Effects of succinic acid on dermal fibroblasts during cultivation under extremely hypoxic conditions.

Succinate is one of the most important raw materials in the energy-producing cycle, enabling a 'shortcut' route for ATP production via oxidative metabolism. Fumarate is produced from succinate by the oxygen-dependent succinate dehydrogenase. In this study we investigated the influence of different succinic acid concentrations on the process of cellular senescence under normal and hypoxic conditions. The most promising doses were chosen by using a cell viability test (0.2-1.5 mM). After the long-term cultivation it was shown that there was no significant difference in senescence ß-galactosidase expression between samples with variable concentrations of succinate. Despite this fact, large differences in expression levels of senescence and pluripotency markers were found between the samples depending on the oxygen level and concentration of succinic acid.

Association of Telomere Length with Cognitive Impairment.

Telomere attrition is attributed to Alzheimer's disease (AD), major depressive disorder, stress levels, physical inactivity, short sleep duration, and reduced educational abilities. In this article, we tried to assess the association between the telomere length in peripheral blood leukocytes and level of cognitive impairment and its dependence on age and sex. Healthy subjects and patients with amnestic mild cognitive impairment (aMCI) and different AD stages were recruited in the study. All patients were assessed by the same standard diagnostic procedure, including neurological examination-Mini-Mental State Examination (MMSE). Blood samples from 66 subjects (18 men and 48 women, mean age 71.2 ± 0.56 years) were collected for DNA extraction from peripheral mononuclear cells (PBMC). Relative telomere length (RTL) was measured by monochrome multiplex polymerase chain reaction. The data obtained in the study indicate that RTL in PBMCs has a statistically significant association with MMSE score (p < 0.02). Moreover, the sex-specific difference was observed for the association between telomere length and various parameters of MMSE. Also, it has been found that a decrease in RTL by one unit is associated with an increase in the odds to get AD at a ratio of 2.54 (95% CI, 1.25 to 5.17). The results obtained in this research are in coherence with other studies that telomere length may be a valuable biomarker of cognitive decline. However, the potential need for longitudinal studies of telomere length, in order to estimate the influence of hereditary and environmental factors, remains.

Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives.

Telomere shortening is a well-known hallmark of both cellular senescence and organismal aging. An accelerated rate of telomere attrition is also a common feature of age-related diseases. Therefore, telomere length (TL) has been recognized for a long time as one of the best biomarkers of aging. Recent research findings, however, indicate that TL per se can only allow a rough estimate of aging rate and can hardly be regarded as a clinically important risk marker for age-related pathologies and mortality. Evidence is obtained that other indicators such as certain immune parameters, indices of epigenetic age, etc., could be stronger predictors of the health status and the risk of chronic disease. However, despite these issues and limitations, TL remains to be very informative marker in accessing the biological age when used along with other markers such as indices of homeostatic dysregulation, frailty index, epigenetic clock, etc. This review article is aimed at describing the current state of the art in the field and at discussing recent research findings and divergent viewpoints regarding the usefulness of leukocyte TL for estimating the human biological age.

Telomere length in different metabolic categories: Clinical associations and modification potential.

IMPACT STATEMENT: Metabolic disorders are known to be associated with accelerated telomere attrition. Their pathophysiological heterogeneity suggests the importance of multiple tests in examining these associations. However, oral glucose tolerance test (OGTT) has rarely been performed in such studies to date. There are few studies aimed at determining leukocyte telomere length (LTL) in different categories of impaired glucose tolerance (IGT), and those that do exist do not take into account the impaired fasting glucose (IFG)/IGT categorization. Therefore, we believe our study, when the OGTT was used, is important to the field. This testing made it possible to determine whether LTLs are associated with glucose levels in different hyperglycemic categories. Our data indicate that relationships between LTLs and IFG/IGT levels are not the same. This distinction can potentially be used in categorization of metabolic disorders and in determining the effectiveness of interventions aimed at treating diabetes and other metabolic abnormalities.

Additional Impact of Glucose Tolerance on Telomere Length in Persons With and Without Metabolic Syndrome in the Elderly Ukraine Population.

Rationale: Association between different components of metabolic syndrome and the rate of age-related telomere shortening was reported repeatedly, although some findings are inconsistent across studies, suggesting the need for further research on the topic. In the present study, we examined relationships between different components of metabolic syndrome (MetS); glucose tolerance reflected in 2-h post-load plasma glucose (2hPG) levels and age on the leukocyte telomere length (LTL) in Ukraine population. Methods: The study was conducted on the 115 adult individuals residing in the Kyiv region (Ukraine). Among them, 79 were diagnosed with MetS according to the International Diabetes Federation definition. LTL were determined by a qPCR-based method. Multivariate logistic regression (MLR) and artificial neural networks (ANN) modeling were used for the analysis of the results. ROC-analysis was also performed to compare the predictively values of this models. Results: MetS was associated with a high (OR = 3.0 CI 1.3-6.7; p = 0.01) risk of having shorter telomeres that remained significant after adjusting for age, gender and 2hPG levels. Fasting plasma glucose (FPG) levels and other MetS components did not affect the magnitude of the relationship and did not reveal the independent influence of these factors. The level of 2hPG in turn, demonstrated a significant relationship (OR = 1.3 CI 1.0-1.6 per 1 mmol/l; p = 0.04) with LTL regardless of the presence of MetS. The non-linearity of the interactions between age, gender and 2hPG level was revealed by neural network modeling (AUC = 0.76 CI 0.68-0.84). Conclusion: Our study found that impaired glucose tolerance, but not FPG levels, affected the association between LTL and MetS, which may be also indicative for pathophysiological differences in these hyperglycemia categories. 2hPG levels can provide an opportunity for a more accurate diagnostics of MetS and for evaluating the rate of aging in patients with MetS. Further research, however, is needed to verify this assumption.

Dynamics of Telomere Length and Telomerase Activity in the Human Fetal Liver at 5-12 Weeks of Gestation.

Fetal stem cell- (FSC-) based therapy is a promising treatment option for many diseases. The differentiation potential of FSCs is greater than that in adult stem cells, and they are more tissue-specific and have lower immunogenicity and better intrinsic homing than embryonic ones. Embryonic stem cells have higher proliferative potential than FSCs but can cause teratomas. Therefore, an evaluation of this potential represents an important biomedical challenge. Since regulation of telomere length (TL) is one mechanism governing cellular proliferation, TL is a useful surrogate marker for cell replicative potential. The prenatal dynamics of TL, however, has never been comprehensively studied. In the present study, dynamics of TL and telomerase activity in the human fetal liver during 5-12 weeks of gestation is examined. Both TL and telomerase activity were positively correlated with week of gestation. For both parameters studied, the trend to increase was evident up to 10th week of gestation. After that, they reached a plateau and remained stable. These findings indicate that telomerase activity remains high during the fetal stage, suggesting high replicative capacity of FSCs and their considerable potential for transplantation therapies. These findings, however, are preliminary only due to small sample size and require further evaluation.

Hyperglycemia attenuates the association between telomere length and age in Ukrainian population.

Diabetes-related conditions such as chronic hyperglycemia and related oxidative stress and inflammation were repeatedly associated with accelerated telomere shortening in epidemiological studies, although some findings are inconsistent. In present study, we aimed to assess the impact of disturbances in glucose metabolism on association between age and leukocyte telomere length (LTL) in the Ukrainian population. The study was conducted on the 119 adult subjects aged between 43 and 87 years residing in the Kyiv region, Ukraine. LTL was determined by a quantitative PCR-based method. LTL was negatively correlated with the measure of abdominal obesity such as waist-hip ratio, as well as with both fasting plasma glucose (FPG) and two-hour post-load glucose (2hPG) levels. Consistently with previous studies, a significant negative association between LTL and age was observed in individuals with normal (<5.6 mmol/L) FPG levels. Unexpectedly, however, no association was found in subjects with impaired glucose metabolism assessed by abnormal FPG or/and 2hPG levels. No association between LTL and age was observed in a logistic regression model; the association between LTL and age became significant after adjusting for FPG level. In the FPG-adjusted model, 1.6-time lower odds to have long telomere length were indicated for each 10 years increase in age. We hypothesize that the attenuation of association between LTL and age in hyperglycemic persons can likely be attributed to the interaction of multidirectional processes determining this relationship.

Leukocyte telomere length is inversely associated with post-load but not with fasting plasma glucose levels.

Type 2 diabetes mellitus is characterized by shorter leukocyte telomere length, but the relationship between leukocyte telomere length and type 2 diabetes mellitus development is rather questioned. Fasting and post-load glycaemia associated with different types of insulin resistance and their relation with leukocyte telomere length remains unknown. We compared leukocyte telomere length and fasting or post-load glucose levels in persons who do not receive glucose lowering treatment. For 82 randomly selected rural residents of Ukraine, aged 45+, not previously diagnosed with type 2 diabetes mellitus, the WHO oral glucose tolerance test and anthropometric measurements were performed. Leukocyte telomere length was measured by standardized method of quantitative monochrome multiplex polymerase chain reaction in real time. Spearman's or Pearson's rank correlation was used for correlation analysis between fasting plasma glucose or 2-h post-load plasma glucose levels and leukocyte telomere length. Logistical regression models were used to evaluate risks of finding short or long telomeres associated with fasting plasma glucose or 2-h post-load plasma glucose levels. No association of fasting plasma glucose and leukocyte telomere length was revealed, whereas 2-h post-load plasma glucose levels demonstrated a negative correlation ( P < 0.01) with leukocyte telomere length. Waist circumference and systolic blood pressure were negatively related ( P = 0.03) with leukocyte telomere length in men. Oral glucose tolerance test result-based glycemic categories did not show differences between mean leukocyte telomere length in categories of normal fasting plasma glucose and 2-h post-load plasma glucose (NGT, n = 33); diabetes mellitus (DM), n = 18 and impaired fasting glucose/tolerance (IFG/IGT, n = 31) levels. A correlation relationship between leukocyte telomere length and 2-h post-load plasma glucose level in NGT; IFG/IGT and DM groups ( P = 0.027; 0.029 and 0.049, respectively) was revealed; the association between leukocyte telomere length and fasting plasma glucose was confirmed in DM group only ( P = 0.009). Increase of 2-h post-load plasma glucose (but not fasting plasma glucose) level improves the chances of revealing short telomeres: OR 1.52 (95% CI 1.04-2.22), P = 0.03. After the adjustment for age, gender, waist circumference, systolic blood pressure, and fasting plasma glucose, these phenomena remain significant. We conclude that 2-h post-load plasma glucose but not fasting plasma glucose is inversely associated with leukocyte telomere length. Impact statement • Contradictory epidemiologic data have been obtained about the link between the leucocyte telomere length (LTL) and diabetes. Type 2 diabetes (T2D) is likely to be pathophysiologically heterogeneous, but comparison of the association of LTL separately with fasting plasma glucose (FPG) and 2-h post-load plasma glucose (2hPG) levels has not been done before. Thus, the study of LTL changes associated with different types of hyperglycaemia, that largely determine the heterogenity of T2D is important. • In a population-based study of rural Ukrainians, we were the first to demonstrate that the increase of 2hPG (but not FPG) level increases the chances of revealing short telomeres. • The obtained data can help to clarify the relationship between the LTL shortening and different conditions of the insulin resistance (mainly liver resistance in high FPG and mostly muscle and adipose tissue resistance in high 2hPG).