Biological Age Predictors: The Status Quo and Future Trends.

There is no single universal biomarker yet to estimate overall health status and longevity prospects. Moreover, a consensual approach to the very concept of aging and the means of its assessment are yet to be developed. Markers of aging could facilitate effective health control, more accurate life expectancy estimates, and improved health and quality of life. Clinicians routinely use several indicators that could be biomarkers of aging. Duly validated in a large cohort, models based on a combination of these markers could provide a highly accurate assessment of biological age and the pace of aging. Biological aging is a complex characteristic of chronological age (usually), health-to-age concordance, and medically estimated life expectancy. This study is a review of the most promising techniques that could soon be used in routine clinical practice. Two main selection criteria were applied: a sufficient sample size and reliability based on validation. The selected biological age calculators were grouped according to the type of biomarker used: (1) standard clinical and laboratory markers; (2) molecular markers; and (3) epigenetic markers. The most accurate were the calculators, which factored in a variety of biomarkers. Despite their demonstrated effectiveness, most of them require further improvement and cannot yet be considered for use in standard clinical practice. To illustrate their clinical application, we reviewed their use during the COVID-19 pandemic.

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.

GWAS reveals genetic basis of a predisposition to severe COVID-19 through in silico modeling of the FYCO1 protein.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is heavily reliant on its natural ability to "hack" the host's genetic and biological pathways. The genetic susceptibility of the host is a key factor underlying the severity of the disease. Polygenic risk scores are essential for risk assessment, risk stratification, and the prevention of adverse outcomes. In this study, we aimed to assess and analyze the genetic predisposition to severe COVID-19 in a large representative sample of the Russian population as well as to build a reliable but simple polygenic risk score model with a lower margin of error. Another important goal was to learn more about the pathogenesis of severe COVID-19. We examined the tertiary structure of the FYCO1 protein, the only gene with mutations in its coding region and discovered changes in the coiled-coil domain. Our findings suggest that FYCO1 may accelerate viral intracellular replication and excessive exocytosis and may contribute to an increased risk of severe COVID-19. We found significant associations between COVID-19 and LZTFL1, FYCO1, XCR1, CCR9, TMLHE-AS1, and SCYL2 at 3p21.31. Our findings further demonstrate the polymorphic nature of the severe COVID-19 phenotype.

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.

Genetics of psycho-emotional well-being: genome-wide association study and polygenic risk score analysis.

Background: Psycho-emotional well-being is essential for living a life of satisfaction and fulfillment. However, depression and anxiety have become the leading mental health issues worldwide, according to the World Health Organization. Both disorders have been linked to stress and other psychological factors. Their genetic basis remains understudied. Methods: In 2020-2021, the psycho-emotional well-being of 30,063 Russians with no known psychiatric history was assessed using the Hospital Anxiety and Depression Scale (HADS) for general mental health and the HADS subscale A (anxiety) for anxiety. Following the original instructions, an anxiety score of ≥11 points was used as the anxiety threshold. A genome-wide association study was performed to find associations between anxiety and HADS/HADS-A scores using linear and logistic regressions based on HADS/HADS-A scores as binary and continuous variables, respectively. In addition, the links between anxiety, sociodemographic factors (such as age, sex, and employment), lifestyle (such as physical activity, sleep duration, and smoking), and markers of caffeine and alcohol metabolism were analyzed. To assess the risk of anxiety, polygenic risk score modeling was carried out using open-access software and principal component analysis (PCA) to simplify the calculations (ROC AUC = 89.4 ± 2.2% on the test set). Results: There was a strong positive association between HADS/HADS-A scores and sociodemographic factors and lifestyle. New single-nucleotide polymorphisms (SNPs) with genome-wide significance were discovered, which had not been associated with anxiety or other stress-related conditions but were located in genes previously associated with bipolar disorder, schizophrenia, or emotional instability. The CACNA1C variant rs1205787230 was associated with clinical anxiety (a HADS-A score of ≥11 points). There was an association between anxiety levels (HADS-A scores) and genes involved in the activity of excitatory neurotransmitters: PTPRN2 (rs3857647), DLGAP4 (rs8114927), and STK24 (rs9517326). Conclusion: Our results suggest that calcium channels and monoamine neurotransmitters, as well as SNPs in genes directly or indirectly affecting neurogenesis and synaptic functions, may be involved in the development of increased anxiety. The role of some non-genetic factors and the clinical significance of physiological markers such as lifestyle were also demonstrated.

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).

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.

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.

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.

Association between the gut microbiota and diet: Fetal life, early childhood, and further life.

Gut microbiota establishment and further microbiota shifts are very important for maintaining host health throughout life. There are some factors, including genetics, the mother's health and diet, delivery mode, breast or formula feeding, that may influence the gut microbiota. By the end of approximately the first 3 y of life, the gut microbiota becomes an adult-like stable system. Once established, 60 to 70% of the microbiota composition remains stable throughout life, but 30 to 40% can be altered by changes in the diet and other factors such as physical activity, lifestyle, bacterial infections, and antibiotic or surgical treatment. Diet-related factors that influence the gut microbiota in people of all ages are of great interest. Nutrition may have therapeutic success in gut microbiota correction. This review describes current evidence concerning the links between gut microbiota composition and dietary patterns throughout life.

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.