BackgroundIn the elderly, chronic low-grade inflammation (inflammaging) is a risk factor for the development of aging-related diseases and frailty. Using data from several thousand Eastern Europeans aged 65 years and older, we investigated whether the serum levels of two proinflammatory factors, interleukin-6 (IL-6) and C-reactive protein (CRP), were associated with physical and cognitive performance, and could predict mortality in successfully aging elderly.ResultsIL-6 and CRP levels systematically increased in an age-dependent manner in the entire study group (IL-6: n = 3496 individuals, p < 0.001 and CRP: n = 3632, p = 0.003), and in the subgroup of successfully aging individuals who had never been diagnosed with cardiovascular disease, myocardial infarction, stroke, type 2 diabetes, or cancer, and had a Mini Mental State Examination (MMSE) score ≥24 and a Katz Activities of Daily Living (ADL) score ≥5 (IL-6: n = 1258, p < 0.001 and CRP: n = 1312, p < 0.001). In the subgroup of individuals suffering from aging-related diseases/disability, only IL-6 increased with age (IL-6: n = 2238, p < 0.001 and CRP: n = 2320, p = 0.249). IL-6 and CRP levels were lower in successfully aging individuals than in the remaining study participants (both p < 0.001). Higher IL-6 and CRP levels were associated with poorer physical performance (lower ADL score) and poorer cognitive performance (lower MMSE score) (both p < 0.001). This association remained significant after adjusting for age, gender, BMI, lipids, estimated glomerular filtration rate, and smoking status. Longer survival was associated with lower concentrations of IL-6 and CRP not only in individuals with aging-related diseases/disability (HR = 1.063 per each pg/mL, 95 % CI: 1.052-1.074, p < 0.001 and HR = 1.020 per each mg/L, 95 % CI: 1.015-1.025, p < 0.001, respectively) but also in the successfully aging subgroup (HR = 1.163 per each pg/mL, 95 % CI: 1.128-1.199, p < 0.001 and HR = 1.074 per each mg/L, 95 % CI: 1.047-1.100, p < 0.001, respectively). These associations remained significant after adjusting for age, gender, BMI, lipids and smoking status. The Kaplan-Meier survival curves showed similar results (all p < 0.001).ConclusionsBoth IL-6 and CRP levels were good predictors of physical and cognitive performance and the risk of mortality in both the entire elderly population and in successfully aging individuals.

Both obesity and weight loss may cause molecular changes in adipose tissue. This study aimed to characterize changes in adipose tissue miRNome in order to identify molecular pathways affected by obesity and weight changes. Next generation sequencing (NGS) was applied to identify microRNAs (miRNAs) differentially expressed in 47 samples of visceral (VAT) and subcutaneous (SAT) adipose tissues from normal-weight (N), obese (O) and obese after surgery-induced weight loss (PO) individuals. Subsequently miRNA expression was validated by real-time PCR in 197 adipose tissues and bioinformatics analysis performed to identify molecular pathways affected by obesity-related changes in miRNA expression. NGS identified 344 miRNAs expressed in adipose tissues with ≥5 reads per million. Using >2 and <−2 fold change as cut-offs we showed that the expression of 54 miRNAs differed significantly between VAT-O and SAT-O. Equally, between SAT-O and SAT-N, the expression of 20 miRNAs differed significantly, between SAT-PO and SAT-N the expression of 79 miRNAs differed significantly, and between SAT-PO and SAT-O, the expression of 61 miRNAs differed significantly. Ontological analyses disclosed several molecular pathways regulated by these miRNAs in adipose tissue. NGS-based miRNome analysis characterized changes of the miRNA profile of adipose tissue, which are associated with changes of weight possibly responsible for a differential regulation of molecular pathways in adipose tissue when the individual is obese and after the individual has lost weight.

We observed obesity-associated downregulation of SIRT1 and upregulation of SIRT7 mRNA levels that were not associated with the methylation status of their promoters. We found a negative correlation between mRNA levels of SIRT1 in VAT of obese individuals and SIRT7 in VAT of the normal-weight subjects and expression of the relevant miRNAs.

Objectives To investigate the influence of overweight and obesity on general performance and mortality in seniors. Design Cross-sectional multidisciplinary study on ageing of the Polish population. Setting Community-dwelling individuals aged 65 years or older, selected using three-stage stratified, proportional draw. Participants 4944 Polish Caucasian seniors, aged 65 years or older recruited between October 2007 and October 2010. Measurements All study subjects underwent measurement of body mass index (BMI), waist circumference (WC), and arm circumference (AC). The physical and cognitive performance was evaluated using the Katz Activities of Daily Living (ADL) score and Mini-Mental State Examination (MMSE), respectively. Morbidity data were obtained from a medical questionnaire. Mortality data were obtained from the Population Register of Poland between October 2015 and October 2018. Results Increasing age was associated with a decreased prevalence of obesity (all p<0.001). Higher BMI, WC and AC values were associated with higher ADL and MMSE scores (all p<0.001). On multivariate analysis, all three body measurements in women remained independent predictors of the ADL score (BMI p=0.002, WC p=0.005, AC p<0.001) and MMSE score (p<0.001, p=0.003, p<0.001). In men, physical functioning was associated with AC (p=0.003), and cognitive status was associated with AC (p<0.001) and BMI (p=0.013). There was no association between general obesity, abdominal obesity, or AC with several aging-related adverse conditions. Kaplan-Meier survival curves showed that overweight and obesity were associated with the lowest mortality. On multivariate analysis, BMI and AC values remained independent predictors of mortality. In successfully aging individuals, neither BMI, WC, nor AC remained such predictors. Conclusions Overweight and obesity in Caucasian seniors are not associated with deterioration of physical and cognitive function or with increased mortality.

Impact statementHigh expression of sirtuins, particularly SIRT1, lowers the risk of age-related diseases and probably slows down the rate of aging; therefore, their sustained expression should be one of the features of longevity. However, in this work we show that in peripheral blood mononuclear cells (PBMC) of long-lived individuals, expression of majority of the SIRT genes is significantly lower than in cells of young study subjects. In long-lived individuals, downregulation of SIRT1 coexists with upregulation of SIRT1 mRNA-interacting miR-34a and miR-9, indicating the role of epigenetic drift in age-dependent deregulation of SIRT1 expression. Such constellation of SIRT1, miR-34a, and miR-9 expression in PBMC of successfully aging long-lived individuals indicates that, at least in these individuals, it is not a risk factor for morbidity and mortality. It might however affect the function of the immune system and, therefore, aging individuals can profit from interventions increasing the level of SIRT1. AbstractIncreased expression of sirtuins lowers the risk of age-related diseases, while their role in the regulation of longevity is not firmly established. Since aging is associated with immunosenescence, we tested whether sirtuin expression was modified in peripheral blood mononuclear cells (PBMC) in an age-related manner and whether this might result from altered expression of the selected miRNAs. The expression of seven SIRT genes and of SIRT1 mRNA-interacting miR-9, miR-34a, miR-132, and miR-199a-5p was evaluated by real-time PCR in PBMC originating from young (Y, n ¼ 57, mean age 27 AE 4.3 years), elderly (E, n ¼ 52, 65 AE 3.4 years), and long-lived (L, n ¼ 56, 94 AE 3.5 years) individuals. Older age was associated with a decreased expression of the majority of the SIRT genes. Most severely affected were median expressions of SIRT1 (P ¼ 0.000001 for the whole studied group, Y vs. E: P < 0.000001, Y vs. L: P < 0.000001), and of SIRT3 (P ¼ 0.000001, Y vs. E: P ¼ 0.000004, Y vs. L: P ¼ 0.000028). Older age was also associated with the increased median expression of miR-34a (P ¼ 0.000001, Y vs. E: P ¼ 0.001, Y vs. L: P ¼ 0.000004) and of miR-9 (P ¼ 0.05, Y vs. L: P ¼ 0.054). In functional studies, miR-9 interacted with the 3 0 UTR of SIRT1 mRNA. The SIRT1 mRNA level negatively correlated with the expression of miR34a (r ¼ À0.234, P ¼ 0.003). In conclusion, age-related decrease of SIRT1 expression in PBMC might in part result from overexpression of miR-34a and miR-9. In addition, the sustained expression of the SIRT genes in PBMC is not a prerequisite to longevity in humans but might be one of the reasons for the immune system dysfunction in the elderly.

BackgroundIn mammals, the IGF-1 pathway affects the phenotype of aging. Since the function of the immune system is modulated by IGF-1, it is plausible that immunosenescence might in part result from altered control by this pathway. We therefore examined whether the expression of IGF-1R, FOXO1, and FOXO3a in peripheral blood mononuclear cells (PBMC) changes with age and if this might be due to changes in the expression of select miRNAs.MethodsThe expression of IGF-1R, FOXO1, FOXO3a, as well as of miR-9, miR-96, miR-99a, miR-132, miR-145, and miR-182 was examined in PBMC of young (27.8 ± 3.7 years), elderly (65.6 ± 3.4 years), and long-lived (94.0 ± 3.7 years) Polish Caucasians using real-time PCR. mRNA/miRNA interactions were studied in HEK 293 cells using luciferase-expressing pmirGLO reporter vector.ResultsThe median expression of IGF-1R decreased with age (p < 0.000001), as did the expression of FOXO1 (p < 0.000001), while the expression of FOXO3a remained stable. We also found an age-associated increase of the median expression of miR-96 (p = 0.002), miR-145 (p = 0.024) and miR-9 (p = 0.026), decrease of the expression of miR-99a (p = 0.037), and no changes regarding miR-132 and miR-182. Functional studies revealed that miR-96 and miR-182 interacted with human IGF-1R mRNA, and that miR-145 and miR-132 interacted with human FOXO1 mRNA.ConclusionsThe age-associated higher expression of miR-96 and miR-145 might contribute to the lower expression of IGF-1R while the higher expression of miR-96, miR-145 and miR-9 might contribute to the lower expression of FOXO1 in peripheral blood mononuclear cells of aging humans. Sustained expression/function of FOXO3a but not of the other two genes might be important for the maintenance of the immune system function in these individuals.

Small-molecule hormones play crucial roles in the development and in the maintenance of an adult mammalian organism. On the molecular level, they regulate a plethora of biological pathways. Part of their actions depends on their transcription-regulating properties, exerted by highly specific nuclear receptors which are hormone-dependent transcription factors. Nuclear hormone receptors interact with coactivators, corepressors, basal transcription factors, and other transcription factors in order to modulate the activity of target genes in a manner that is dependent on tissue, age and developmental and pathophysiological states. The biological effect of this mechanism becomes apparent not earlier than 30–60 minutes after hormonal stimulus. In addition, small-molecule hormones modify the function of the cell by a number of nongenomic mechanisms, involving interaction with proteins localized in the plasma membrane, in the cytoplasm, as well as with proteins localized in other cellular membranes and in nonnuclear cellular compartments. The identity of such proteins is still under investigation; however, it seems that extranuclear fractions of nuclear hormone receptors commonly serve this function. A direct interaction of small-molecule hormones with membrane phospholipids and with mRNA is also postulated. In these mechanisms, the reaction to hormonal stimulus appears within seconds or minutes.

Background. Age-related decrease in bone marrow erythropoietic capacity is often accompanied by the telomere length shortening in peripheral white blood cells. However, limited and conflicting data hamper the conclusive opinion regarding this relationship. Therefore, the aim of this study was to assess an association between telomere length and peripheral blood cell count parameters in the Polish elderly population. Material and Methods. The substudy included 1573 of 4981 subjects aged 65 years or over, participants of the population-based PolSenior study. High-molecular-weight DNA was isolated from blood mononuclear cells. Telomere length (TL) was measured by QRT-PCR as abundance of telomere template versus a single gene copy encoding acidic ribosomal phosphoprotein P0. Results. Only white blood count (WBC) was significantly different in TL tertile subgroups in all subjects (P = 0.02) and in men (P = 0.01), but not in women. Merely in men significant but weak positive correlations were found between TL and WBC (r = 0.11, P < 0.05) and RBC (r = 0.08, P < 0.05). The multiple regression analysis models confirmed a weak, independent contribution of TL to both RBC and WBC. Conclusions. In the elderly, telomere shortening limits hematopoiesis capacity to a very limited extent.