Aberrant telomeric structures and serum markers of telomere dysfunction in healthy aging: a preliminary study.

Telomeres undergo a progressive shortening process as individuals age, and it has been proposed that severely shortened and dysfunctional telomeres play a role in the aging process and the onset of age-related diseases in human beings. An emerging body of evidence indicates that the shortening of telomeres in cultured human cells is also influenced by other replication defects occurring within telomeric repeats. These abnormalities can be detected on metaphase chromosomes. Recent studies have also identified a set of serological markers for telomere dysfunction and DNA damage (elongation factor 1α [EF-1α], stathmin, and N-acetyl-glucosaminidase). With this study, the correlation between telomere abnormalities (by FISH) and these biomarkers as measured in blood serum (by ELISA) from a cohort of 22 healthy subjects at different ages (range 26-101 years) was analyzed. A strong positive correlation between aging and the presence of aberrant telomere structures, sister telomere loss (STL), and sister telomere chromatid fusions (STCF) was detected. When serum markers of telomere dysfunction were correlated with telomere abnormalities, we found that stathmin correlated with total aberrant telomeres structures (r = 0.431, p = 0.0453) and STCF (r = 0.533, p = 0.0107). These findings suggest that serum stathmin can be considered an easy-to-get marker of telomere dysfunction and may serve as valuable indicators of aging.

miRNAs and Alzheimer's Disease: Exploring the Role of Inflammation and Vitamin E in an Old-Age Population.

Alzheimer's disease (AD) is the most frequent cause of dementia worldwide and represents one of the leading factors for severe disability in older persons. Although its etiology is not fully known yet, AD may develop due to multiple factors, including inflammation and oxidative stress, conditions where microRNAs (miRNAs) seem to play a pivotal role as a molecular switch. All these aspects may be modulated by nutritional factors. Among them, vitamin E has been widely studied in AD, given the plausibility of its various biological functions in influencing neurodegeneration. From a cohort of old-aged people, we measured eight vitamin E forms (tocopherols and tocotrienols), thirty cytokines/chemokines, and thirteen exosome-extracted miRNAs in plasma of subjects suffering from subjects affected by AD and age-matched healthy controls (HC). The sample population included 80 subjects (40 AD and 40 HC) with a mean age of 77.6 ± 3.8 years, mostly women (45; 56.2%). Of the vitamin E forms, only α-tocopherol differed between groups, with significantly lower levels in AD. Regarding the examined inflammatory molecules, G-CSF, GM-CSF, INF-α2, IL-3, and IL-8 were significantly higher and IL-17 lower in AD than HC. Among all miRNAs examined, AD showed downregulation of miR-9, miR-21, miR29-b, miR-122, and miR-132 compared to controls. MiR-122 positively and significantly correlated with some inflammatory molecules (GM-CSF, INF-α2, IL-1α, IL-8, and MIP-1ß) as well as with α-tocopherol even after correction for age and gender. A final binary logistic regression analysis showed that α-tocopherol serum levels were associated with a higher AD probability and partially mediated by miR-122. Our results suggest an interplay between α-tocopherol, inflammatory molecules, and microRNAs in AD, where miR-122 may be a good candidate as modulating factor.

Beta-carotene, telomerase activity and Alzheimer's disease in old age subjects.

PURPOSE: Advancing age represents the strongest risk factor for Alzheimer's disease (AD), and the identification of biomarkers able to define what characterizes physiological aging from AD may represent a potential starting point for novel preventive strategies. Among these biomarkers, telomeres seem to be a promising target. Interestingly, high intake of carotenoid-rich food may play a role in protecting telomeres by oxidative stress reduction. Accordingly, low plasma ß-carotene concentrations have been found in AD subjects when compared with cognitively healthy subjects. In this study, we aim at investigating the hypothesis that low ß-carotene might be associated with markers of accelerated cellular aging, including leucocyte telomere length (LTL) and peripheral mononuclear cell (PBMC) telomerase activity in a cohort of old age subjects. METHODS: The study was conducted in 68 old age subjects, 37 AD, and 31 age-matched healthy controls. In all subjects, ß-carotene plasma level, LTL and peripheral telomerase activity were measured. RESULTS: In all populations, ß-carotene significantly and positively (r = 0.320, p = 0.008) correlated with telomerase activity, independent of gender. A model having telomerase activity levels as the dependent variable, and age, gender, smoking habit, and ß-carotene as independent variables, confirmed that ß-carotene was independently associated with telomerase activity (ß = 0.319, p = 0.012). Subjects affected by AD had significantly lower plasmatic levels of ß-carotene (448 ± 66 mg/ml vs 497 ± 59 mg/ml, p = 0.001) and LTL (0.53 ± 0.25 vs 0.69 ± 0.29; p = 0.009) as compared with healthy controls. Β-carotene plasma level was associated with AD diagnosis (OR 0.988; IC95% 0.978-0.997; p = 0.013) independently of age, gender, smoking habit, ApoE genotype, and LTL. CONCLUSION: Our data show that ß-carotene may modulate telomerase activity in old age. Moreover, lower plasma ß-carotene levels, correlating with peripheral telomerase activity, are associated with AD diagnosis independent of multiple covariates.

Lymphocyte mitochondria: toward identification of peripheral biomarkers in the progression of Alzheimer disease.

Alzheimer disease (AD) is an age-related neurodegenerative condition. AD is histopathologically characterized by the presence of three main hallmarks: senile plaques (rich in amyloid-ß peptide), neuronal fibrillary tangles (rich in phosphorylated tau protein), and synapse loss. However, definitive biomarkers for this devastating disease in living people are still lacking. In this study, we show that levels of oxidative stress markers are significantly increased in the mitochondria isolated from lymphocytes of subjects with mild cognitive impairment (MCI) compared to cognitively normal individuals. Further, an increase in mitochondrial oxidative stress in MCI is associated with MMSE score, vitamin E components, and ß-carotene. Further, a proteomics approach showed that alterations in the levels of thioredoxin-dependent peroxide reductase, myosin light polypeptide 6, and ATP synthase subunit ß might be important in the progression and pathogenesis of AD. Increased understanding of oxidative stress and protein alterations in easily obtainable peripheral tissues will be helpful in developing biomarkers to combat this devastating disorder.