Telomeres and their role in aging and longevity.

Telomeres are DNA-protein structures that form protective caps at the end of eukaryotic chromosomes. They constitute the safeguards of chromosome degradation and are responsible for maintaining genomic integrity. The multifactorial nature of telomere length (TL) regulation increases the perplexity of studies in the field. TL is characterized by a high variability among individuals (birth and later life) and among species but it is unknown whether this is associated with their lifespan potential. TL is also highly heritable, longer in women than in men; it is highly variable between tissues and organs and inversely related to chronological age. Accelerated telomere loss has been associated with many chronic diseases of aging. Premature aging or cellular senescence, seen in early life, through increased oxidative stress and DNA damage to telomeric ends may be initiators of processes related to these diseases. During the recent decade, research around telomere biology has rapidly expanded due to its dynamic involvement in aging and longevity. However, longevity is not necessarily an indication of disability-free aging. There is substantial scientific disagreement and controversial results, regarding even the basic nature of aging and the path to longevity. We review the current evidence linking telomere biology to aging processes and mechanisms leading to longevity.

Influence of the AGTR1 A1166C genotype on the progression of arterial stiffness: A 16-year longitudinal study.

BACKGROUND: We examined the influence of the AGTR1 A1166C genotype on the 16-year evolution of pulse wave velocity (PWV) in a middle-aged population. In a cross-sectional study, we reported that the presence of the AGTR1 1166C allele was associated with higher aortic stiffness compared with the AGTR1 1166AA genotype. METHODS: The study was conducted in 259 subjects who underwent 3 health check-ups over 16 years at the Centre IPC-Paris: an initial visit in 1992-1993, an intermediate visit in 1998-1999, and a final visit in 2007-2008. Aortic stiffness was assessed during the 3 visits by measuring carotid-femoral PWV. AGTR1 A1166C polymorphism was assayed by allele-specific oligonucleotide hybridization. RESULTS: AGTR1 1166C allele carriers (AC + CC genotypes) had a 35% more pronounced increase in PWV over this 16-year period when compared with the AGTR1 1166AA subjects (3.01 ± 0.32 vs. 1.92 ± 0.23 m/s; P < 0.001). This increase remained significant after adjustment for age, sex, initial PWV values, and changes in blood pressure (+37%; P < 0.05). The genotype-related differences in PWV were only observed at the last visit (i.e., later in life, after the age of 55 years). The effects of this genotype on PWV were not related to the presence of antihypertensive treatment. CONCLUSIONS: This is the first long-term longitudinal study indicating that AT1 1166C carriers are at increased risk of pronounced arterial stiffening during aging especially after the age of 55.

Fatty acids impair endothelium-dependent vasorelaxation: a link between obesity and arterial stiffness in very old Zucker rats.

To analyze age-related interactions between obesity, its associated metabolic disorders, and macrocirculation, we studied large artery stiffness and fatty acid responsiveness in lean and obese Zucker rats, aged 25 (adult) and 80 weeks (very old). Systolic arterial pressure was higher in old obese than in old lean rats (178 ± 10 vs 134 ± 8 mmHg, respectively). Carotid elastic modulus-wall stress curves showed increased age-dependent arterial stiffening, which was greater in obese animals. Old obese exhibited endothelial dysfunction with increased systemic oxidative stress. Adult obese had elevated plasma free fatty acid levels (1,866 ± 177 vs 310 ± 34 µg/µL in lean animals). In old obese, linoleate and palmitate increased contractility to phenylephrine and reduced relaxation to acetylcholine. Thus, obesity at 25 weeks appears to trigger accelerated arterial aging observed at 80 weeks. The early increase in free fatty acids may be a key effector in the severe arterial stiffness of the aged obese Zucker model.

Klotho KL-VS genotype is involved in blood pressure regulation.

BACKGROUND AND AIMS: Genome-wide linkage analysis studies reported the importance of the long arm of chromosome 13 in systolic blood pressure regulation. Therefore, isolating a genetic variant related to this chromosomal region could be challenging. Klotho KL-VS allele is located on this chromosomal region and its relationships with cardio-vascular risk factors need extensive investigations. The aim of the present study is to examine whether the klotho KL-VS genotype is associated with cardio-vascular risk factors, more particularly hypertension, in two independent cohorts. A secondary objective was to investigate relationships with antihypertensive treatment, arterial stiffness and carotid artery parameters. METHODS AND RESULTS: A total of 1023 French individuals were genotyped for klotho KL-VS. Participants were part of the French ERA and STANISLAS cohorts. In both cohorts, klotho KL-VS/KL-VS genotype was significantly associated with lower systolic blood pressure and pulse pressure when compared to homozygous and heterozygous more frequent (WT) allele carriers (p=0.003 and p<0.001 respectively). Antihypertensive treatment stratification confirmed the previous significant associations, while a significant interaction between klotho KL-VS genotype and antihypertensive treatment was also interestingly found (0.019 for p interaction). CONCLUSION: Klotho KL-VS/KL-VS genotype may be associated with decreased cardio-vascular risk and may interact with antihypertensive treatment in order to reduce blood pressure. This finding could lead to identify subgroups of hypertensive adults who might benefit antihypertensive drug therapies.

Leukocyte telomere length is inversely correlated with plasma Von Willebrand factor.

INTRODUCTION: Leukocyte telomere length (LTL) is short, while the plasma level of Von Willebrand (VWF) is high in persons with atherosclerosis. Moreover, both short LTLs and high VWF levels are observed in individuals who display risks for atherosclerosis, including hypertension, obesity, insulin resistance, cigarette smoking and low socio-economic status. We examined the association between LTL and VWF plasma levels to test the hypothesis that high levels of VWF promote an increase in the turnover of blood cells, including leukocytes. Such a process would heighten the rate of age-dependent LTL attrition, ultimately resulting in shortened LTL. METHODS: We studied 3 cohorts: the ADELAHYDE study (age 60-87years), the ERA study (age 41-88years) and the Longitudinal Study of Aging Danish Twins (LSADT) (age 73-94years). RESULTS: Multiple regression analysis with LTL as the dependent variable, and age, sex and VWF as the independent variables showed that LTL was inversely correlated with VWF in the ADELAHYDE (beta=-0.125, p<0.001) and the ERA study (beta=-0.148, p=0.010). The LSADT displayed VWF x age interaction, which was incorporated into the model, showing that LTL was also inversely correlated with VWF (beta=-0.057, p=0.04). CONCLUSIONS: The inverse relationship between LTL and VWF, observed in 3 different populations, suggests that LTL might be linked to the coagulative status of the individual. Further research will be required to confirm our observations and their clinical ramifications.

Immune constitution monitoring after PBMC transplantation in complete DiGeorge syndrome: an eight-year follow-up.

A young boy with a confirmed complete DiGeorge Syndrome (cDGS) underwent a peripheral blood mononuclear cell transplantation (PBMCT) from his HLA-identical sister at 4.5 years of age, without a conditioning regimen. Eight years later, he is healthy with good immunological functions in the presence of a stable mixed T-cell chimerism. Absence of recent thymic emigrants is confirmed. We observe an inverted CD4+/CD8+ ratio, related to the CD8 subset expansion, a skewing of the TCR repertoire, especially on the CD8+ subset and a telomere loss on the CD8+ cells compared to the donor. However, these anomalies do not seem to have an impact on functional immunity. PBMCT in cDGS using an HLA-matched sibling donor provides good long-lasting immunity and is an easy alternative to bone marrow transplantation and to thymic transplantation.

Chronic oxidative stress induces a tissue-specific reduction in telomere length in CAST/Ei mice.

We examine whether increased oxidative stress in vivo promotes telomere shortening in CAST/Ei mice. We explored the effects of L-buthionine sulfoximine treatment (BSO) on telomere length. BSO shortened telomere length in white fat, brown fat, skin, tail, and testis in concert with diminished tissue glutathione content, increased tissue carbonyl content, and increased plasma advanced oxidized protein products. Telomerase activity was mainly detected in testis but no reduction of telomerase activity was observed in response to BSO. In conclusion, BSO-mediated increase in systemic oxidative stress shortens telomeres in several tissues of the mouse. The variable effect of BSO treatment on telomere length in different tissue may result from their different adaptive antioxidative capacity.

White blood cells telomere length is shorter in males with type 2 diabetes and microalbuminuria.

OBJECTIVE: To examine differences in telomere (terminal restriction fragment [TRF]) length and pulse wave velocity (PWV)--an index of arterial stiffness--in patients with type 2 diabetes with and without microalbuminuria (MA). RESEARCH DESIGN AND METHODS: A total of 84 men with type 2 diabetes, 40 with MA and 44 without MA (aged 63.5 +/- 9.0 vs. 61.2 +/- 9.8 years), were studied. TRF length was determined in white blood cells. MA was defined as albumin excretion rate (AER) in the range of 30-300 mg/24 h in at least two of three 24-h urine collections. PWV was assessed using applanation tonometry. Markers of oxidative stress were also measured. RESULTS: TRF length was shorter in patients with MA than in those without MA (6.64 +/- 0.74 vs. 7.23 +/- 1.01 kb, respectively, P = 0.004). PWV was significantly higher in the patients with MA. Multivariate linear regression analysis in the total sample demonstrated an independent association between TRF length and age (P = 0.02), MA status (P = 0.04) or AER (P = 0.002), and plasma nitrotyrosine levels (P = 0.02). AER was associated significantly with PWV (P < 0.01). CONCLUSIONS: Subjects with type 2 diabetes and MA have shorter TRF length and increased arterial stiffness than those without MA. Additionally, TRF length is associated with age, AER, and nitrosative stress. As shorter TRF length indicates older biological age, the increased arterial stiffness in patients with type 2 diabetes who have MA may be due to the more pronounced "aging " of these subjects.

Metabolic syndrome and age-related progression of aortic stiffness.

UNLABELLED: Aortic stiffness measured from pulse wave velocity (PWV) was studied during a six-year period in a population of subjects with zero to three and more cardiovascular (CV) factors involving hypertension, body mass index, dyslipidemia, hypertriglyceridemia, and hyperglycemia. During the follow-up, the increase in PWV was significantly higher in subjects with three and more CV risk factors (i.e., in subjects with metabolic syndrome) than in subjects with zero, one, or two factors, even after adjustments for confounding factors. Metabolic syndrome involves an increased progression of arterial stiffness with age and, thus, favors premature senescence. OBJECTIVES: The purpose of the study was to evaluate whether a clustering of metabolic risk factors might accelerate the progression of arterial stiffness with age in subjects with metabolic syndrome (MS). BACKGROUND: Arterial stiffness is increased in MS, but the genetic and environmental factors that might influence its progression are unknown. METHODS: Four hundred seventy-six subjects were classified at baseline according to their number of cardiovascular (CV) risk factors (from zero to three and more), after adjustment for smoking habits. The CV risk factors were: hypertension, body mass index, dyslipidemia, hypertriglyceridemia, and hyperglycemia, classified according to traditional criterions. Subjects were followed for six years and had, at the beginning and end of the survey, determinations of blood pressure (BP), heart rate (HR), and aortic pulse wave velocity (PWV). RESULTS: At baseline, BP, HR, plasma creatinine, and PWV were significantly higher (p < 0.001) in the group with three and more CV risk factors than in groups with zero to two risk factors. During the follow-up, the increase in PWV, but not in pulse pressure, was significantly higher (p < 0.01) in the group with three and more risk factors (i.e., metabolic syndrome) than in other groups. Results were unmodified after adjustments for age, gender, baseline values, drug treatment, smoking habits, and mean arterial pressure. CONCLUSIONS: Metabolic syndrome is associated with an increased progression of aortic stiffness with age, supporting premature senescence in these patients.

Aldosterone and telomere length in white blood cells.

BACKGROUND: Aldosterone accelerates cardiovascular aging by mechanisms that generate reactive oxygen species. Telomere length in white blood cells (WBCs) may be a bioindicator that registers the accruing burden of systemic oxidative stress. The aim of the present study was, therefore, to examine the relationship between plasma aldosterone and telomere length in WBCs. METHODS: We studied 75 normotensive and never-treated mildly hypertensive men whose blood was drawn for the measurements of plasma aldosterone concentration and the terminal restriction fragment (TRF) length in WBCs. RESULTS: The slope of the TRF-age relationship in the entire cohort showed a decrease in telomere length of 26 +/- 5 base pairs per year (r = -0.46, p <.001). Age-adjusted TRF length was the longest in the lowest aldosterone quartile (6.74 +/- 0.12 kb) and shortest in the highest aldosterone quartile (6.36 +/- 0.11 kb), with intermediate TRF lengths in the second and third aldosterone quartiles (analysis of variance [ANOVA] trend test, p =.025). In telomeric attrition equivalence, participants in the upper aldosterone quartile were 15 years older than their peers in the lowest quartile. CONCLUSIONS: The inverse relationship between aldosterone and WBC telomere length suggests not only that aldosterone is pro-oxidant but that elevated concentrations of this hormone might be linked to a higher rate of telomere attrition and perhaps increased biological aging in humans.

Mechanisms implicated in the effects of boron on wound healing.

Recently, we demonstrated that boron modulates the turnover of the extracellular matrix and increases TNFalpha release. In the present study, we used an in vitro test to investigate the direct effect of boron on specific enzymes (elastase, trypsin-like enzymes, collagenase and alkaline phosphatase) implicated in extracellular matrix turnover. Boron decreased the elastase and alkaline phosphatase activity, but had no effect on trypsin and collagenase activities. The effect of boron on the enzyme activities was also tested in fibroblasts considered as an in vivo test. In contrast to the results obtained in vitro, boron enhanced the trypsin-like, collagenase, and cathepsin D activities in fibroblasts. Boron did not modify the generation of free radicals compared to the control and did not seem to act on the intracellular alkaline phosphatase activity, However, as it did enhance phosphorylation, it can be hypothesized that boron may affect living cells via a mediator, which could be TNFalpha whose transduction signal involves a cascade of phosphorylations.