76 research outputs found
Leukocyte Telomere Length in the Neonatal Offspring of Mothers with Gestational and Pre-Gestational Diabetes
No full textTelomeres undergo shortening with cell division, accelerated by increased oxidative stress. We aimed to demonstrate shortened telomeres in the offspring of mothers who have diabetes as a consequence of exposure to increased oxidative stress during intrauterine development.We examined the level of glycaemia (glucose, HbA1c, fructosamine), oxidative stress (lipid peroxidation) and the levels of antioxidant enzymes (Superoxide dismutase (SOD) and Selenium dependent glutathione peroxidase) and correlate these findings with mean telomere length (TL) in maternal and foetal blood in groups of pregnant women with pre-gestational diabetes (PGD), gestational diabetes (GD) and a euglycaemic control group.Foetal and maternal glucose, maternal HbA1c, and foetal insulin and C-peptide were higher in the PGD group with the GD group being intermediate. Markers of oxidative stress did not vary between groups with the exception of foetal SOD activity that was highest in the GD group. There were no detectable differences in maternal or foetal TL between study groups. An exploratory analysis looking at correlations between glycaemic and oxidative stress parameters and TL revealed a negative correlation between maternal and foetal glucose and TL across the whole study population. This relationship held for the short-term marker of glycaemic control, fructosamine.We were unable to show significant telomere shortening in the offspring of mothers with PGD or GD. Exploratory analysis revealed a relationship between foetal TL and short-term glycaemia particularly in PGD. It is possible that increased telomerase activity can compensate for long-term increased oxidative stress but not for short-term dysglycaemia
Longer leukocyte telomeres are associated with ultra-endurance exercise independent of cardiovascular risk factors.
No full textTelomere length is recognized as a marker of biological age, and shorter mean leukocyte telomere length is associated with increased risk of cardiovascular disease. It is unclear whether repeated exposure to ultra-endurance aerobic exercise is beneficial or detrimental in the long-term and whether it attenuates biological aging. We quantified 67 ultra-marathon runners' and 56 apparently healthy males' leukocyte telomere length (T/S ratio) using real-time quantitative PCR. The ultra-marathon runners had 11% longer telomeres (T/S ratio) than controls (ultra-marathon runners: T/S ratio = 3.5±0.68, controls: T/S ratio = 3.1±0.41; β = 0.40, SE = 0.10, P = 1.4×10(-4)) in age-adjusted analysis. The difference remained statistically significant after adjustment for cardiovascular risk factors (P = 2.2×10(-4)). The magnitude of this association translates into 16.2±0.26 years difference in biological age and approximately 324-648bp difference in leukocyte telomere length between ultra-marathon runners and healthy controls. Neither traditional cardiovascular risk factors nor markers of inflammation/adhesion molecules explained the difference in leukocyte telomere length between ultra-marathon runners and controls. Taken together these data suggest that regular engagement in ultra-endurance aerobic exercise attenuates cellular aging
Mediterranean diet and the hallmarks of ageing
No full textAgeing is a multifactorial process associated with reduced function and increased risk of morbidity and mortality. Recently, nine cellular and molecular hallmarks of ageing have been identified, which characterise the ageing process, and collectively, may be key determinants of the ageing trajectory. These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. Healthier dietary patterns reduce the risk of age-related diseases and increase longevity and may influence positively one or more of these hallmarks. The Mediterranean dietary pattern (MedDiet) is a plant-based eating pattern that was typical of countries such as Greece, Spain, and Italy pre-globalisation of the food system and which is associated with better health during ageing. Here we review the potential effects of a MedDiet on each of the nine hallmarks of ageing, and provide evidence that the MedDiet as a whole, or individual elements of this dietary pattern, may influence each hallmark positively—effects which may contribute to the beneficial effects of this dietary pattern on age-related disease risk and longevity. We also highlight potential avenues for future research
A mechanistic investigation into candidate markers of telomere-induced senescence in normal human epidermal keratinocytes
No full textPhDTelomere dysfunction is one mechanism of cellular and tissue ageing.
Dysfunctional telomeres in fibroblasts are recognised as DNA double-strand
breaks (DSBs) and trigger the DNA damage pathway of senescence. However,
telomere uncapping in normal human epidermal keratinocytes, via expression
of the dominant negative mutant of the telomere repeat-binding factor 2
(TRF2!B!M), resulted in a senescent-like arrest without a significant DNA damage
response (DDR). This suggests that either keratinocytes are unusually sensitive to
telomere uncapping and the low DDR is sufficient to induce senescence or that
dysfunctional telomeres may also be signalled through an alternative pathway.
Subsequent analysis revealed genes HIST2H2BE, ICEBERG, S100A7 and HOPX as
potential markers for telomere dysfunction-induced senescence (TDIS) since
they were induced by telomere uncapping and seemed to be regulated by
telomerase. The aim of this project was to assess the specificity of these
candidate markers for TDIS and to select the most promising for use as a
biomarker. To this end, keratinocytes were exposed to doses of ionising
radiation, capable of generating transient or permanent damage to the DNA,
or transduced with retroviral constructs expressing p14ARF, p16INK4a, p53 or
TRF2!B!M and the gene expression levels of the candidates assessed after a
recovery period or at the early stages of senescence. Whilst S100A7, HOPX or
ICEBERG were not induced by a transient or persistent DDR or by p16INK4a,
ICEBERG and HOPX were induced by p53 and p14ARF when these were
ectopically expressed at higher levels. Thus, S100A7 seems to be the most
specific early marker for telomere dysfunction in keratinocytes since it was
selectively induced by telomere uncapping via expression of TRF2!B!M and not
by DSBs or by over expression of p14ARF, p53 or p16INK4a. S100A7 may have the
potential to identify cells with telomere dysfunction in human epithelia and
body fluids.
iiiAge U
Where you live may make you old: The association between perceived poor neighborhood quality and leukocyte telomere length
No full textBackground: Strong evidence supports that living in disadvantaged neighborhoods has direct unfavorable impact on mental and physical health. However, whether it also has direct impact on cellular health is largely unknown. Thus we examined whether neighborhood quality was associated with leukocyte telomere length, an indicator of cellular aging. Methods: In May 2014, we extracted and analyzed baseline data from the Netherlands Study of Depression and Anxiety (NESDA), a large epidemiological study of individuals age between 18-65 years (n=2902). Telomere length was determined using quantitative polymerase chain reaction. Neighborhood quality was assessed using modified measures of perceived neighborhood disorder, fear of crime, and noise. We used multivariable linear regression models to examine association between perceived neighborhood quality and telomere length with comprehensive adjustment for individual and community characteristics related to socioeconomic and demographic status, urbanization level, mental and physical health, and lifestyle. Results: Compared to individuals who reported good neighborhood quality, the mean telomere length of those who reported moderate neighborhood quality was approximately 69 base pair shorter (β =-69.33, 95% CI: -119.49, -19.17, p= 0.007), and that of those who reported poor neighborhood quality were 174 base pair shorter (β =-173.80, 95% CI: -298.80, -49.01, p=0.006). For illustrative purposes, one could extrapolate these outcomes to 8.7 and 11.9 years in chronological age, respectively. Conclusion: We have established an association between perceived neighborhood quality and cellular aging over and above a range of individual attributes. Biological aging processes may be impacted by socioeconomic milieu
DNA damage in telomeres and mitochondria during cellular senescence: Is there a connection?
No full textCellular senescence is the ultimate and irreversible loss of replicative capacity occurring in primary somatic cell culture. It is triggered as a stereotypic response to unrepaired nuclear DNA damage or to uncapped telomeres. In addition to a direct role of nuclear DNA double-strand breaks as inducer of a DNA damage response, two more subtle types of DNA damage induced by physiological levels of reactive oxygen species (ROS) can have a significant impact on cellular senescence: Firstly, it has been established that telomere shortening, which is the major contributor to telomere uncapping, is stress dependent and largely caused by a telomere-specific DNA single-strand break repair inefficiency. Secondly, mitochondrial DNA (mtDNA) damage is closely interrelated with mitochondrial ROS production, and this might also play a causal role for cellular senescence. Improvement of mitochondrial function results in less telomeric damage and slower telomere shortening, while telomere-dependent growth arrest is associated with increased mitochondrial dysfunction. Moreover, telomerase, the enzyme complex that is known to re-elongate shortened telomeres, also appears to have functions independent of telomeres that protect against oxidative stress. Together, these data suggest a self-amplifying cycle between mitochondrial and telomeric DNA damage during cellular senescence. \ua9 2007 The Author(s)
An iPSC Patient Specific Model of CFH (Y402H) Polymorphism Displays Characteristic Features of AMD and Indicates a Beneficial Role for UV Light Exposure
No full textAge related macular degeneration (AMD) is the most common cause of blindness, accounting for 8.7% of all blindness globally. Vision loss is caused ultimately by apoptosis of the retinal pigment epithelium (RPE) and overlying photoreceptors. Treatments are evolving for the wet form of the disease, however these do not exist for the dry form. Complement factor H (CFH) polymorphism in exon 9 (Y402H) has shown a strong association with susceptibility to AMD resulting in complement activation, recruitment of phagocytes, retinal pigment epithelium (RPE) damage and visual decline. We have derived and characterised induced pluripotent stem cell (iPSCs) lines from two patients without AMD and low risk genotype and two patients with advanced AMD and high risk genotype and generated RPE cells that show local secretion of several proteins involved in the complement pathway including factor H (FH), factor I (FI) and factor H like 1 (FHL-1). The iPSC RPE cells derived from high risk patients mimic several key features of AMD including increased inflammation and cellular stress, accumulation of lipid droplets, impaired autophagy and deposition of “drüsen” like deposits. The low and high risk RPE cells respond differently to intermittent exposure to UV light which leads to an improvement in cellular and functional phenotype only in the high risk AMD-RPE cells. Taken together our data indicate that the patient specific iPSC model provides a robust platform for understanding the role of complement activation in AMD, evaluating new therapies based on complement modulation and drug testing
DNA damage in telomeres and mitochondria during cellular senescence: is there a connection?
No full textRate of telomere shortening and cardiovascular damage: a longitudinal study in the 1946 British Birth Cohort.
No full textCross-sectional studies reported associations between short leucocyte telomere length (LTL) and measures of vascular and cardiac damage. However, the contribution of LTL dynamics to the age-related process of cardiovascular (CV) remodelling remains unknown. In this study, we explored whether the rate of LTL shortening can predict CV phenotypes over 10-year follow-up and the influence of established CV risk factors on this relationship
Mediterranean diet and the hallmarks of ageing
No full textAgeing is a multifactorial process associated with reduced function and increased risk of morbidity and mortality. Recently, nine cellular and molecular hallmarks of ageing have been identified, which characterise the ageing process and, collectively, may be key determinants of the ageing trajectory. These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Healthier dietary patterns reduce the risk of age-related diseases and increase longevity and may influence positively one or more of these hallmarks. The Mediterranean dietary pattern (MedDiet) is a plant-based eating pattern that was typical of countries such as Greece, Spain, and Italy pre-globalisation of the food system and which is associated with better health during ageing. Here we review the potential effects of a MedDiet on each of the nine hallmarks of ageing, and provide evidence that the MedDiet as a whole, or individual elements of this dietary pattern, may influence each hallmark positively – effects which may contribute to the beneficial effects of this dietary pattern on age-related disease risk and longevity. We also highlight potential avenues for future research
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