Cognitive Impairment in Nonagenarians: Potential Metabolic Mechanisms Revealed by the Synergy of In Silico Gene Expression Modeling and Pathway Enrichment Analysis.

Previous studies examining the molecular and genetic basis of cognitive impairment, particularly in cohorts of long-living adults, have mainly focused on associations at the genome or transcriptome level. Dozens of significant dementia-associated genes have been identified, including APOE, APOC1, and TOMM40. However, most of these studies did not consider the intergenic interactions and functional gene modules involved in cognitive function, nor did they assess the metabolic changes in individual brain regions. By combining functional analysis with a transcriptome-wide association study, we aimed to address this gap and examine metabolic pathways in different areas of the brain of older adults. The findings from our previous genome-wide association study in 1155 older adults, 179 of whom had cognitive impairment, were used as input for the PrediXcan gene prediction algorithm. Based on the predicted changes in gene expression levels, we conducted a transcriptome-wide association study and functional analysis using the KEGG and HALLMARK databases. For a subsample of long-living adults, we used logistic regression to examine the associations between blood biochemical markers and cognitive impairment. The functional analysis revealed a significant association between cognitive impairment and the expression of NADH oxidoreductase in the cerebral cortex. Significant associations were also detected between cognitive impairment and signaling pathways involved in peroxisome function, apoptosis, and the degradation of lysine and glycan in other brain regions. Our approach combined the strengths of a transcriptome-wide association study with the advantages of functional analysis. It demonstrated that apoptosis and oxidative stress play important roles in cognitive impairment.

Machine Learning-Based Decision-Making in Geriatrics: Aging Phenotype Calculator and Survival Prognosis.

Aging is a natural process with varying effects. As we grow older, our bodies become more susceptible to aging-associated diseases. These diseases, individually or collectively, lead to the formation of distinct aging phenotypes. Identifying these aging phenotypes and understanding the complex interplay between coexistent diseases would facilitate more personalized patient management, a better prognosis, and a prolonged lifespan. Many studies distinguish between successful aging and frailty. However, this simple distinction fails to reflect the diversity of underlying causes. In this study, we sought to establish the underlying causes of frailty and determine the patterns in which these causes converge to form aging phenotypes. We conducted a comprehensive geriatric examination, cognitive assessment, and survival analysis of 2,688 long-living adults (median age = 92 years). The obtained data were clustered and used as input data for the Aging Phenotype Calculator, a multiclass classification model validated on an independent dataset of 96 older adults. The accuracy of the model was assessed using the receiver operating characteristic curve and the area under the curve. Additionally, we analyzed socioeconomic factors that could contribute to specific aging patterns. We identified five aging phenotypes: non-frailty, multimorbid frailty, metabolic frailty, cognitive frailty, and functional frailty. For each phenotype, we determined the underlying diseases and conditions and assessed the survival rate. Additionally, we provided management recommendations for each of the five phenotypes based on their distinct features and associated challenges. The identified aging phenotypes may facilitate better-informed decision-making. The Aging Phenotype Calculator (ROC AUC = 92%) may greatly assist geriatricians in patient management.

Decelerated Epigenetic Aging in Long Livers.

Epigenetic aging is a hot topic in the field of aging research. The present study estimated epigenetic age in long-lived individuals, who are currently actively being studied worldwide as an example of successful aging due to their longevity. We used Bekaert's blood-based age prediction model to estimate the epigenetic age of 50 conditionally "healthy" and 45 frail long-livers over 90 years old. Frailty assessment in long-livers was conducted using the Frailty Index. The control group was composed of 32 healthy individuals aged 20-60 years. The DNA methylation status of 4 CpG sites (ASPA CpG1, PDE4C CpG1, ELOVL2 CpG6, and EDARADD CpG1) included in the epigenetic clock was assessed through pyrosequencing. According to the model calculations, the epigenetic age of long-livers was significantly lower than their chronological age (on average by 21 years) compared with data from the group of people aged 20 to 60 years. This suggests a slowing of epigenetic and potentially biological aging in long livers. At the same time, the obtained results showed no statistically significant differences in delta age (difference between the predicted and chronological age) between "healthy" long livers and long livers with frailty. We also failed to detect sex differences in epigenetic age either in the group of long livers or in the control group. It is possible that the predictive power of epigenetic clocks based on a small number of CpG sites is insufficient to detect such differences. Nevertheless, this study underscores the need for further research on the epigenetic status of centenarians to gain a deeper understanding of the factors contributing to delayed aging in this population.

Gut Microbiome in Post-COVID-19 Patients Is Linked to Immune and Cardiovascular Health Status but Not COVID-19 Severity.

The composition of the gut microbiome stores the imprints of prior infections and other impacts. COVID-19 can cause changes in inflammatory status that persist for a considerable time after infection ends. As the gut microbiome is closely associated with immunity and inflammation, the infection severity might be linked to its community structure dynamics. Using 16S rRNA sequencing of stool samples, we investigated the microbiome three months after the end of the disease/infection or SARS-CoV-2 contact in 178 post-COVID-19 patients and those who contacted SARS-CoV-2 but were not infected. The cohort included 3 groups: asymptomatic subjects (n = 48), subjects who contacted COVID-19 patients with no further infection (n = 46), and severe patients (n = 86). Using a novel compositional statistical algorithm (nearest balance) and the concept of bacterial co-occurrence clusters (coops), we compared microbiome compositions between the groups as well as with multiple categories of clinical parameters including: immunity, cardiovascular parameters and markers of endothelial dysfunction, and blood metabolites. Although a number of clinical indicators varied drastically across the three groups, no differences in microbiome features were identified between them at this follow-up point. However, there were multiple associations between the microbiome features and clinical data. Among the immunity parameters, the relative lymphocyte number was linked to a balance including 14 genera. Cardiovascular parameters were associated with up to four bacterial cooperatives. Intercellular adhesion molecule 1 was linked to a balance including ten genera and one cooperative. Among the blood biochemistry parameters, calcium was the only parameter associated with the microbiome via a balance of 16 genera. Our results suggest comparable recovery of the gut community structure in the post-COVID-19 period, independently of severity or infection status. The multiple identified associations of clinical analysis data with the microbiome provide hypotheses about the participation of specific taxa in regulating immunity and homeostasis of cardiovascular and other body systems in health, as well as their disruption in SARS-CoV-2 infections and other diseases.

Mortality and survival in nonagenarians during the COVID-19 pandemic: Unstable equilibrium of aging.

Introduction: Aging puts the human body under an immense stress and makes it extremely susceptible to many diseases, often leading to poor outcomes and even death. Long-living individuals represent a unique group of people who withstood the stress of time and offer an abundance of information on the body's ability to endure the pressure of aging. In this study, we sought to identify predictors of overall one-year mortality in 1641 long-living individuals. Additionally, we analyzed risk factors for COVID-19-related morality, since statistics demonstrated an extreme vulnerability of older adults. Methods: We conducted a two-stage evaluation, including a comprehensive geriatric assessment for major aging-associated: frailty, cognitive impairment, frontal lobe dysfunction, chronic pain, anxiety, risk of falls, sensory deficit, depression, sarcopenia, risk of malnutrition, fecal and urinary incontinence, dependence in Activities of Daily Living, dependence in Instrumental Activities of Daily Living, polypragmasia, and orthostatic hypotension; extensive blood testing, a survey, and a one-year follow-up interview. Results: The most reliable predictors of overall mortality were cognitive impairment, malnutrition, frailty, aging-associated diseases and blood markers indicating malnutrition-induced metabolic dysfunctions (decreased levels of protein fractions, iron, 25-hydroxyvitamin D, and HDL), and aging biomarkers, such as IGF-1 and N-terminal pro b-type natriuretic peptide. In post-COVID 19 participants, the most significant mortality predictors among geriatric syndromes were depression, frontal lobe dysfunction and frailty, and similar to overall mortality blood biomarkers - 25-hydroxyvitamin D, IGF-1, HDL as well as high white blood cell, neutrophils counts and proinflammatory markers. Based on the results, we built a predictive model of overall mortality in the long-living individuals with f-score=0.76. Conclusion: The most sensitive and reliable predictors of mortality were modifiable. This is another evidence of the critical importance of proper geriatric care and support for individuals in their "golden years". These results could facilitate geriatric institutions in their pursuit for providing improved care and could aid physicians in detecting early signs of potentially deadly outcomes. Additionally, our findings could be used in developing day-to-day care guidelines, which would greatly improve prevention statistics.

Clusters of risk factors in metabolic syndrome and their influence on central blood pressure in a global study.

The effect of metabolic syndrome (MetS) and clusters of its components on central blood pressure (CBP) has not been well characterized. We aimed to describe the effect of MetS and clusters of its components on CBP in a large population and to identify whether this effect differs in men and women. We studied 15,609 volunteers (43% women) from 10 cohorts worldwide who participated in the Metabolic syndrome and Artery REsearch Consortium. MetS was defined according to the NCEP-ATP III criteria (GHTBW, glucose, high-density lipoprotein cholesterol, triglyceride, blood pressure, waist circumference). CBP was measured noninvasively and acquired from pulse wave analysis by applanation tonometry. MetS was associated with a 50% greater odds of having higher CSBP. After controlling for age, male sex, non HDL cholesterol, diabetes mellitus, and mean arterial pressure, only specific clusters of MetS components were associated with a higher CSBP; and some of them were significant in women but not in men. We identified "risky clusters" of MetS variables associated with high CSBP. Future studies are needed to confirm they identify subjects at high risk of accelerated arterial aging and, thus, need more intensive clinical management.

Tocilizumab, netakimab, and baricitinib in patients with mild-to-moderate COVID-19: An observational study.

OBJECTIVE: The aim of the study was to assess inflammatory markers and clinical outcomes in adult patients admitted to hospital with mild-to-moderate COVID-19 and treated with a combination of standard-of-care (SOC) and targeted immunosuppressive therapy including anti-IL-17A (netakimab), anti-IL-6R (tocilizumab), or JAK1/JAK2 inhibitor (baricitinib) or with a standard-of-care therapy alone. METHODS: The observational cohort study included 154 adults hospitalized between February and August, 2020 with RT-PCR-confirmed SARS-CoV-2 with National Early Warning Score2 (NEWS2) < 7 and C-reactive protein (CRP) levels ≤ 140 mg/L on the day of the start of the therapy or observation. Patients were divided into the following groups: I) 4 mg baricitinib, 1 or 2 times a day for an average of 5 days (n = 38); II) 120 mg netakimab, one dose (n = 48); III) 400 mg tocilizumab, one dose (n = 34), IV) SOC only: hydroxychloroquine, antiviral, antibacterial, anticoagulant, and dexamethasone (n = 34). RESULTS: CRP levels significantly decreased after 72 h in the tocilizumab (p = 1 x 10-5) and netakimab (p = 8 x 10-4) groups and remained low after 120 h. The effect was stronger with tocilizumab compared to other groups (p = 0.028). A significant decrease in lactate dehydrogenase (LDH) levels was observed 72 h after netakimab therapy (p = 0.029). NEWS2 scores significantly improved 72 h after tocilizumab (p = 6.8 x 10-5) and netakimab (p = 0.01) therapy, and 120 h after the start of tocilizumab (p = 8.6 x 10-5), netakimab (p = 0.001), or baricitinib (p = 4.6 x 10-4) therapy, but not in the SOC group. Blood neutrophil counts (p = 6.4 x 10-4) and neutrophil-to-lymphocyte ratios (p = 0.006) significantly increased 72 h after netakimab therapy and remained high after 120 h. The percentage of patients discharged 5-7 days after the start of therapy was higher in the tocilizumab (44.1%) and netakimab (41.7%) groups than in the baricitinib (31.6%) and SOC (23.5%) groups. Compared to SOC (3 of the 34; 8.8%), mortality was lower in netakimab (0 of the 48; 0%, RR = 0.1 (95% CI: 0.0054 to 1.91)), tocilizumab (0 of the 34; 0%, RR = 0.14 (95% CI: 0.0077 to 2.67)), and baricitinib (1 of the 38; 2.6%, RR = 0.3 (95% CI: 0.033 to 2.73)) groups. CONCLUSION: In hospitalized patients with mild-to-moderate COVID-19, the combination of SOC with anti-IL-17A or anti-IL-6R therapy were superior or comparable to the combination with JAK1/JAK2 inhibitor, and all three were superior to SOC alone. Whereas previous studies did not demonstrate significant benefit of anti-IL-17A therapy for severe COVID-19, our data suggest that such therapy could be a rational choice for mild-to-moderate disease, considering the generally high safety profile of IL-17A blockers. The significant increase in blood neutrophil count in the netakimab group may reflect efflux of neutrophils from inflamed tissues. We therefore hypothesize that neutrophil count and neutrophil-to-lymphocyte ratio could serve as markers of therapeutic efficiency for IL-17A-blocking antibodies in the context of active inflammation.

Analyzing Successful Aging and Longevity: Risk Factors and Health Promoters in 2020 Older Adults.

Geriatric syndromes (GSs) and aging-associated diseases (AADs) are common side effects of aging. They are affecting the lives of millions of older adults and placing immense pressure on healthcare systems and economies worldwide. It is imperative to study the factors causing these conditions and develop a holistic framework for their management. The so-called long-lived individuals-people over the age of 90 who managed to retain much of their health and functionality-could be holding the key to understanding these factors and their health implications. We analyzed the health status and lifestyle of the long-lived individuals and identified risk factors for GSs. Family history greatly contributes to the health and prevention of cognitive decline in older adults. Lifestyle and certain socioeconomic factors such as education, the age of starting to work and retiring, job type and income level, physical activity, and hobby were also associated with certain GSs. Moreover, the levels of total protein, albumin, alpha-1 globulins, high-density lipoprotein, free triiodothyronine, and 25-hydroxyvitamin D were direct indicators of the current health status. The proposed mathematical model allows the prediction of successful aging based on family history, social and economic factors, and life-long physical activity (f1 score = 0.72, AUC = 0.68, precision = 0.83 and recall = 0.64).

Physiological health indexes predict deterioration and mortality in patients with COVID-19: a comparative study.

Old age is a crucial risk factor for severe coronavirus disease 2019 (COVID-19), with serious or fatal outcomes disproportionately affecting older adults compared with the rest of the population. We proposed that the physiological health status and biological age, beyond the chronological age itself, could be the driving trends affecting COVID-19 severity and mortality. A total of 155 participants hospitalized with confirmed COVID-19 aged 26-94 years were recruited for the study. Four different physiological summary indices were calculated: Klemera and Doubal's biological age, PhenoAge, physiological dysregulation (PD; globally and in specific systems), and integrated albunemia. All of these indices significantly predicted the risk of death (p < 0.01) after adjusting for chronological age and sex. In all models, men were 2.4-4.4-times more likely to die than women. The global PD was shown to be a good predictor of deterioration, with the odds of deterioration increasing by 41.7% per 0.5-unit increase in the global PD. As for death, the odds also increased by 68.3% per 0.5-unit increase in the global PD. Our results are partly attributed to common chronic diseases that aggravate COVID-19, but they also suggest that the underlying physiological state could capture vulnerability to severe COVID-19 and serve as a tool for prognosis that would, in turn, help inpatient management.

Subfractional Spectrum of Serum Lipoproteins and Gut Microbiota Composition in Healthy Individuals.

Aim: To reveal the relationship between gut microbiota composition and subfractional spectrum of serum lipoproteins and metabolic markers in healthy individuals from Moscow. Methods: The study included 304 participants (104 were men), who underwent thorough preclinical assessment to exclude any chronic disease as well as cardiovascular pathology. Lipoprotein subfractional distribution was analyzed by Lipoprint LDL System (Quantimetrix, Redodno Beach, CA, USA). Gut microbiota composition was assessed by 16S rRNA sequencing of V3-V4 regions. Results: High gut microbiota diversity was positively associated with HDL-cholesterol (C) level and negatively associated with abdominal obesity, BMI, and dyslipidemia. According to selbal analysis, excessive representation of Prevotella spp. was positively associated with IDL-C and LDL-2-C. VLDL-C correlated with Ruminococcus_u/Faecalibacterium_prausnitzii balance. An unexpected positive relationship between LDL-C level and Bifidobacteriaceae_u/Christensenellaceae_u to Bifidobacterium_u balance was found, which may reflect the importance of the integrative microbiota assessment. Low microbiota diversity was associated with obesity, abdominal obesity and low HDL-C level. Conclusions: Gut microbiota imbalance may be one of the components involved in metabolic disorders. The balance of microorganisms and the microbiota diversity may play a more significant role in human health than individual bacterial genera.

[Telomere biology and metabolic disorders: the role of insulin resistance and type 2 diabetes].

BACKGROUND: Insulin resistance accelerates the aging process, but its speed depends on the individual characteristics of the metabolism. One of the reasons for the different aging rates in individuals with insulin resistance is the initially different "genetic protection" of cells, which many scientists associate with replicative cellular aging. AIMS: to study the relationship between the state of carbohydrate metabolism and markers of replicative cell aging in individuals with different sensitivity to insulin. MATERIALS AND METHODS: The observation study included 305 patients. The parameters of glucose metabolism and telomere biology were studied. RESULTS: The mean age of the patients was 51.5±13.3 years. Patients were divided into three groups depending on presence of insulin resistance: healthy, with insulin resistance and with type 2 diabetes. The mean age of healthy patients was 48.82±13.87 years, in insulin resistance group - 53.04±12.8, in 2 diabetes mellitus - 58.4±7.90. The median telomere length was 9.76. The median telomerase activity was 0.48. Both telomere length and telomerase activity progressively decrease as insulin resistance increases. In patients with diabetes, short telomere lengths and low telomerase activity predominated. The insulin resistance index has the greatest impact on the risk of detecting "short" telomeres. In patients with insulin resistance, an increase in glycated hemoglobin increases the likelihood of detecting short telomeres by 2.4 times, and in diabetes mellitus by 4.26 times, an increase in fasting plasma glucose by 90%, and an increase in HOMA-IR by 35%. An increase in insulin resistance increases the risk of detecting «low¼ telomerase activity by 53% and the risk of detecting «very low¼ telomerase activity by 92%. A decrease in synsulin resistance increases the chance of increasing telomerase activity to «very high¼ by 51%. CONCLUSION: Shorter telomeres are associated with more pronounced disorders of carbohydrate metabolism and a higher degree of insulin resistance. Further studies of metabolic status are necessary to personalize their lifestyle and treatment goals.

A Cross-Sectional Study of the Gut Microbiota Composition in Moscow Long-Livers.

The aim was to assess the gut microbiota of long-livers from Moscow. This study included two groups of patients who signed their consent to participate. The group of long-livers (LL) included 20 participants aged 97-100 years (4 men and 16 women). The second group included 22 participants aged 60-76 years (6 men) without clinical manifestations of chronic diseases (healthy elderly). Gut microbiota was studied by 16S rRNA sequencing. Long-livers underwent a complex geriatric assessment as well as expanded blood biochemistry. Gut microbiota composition in the cohorts was also compared with microbiome in long-livers from Japan and Italy. Russian long-livers' microbiome contained more beneficial bacteria than healthy elderly including Ruminococcaceae, Christensenellaceae, Lactobacillaceae families. Conditional pathogens like Veillonellaceae, Mogibacteriaceae, Alcaligenaceae, Peptococcaceae, Peptostreptococcaceae were more abundant in the healthy elderly. Compared with Italian and Japanese microbiome LL, the Russian LL appeared to be more similar to the Italian cohort. Bifidobacterium/Coprococcus and Faecalibacterium/Coprococcus balances were associated with femoral and carotid intima-media thickness, respectively. Bifidobacterium/Coriobacteriaceae balance was assessed with the folic acid level and Faecalibacterium/Coriobacteriaceae_u the with Mini Nutritional Assessment score. Long-livers' microbiome appeared to be unexpectedly balanced. The high representation of beneficial bacteria in long-livers may prevent them from low-grade inflammation and thus protect them from the development of atherosclerosis and other aging-associated conditions.

Gut Microbiota in Patients with Different Metabolic Statuses: Moscow Study.

The aim of this paper was to study gut microbiota composition in patients with different metabolic statuses. METHODS: 92 participants aged 25⁻76 years (26 of whom were men), with confirmed absence of cardiovascular and other chronic diseases (but with the possible presence of cardiovascular risk factors) were included. Carotid ultrasound examinations, 16S rRNA sequencing of stool samples and diet assessments were performed. Statistical analysis was performed using R programming language, 3.1.0. RESULTS: Enterotyping yielded two clusters differentiated by alpha-diversity. Intima-media thickness was higher in the cluster with lower diversity (adj. p < 0.001). Obesity was associated with higher Serratia (adj. p = 0.003) and Prevotella (adj. p < 0.0003) in relative abundance. Abdominal obesity was associated with higher abundance of Serratia (adj. p = 0.004) and Prevotella (adj. p = 0.0008) and lower levels of Oscillospira (adj. p = 0.0005). Glucose metabolism disturbances were associated with higher Blautia (adj. p = 0.0007) and Serratia (adj. p = 0.003) prevalence. Arterial hypertension was associated with high Blautia levels (adj. p = 0.002). The Blautia genus strongly correlated with low resistant starch consumption (adj. p = 0.007). A combination of high-fat diet and elevated Blautia levels was very common for diabetes mellitus type 2 patients (adj. p = 0.0001). CONCLUSION: The results show that there is a relationship between metabolic changes and higher representation of opportunistic pathogens and low diversity of gut microbiota even in apparently healthy participants.

Characteristics of healthy vascular ageing in pooled population-based cohort studies: the global Metabolic syndrome and Artery REsearch Consortium.

OBJECTIVE: Arterial ageing is characterized by increasing arterial stiffness as measured by pulse wave velocity (PWV). This process is enhanced in participants with early vascular ageing (EVA), but slowed in participants with healthy vascular ageing (HVA). We aimed to describe characteristics of EVA and HVA in a transcontinental study including 11 cohorts. METHODS: In all, 18 490 participants from the global MARE Consortium, free of cardiovascular disease, participated with data on PWV and cardiometabolic risk factors. We defined HVA as the lowest 10% and EVA as the highest 10% of the standardized PWV distribution, adjusted for age intervals. HVA individuals were compared with the 90% of non-HVA individuals with ANCOVA, adjusted for age, sex and hypertension. RESULTS: The 1723 HVA participants were at the same age as the rest of the population, more likely women (59.4 vs 57.0%), and with significantly lower levels of established cardiovascular risk factors (blood pressure, lipids, glucose). Similarly, the prevalence rate of obesity, diabetes mellitus, hypertension and the metabolic syndrome was lower in the HVA participants. In the presence of similar levels of cardiovascular risk factors, HVA participants in the 50-64 years of age group presented lower PWV 5.8 (SD 0.5) vs. 7.4 (1.4) m/s (P < 0.0001) than control individuals in the 35-49 years of age group, corresponding to an estimated difference in chronological age of 14 years. CONCLUSION: Participants with healthy vascular ageing (HVA), belonging to the lowest end of the PWV distribution, are in general characterized by an up to 14 years estimated younger biological (vascular) age than those with higher PWV values, and have lower levels of risk factors.

Markers of arterial health could serve as accurate non-invasive predictors of human biological and chronological age.

The decline in functional capacity is unavoidable consequence of the process of aging. While many anti-aging interventions have been proposed, clinical investigations into anti-aging medicine are limited by lack of reliable techniques for evaluating the rate of ageing. Here we present simple, accurate and cost-efficient techniques for estimation of human biological age, Male and Female Arterial Indices. We started with developing a model which accurately predicts chronological age. Using machine learning, we arrived on a set of four predictors, all of which reflect the functioning of the cardiovascular system. In Arterial Indices models, results of carotid artery duplex scan that show the thickness of the intima media complex and quantitatively describe the degree of stenosis are combined with pulse wave velocity and augmentation index measurements performed by applanation tonometry. In our cohort, the age of men was determined with MAE = 6.91 years (adjusted R-squared = 0.55), and the age of women with MAE = 5.87 years (adjusted R2 = 0.69). The Epsilon-accuracies of age-predicting models were at 86.5% and 80% for women and men, respectively. Substantially higher differences between the predicted age and the calendar age were noted for patients with Type 2 Diabetes Mellitus (T2D) as compared to non-T2D controls, indicating that the model could serve as a good approximation for an elusive biological age. Notably, in females with chronological and biological ages mismatching by 5 or more years, significant increases in in Framingham CVD scores and lower levels of IGF-1 were observed. Proposed Male and Female Arterial Indices derive biological age from the results of functional tests which do not require specialized laboratory equipment and, therefore, could be performed in hospitals and community health clinics.

Growth Hormone, Insulin-Like Growth Factor-1, Insulin Resistance, and Leukocyte Telomere Length as Determinants of Arterial Aging in Subjects Free of Cardiovascular Diseases.

Background: Increased arterial stiffness (AS), intima-media thickness (IMT), and the presence of atherosclerotic plaques (PP) have been considered as important aspects of vascular aging. It is well documented that the cardiovascular system is an important target organ for growth hormone (GH) and insulin-like growth factor (IGF)-1 in humans, and GH /IGF-1 deficiency significantly increases the risk for cardiovascular diseases (CVD). The telomere length of peripheral blood leukocytes (LTL) is a biomarker of cellular senescence and that has been proposed as an independent predictor of (CVD). The aim of this study is to determine the role of GH/IGF-1, LTL and their interaction cardiovascular risk factors (CVRF) in the vascular aging. Methods: The study group included 303 ambulatory participants free of known CVD (104 males and 199 females) with a mean age of 51.8 ± 13.3 years. All subjects had one or more CVRF [age, smoking, arterial hypertension, obesity, dyslipidemia, fasting hyperglycemia, insulin resistance-HOMA (homeostatic model assessment) >2.5, or high glycated hemoglobin]. The study sample was divided into the two groups according to age as "younger" (m ≤ 45 years, f ≤ 55 years) and "older" (m > 45 years, f > 55 years). IMT and PP were determined by ultrasonography, AS was determined by measuring the carotid-femoral pulse wave velocity (c-f PWV) using the SphygmoCor system (AtCor Medical). LTL was determined by PCR. Serum IGF-1 and GH concentrations we measured by immunochemiluminescence analysis. Results: Multiple linear regression analysis with adjustment for CVRF indicated that HOMA, GH, IGF-1, and LTL had an independent relationship with all the arterial wall parameters investigated in the younger group. In the model with c-f PWV as a dependent variable, p < 0.001 for HOMA, p = 0.03 for GH, and p = 0.004 for LTL. In the model with IMT as a dependent variable, p = 0.0001 for HOMA, p = 0.044 for GH, and p = 0.004 for IGF-1. In the model with the number of plaques as a dependent variable, p = 0.0001 for HOMA, and p = 0.045 for IGF-1. In the older group, there were no independent significant associations between GH/IGF-1, LTL, HOMA, and arterial wall characteristics. Conclusions: GH/IGF-1, IR, HOMA, and LTL were the important parameters of arterial aging in younger healthy participants.

Atorvastatin Therapy Modulates Telomerase Activity in Patients Free of Atherosclerotic Cardiovascular Diseases.

Background: Telomerase activity (TA) is considered as the biomarker for cardiovascular aging and cardiovascular diseases (CVDs). Recent studies suggest a link between statins and telomere biology that may be explained by anti-inflammatory actions of statins and their positive effect on TA. Until now, this effect has not been investigated in prospective randomized studies. We hypothesized that 12 months of atorvastatin therapy increased TA in peripheral blood mononuclear cells. Methods: In a randomized, placebo-controlled study 100 hypercholesterolemic patients, aged 35-75 years, free of known CVDs and diabetes mellitus type 2 received 20 mg of atorvastatin daily or placebo for 12 months. TA was measured by quantitative polymerase chain reaction. Results: At study end, 82 patients had sufficient peripheral blood mononuclear cells needed for longitudinal analysis. TA expressed as natural logarithms changed from 0.46 ± 0.05 to 0.68 ± 0.06 (p = 0.004) in the atorvastatin group and from 0.67 ± 0.06 to 0.60 ± 0.07 (p = 0.477) in the control group. In multiple regression analysis, atorvastatin therapy was the only independent predictor (p = 0.05) of the changes in TA independently of markers of chronic inflammation and oxidative stress. Atorvastatin therapy was associated with increases in interleukin-6 within the normal range and a tendency toward reduction in blood urea. Conclusion: These initial observations suggest atorvastatin can act as telomerase activator and potentially as effective geroprotector. Trial registration: The trial was registered in ISRCTN registry ISRCTN55050065.

Association of Insulin Resistance, Arterial Stiffness and Telomere Length in Adults Free of Cardiovascular Diseases.

BACKGROUND: Chronic inflammation and oxidative stress might be considered the key mechanisms of aging. Insulin resistance (IR) is a phenomenon related to inflammatory and oxidative stress. We tested the hypothesis that IR may be associated with cellular senescence, as measured by leukocyte telomere length (LTL), and arterial stiffness (core feature of arterial aging), as measured by carotid-femoral pulse wave velocity (c-f PWV). METHODS: The study group included 303 subjects, mean age 51.8 ±13.3 years, free of known cardiovascular diseases and regular drug consumption. For each patient, blood pressure was measured, blood samples were available for biochemical parameters, and LTL was analyzed by real time q PCR. C-f PWV was measured with the help of SphygmoCor. SAS 9.1 was used for statistical analysis. RESULTS: Through multiple linear regression analysis, c-f PWV is independently and positively associated with age (p = 0.0001) and the homeostasis model assessment of insulin resistance (HOMA-IR; p = 0.0001) and independently negatively associated with LTL (p = 0.0378). HOMA-IR seems to have a stronger influence than SBP on arterial stiffness. In all subjects, age, HOMA-IR, LTL, and SBP predicted 32% of the variance in c-f PWV. LTL was inversely associated with HOMA-IR (p = 0.0001) and age (p = 0.0001). In all subjects, HOMA-IR, age, sex, and SBP predicted 16% of the variance in LTL. CONCLUSIONS: These data suggest that IR is associated with cell senescence and arterial aging and could, therefore, become the main target in preventing accelerated arterial aging, besides blood pressure control. Research in telomere biology may reveal new ways of estimating cardiovascular aging and risk.

Age-Related Left Ventricular Changes and Their Association with Leukocyte Telomere Length in Healthy People.

INTRODUCTION: With advancing age the left ventricle (LV) undergoes structural and functional changes, thereby creating the substrate for the development of diseases. One possible mechanism of the ageing heart is a cellular senescence. Leukocyte telomere length (LTL) is a marker of replicative ageing. The purpose of this study was to evaluate the structure and function of the LV in people of different ages free of cardiovascular diseases (CVD) and regular drug medication and to assess their relationship with LTL. We hypothesized that age-related changes in LV myocardium are associated with telomere length. METHODS: The study population consisted of 150 healthy, non-obese volunteers aged 28 to 78 years without history of CVD, significant deviations by 12-lead electrocardiogram and negative exercise test (treadmill stress test). All the participants underwent standardized transthoracic echocardiography using an available system (iE33; Philips). The LTL was measured by real-time quantitative polymerase chain reaction. We determined the relative ratio of telomere repeat copy number (T) to single-copy gene copy number (S). RESULTS: In the older people there was a higher wall thickness than in the younger (1.03 ± 0.09 vs. 0.88 ± 0.10, p<0.01), whereas LV mass index was comparable between them (85.8 ± 15.40 vs. 83.1 ± 11.8, p = 0.20). There was a decrease in LV dimensions with advancing age (p<0.001). Older subjects had impairment in LV relaxation. LTL was associated with decreased E/A, Em/Am ratio (ß = -0.323, p = 0.0001) after adjusting for age, sex and risk factors. There is no relation between the LTL and the structure of LV. CONCLUSIONS: Our data suggest that the ageing process leads to changes in LV structure and diastolic function and is linked with a phenotype of concentric LV remodeling. Telomere attrition is associated with age-related LV diastolic dysfunction. Telomere length appears to be a biomarker of myocardial ageing.