retirement communities, there was no consistent evidence indicating that circulating inflammatory or neurological markers were associated with the key physical or mental HR-QoL domains or overall well-being. This suggests that these biomarkers may not be effective predictors in relatively healthy communities, and may be more beneficial in frail or clinical populations. Clinical Trials registry: Australian New Zealand Clinical Trials Registry (ACTRN12613001161718). http://www.anzctr.org.au/.

Serum glycomarkers of endoplasmic reticulum and lysosomal-endosomal system stress in human healthy aging and diseases.

To verify the idea that extracellular free oligosaccharides might be able to reflect the functional status of the endoplasmic reticulum (ER) and lysosomal-endosomal system, HPLC-profiles of serum-derived free oligosaccharides (FOS) in human healthy aging, acute myeloproliferative neoplasms, and cardiovascular pathologies were compared with intracellular glycans. After plasma deproteinization and FOS purification the oligosaccharides were labelled with anthranilic acid, separated into the neutral and charged with QAE Sephadex (Q25-120) chromatography and analysed using high-performance liquid chromatography (HPLC). The charged FOS were digested with a sialidase and compared with free oligosaccharides from transferrin for structural decoding. HPLC-profiles of serum-derived FOS revealed mild delay of the dolichol phosphate cycle in ER, moderate intensification of ER-associated degradation (ERAD) and degradation in endosomal-lysosomal system with aging; an inhibition of the dolichol phosphate cycle, intensification of ERAD and increasing of lysosomal exocytosis in acute myeloproliferative neoplasms; intensification of ERAD and glycocojugate degradation with endosomal-lysosomal system in cardiovascular diseases. As serum free oligosaccharides are able to reflect specifically perturbations in ER and endosomal-lysosomal system under wide range of stressors they can serve as extracellular markers of functionality of these organelles.

Changes in pro-inflammatory markers and leucine concentrations in response to Nordic Walking training combined with vitamin D supplementation in elderly women.

Mechanisms underpinning age-related decreases in muscle strength and muscle mass relate to chronic inflammation. Physical activity induces an anti-inflammatory effect, but it is modulated by additional factors. We hypothesized that vitamin D, which has also anti-inflammatory activity will modify adaptation to exercise and reduce inflammation in elderly women. Twenty-seven women aged 67 ± 8 years were included and divided into groups with baseline vitamin D concentration more than 20 ng mL-1 (MVD) and less than 20 ng mL-1 (LVD). Both groups performed 1 h Nordic Walking (NW) training combined with vitamin D supplementation for 12 weeks. Serum concentrations of inflammation markers, branched amino acids, vitamin D, muscle strength and balance were assessed at the baseline and three days after intervention. The training caused the significant decrease in concentration of pro-inflammatory proteins HMGB1 (30 ± 156%; 90% CI) and IL-6 (-10 ± 66%; 90% CI) in MVD group. This effects in group MVD were moderate, indicating vitamin D as one of the modifiers of these exercise-induced changes. Rise of myokine irisin induced by exercise correlated inversely with HMGB1 and the correlation was more pronounced at the baseline as well as after training among MVD participants. Although the intervention caused the leucine level to rise, a comparison of the recorded response between groups and the adjusted effect indicated that the effect was 20% lower in the LVD group. Overall the applied training program was effective in reducing HMGB1 concentration. This drop was accompanied by the rise of myokine irisin and better uptake of leucine among women with higher baseline vitamin D.

Nordic walking training attenuation of oxidative stress in association with a drop in body iron stores in elderly women.

Excess body iron accumulation and oxidative stress has been associated with ageing. Regular exercise has been shown to reduce oxidative stress and induce some changes in iron metabolism. However, the effects of exercise on both of these parameters have been poorly investigated. In our study, 35 elderly women participated in 12 weeks of Nordic walking (NW) training (three times a week). We demonstrated that the training caused a significant reduction in malondialdehyde advanced oxidation protein products-markers of oxidative stress but had no effects on paraoxonase 1 activity. These changes were associated with the decrease of blood ferritin (99.4 ± 62.7 vs. 81.4 ± 61.7 ng/ml p < 0.05). Measurement of physical fitness revealed that the training caused a significant improvement in performance and a negative correlation between the blood ferritin and endurance test was recorded (r = -0.34, p = 0.03). In addition, a significant correlation between blood ferritin and fasting glucose level was noted. The training induced a rise of HDL cholesterol from 70.8 ± 19.3-75.3 ± 21.1, p < 0.05, whereas other lipid parameters remained unchanged. In conclusion, NW training reduced body iron stores and it was associated with lower oxidative stress and better endurance.