Lucas Kich Grun

Effect of obesity on telomere length: Systematic review and meta-analysis.

The main objective of this systematic review is to assess the effects of obesity on telomere length.

Telomere length in subjects with schizophrenia, their unaffected siblings and healthy controls: Evidence of accelerated aging

Schizophrenia (SZ) is associated with broad burden. The clinical manifestations of SZ are related to pathophysiological alterations similar to what is seen in normal aging. Our aim was to evaluate the differences in telomere length (TL), a biomarker of cellular aging, in subjects with SZ (n=36), unaffected siblings (SB, n=36) and healthy controls (HC, n=47). SZ had shorter TL compared to HC, but no difference was found in SB comparing to SZ. These findings indicate that a pathological accelerated aging profile could be present in the course of SZ and further studies are needed to confirm TL as potential endophenotype, especially in at risk populations.

Telomere Length, Oxidative Stress, Inflammation and BDNF Levels in Siblings of Patients with Bipolar Disorder: Implications for Accelerated Cellular Aging

Abstract Background: Growing evidence supports the existence of neurobiological trait abnormalities in individuals at genetic risk for bipolar disorder. The aim of this study was to examine potential differences in brain-derived neurotrophic factor, cytokines, oxidative stress, and telomere length markers between patients with bipolar disorder, their siblings, and healthy controls. Methods: Thirty-six patients with bipolar disorder type I, 39 siblings, and 44 healthy controls were assessed. Serum levels of brain-derived neurotrophic factor, interleukin-6, interleukin-10, tumor necrosis factor-α, C-C motif chemokine 11, C-C motif chemokine 24, and 3-nitrotyrosine were measured, as were the activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Telomere length (T/S ratio) was measured using quantitative polymerase chain reaction. Results: Telomere length was different between the 3 groups (P = .041) with both patients and siblings showing a shorter T/S ratio compared with healthy controls. Patients showed increased levels of interleukin-6 (P = .005) and interleukin-10 (P = .002) compared with controls as well as increased levels of interleukin-6 (p = 0.014) and CCL24 (P = .016) compared with their siblings. C-C motif chemokine 11 levels were increased in siblings compared with controls (P = .015), and a similar tendency was found in patients compared with controls (P = .045). Glutathione peroxidase activity was decreased in patients compared with controls (P = .006) and siblings (P = .025). No differences were found for the other markers. Conclusions: The present results suggest that unaffected siblings may present accelerated aging features. These neurobiological findings may be considered as endophenotypic traits. Further prospective studies are warranted.

Shortened telomere length in bipolar disorder: a comparison of the early and late stages of disease

Objective: Bipolar disorder (BD) has been associated with increased rates of age-related diseases, such as type II diabetes, metabolic syndrome, osteoporosis, and cardiovascular disorders. Several biological findings have been associated with age-related disorders, including increased oxidative stress, inflammation, and telomere shortening. The objective of this study was to compare telomere length among participants with BD at early and late stages and age- and gender-matched healthy controls. Methods: Twenty-six euthymic subjects with BD and 34 healthy controls were recruited. Genomic DNA was extracted from peripheral blood and mean telomere length was measured using real-time quantitative polymerase chain reaction. Results: Telomere length was significantly shorter in both the early and late subgroups of BD subjects when compared to the respective controls (p = 0.002 and p = 0.005, respectively). The sample size prevented additional subgroup analyses, including potential effects of medication, smoking status, and lifestyle. Conclusion: This study is concordant with previous evidence of telomere shortening in BD, in both early and late stages of the disorder, and supports the notion of accelerated aging in BD.

Telomere Length and CCL11 Levels are Associated With Gray Matter Volume and Episodic Memory Performance in Schizophrenia: Evidence of Pathological Accelerated Aging

Schizophrenia (SZ) is associated with increased somatic morbidity and mortality, in addition to cognitive impairments similar to those seen in normal aging, which may suggest that pathological accelerated aging occurs in SZ. Therefore, we aim to evaluate the relationships of age, telomere length (TL), and CCL11 (aging and inflammatory biomarkers, respectively), gray matter (GM) volume and episodic memory performance in individuals with SZ compared to healthy controls (HC). One hundred twelve participants (48 SZ and 64 HC) underwent clinical and memory assessments, structural MRI, and had their peripheral blood drawn for biomarkers analysis. Comparisons of group means and correlations were performed. Participants with SZ had decreased TL and GM volume, increased CCL11, and worse memory performance compared to HC. In SZ, shorter TL was related to increased CCL11, and both biomarkers were related to reduced GM volume, all of which were related to worse memory performance. Older age was only associated with reduced GM, but longer duration of illness was related with all the aforementioned variables. Younger age of disease onset was associated with increased CCL11 levels and worse memory performance. In HC, there were no significant correlations except between memory and GM. Our results are consistent with the hypothesis of accelerated aging in SZ. These results may indicate that it is not age itself, but the impact of the disease associated with a pathological accelerated aging that leads to impaired outcomes in SZ.

Analyzing leukocyte telomere length in bipolar disorder: Authors’ reply

Our original study adds important information to the evidence base for bipolar disorder (BD) pathology. We show, for the first time, that shorter leukocyte telomere length (LTL) is already present in individuals with the early stages of BD and is comparable to LTL from individuals in the late stages of the disease. This result is at least surprising. We might speculate that, in BD, LTL would be proportional to disease duration. A recent study from our group in patients with schizophrenia (SZ) showed that duration of illness, but not age itself, is related to many markers of aging; these results are consistent with the hypothesis of accelerated aging induced by a pathological state. Still, SZ is associated with a higher burden of disease. In our recent study, the similar LTL among early-stage and late-stage BD patients could indeed have many other explanations. First, although hypertension, dyslipidemia, and diabetes mellitus are risk factors for telomere erosion and senescence, and were present in our cohort of BD patients, we chose not to report these data, because we have no information regarding comorbidity duration and its differential impact. Telomeres are naturally shortened during cell division and this process can be accelerated under oxidative, inflammatory or glucocorticoid stress, all of which are present in patients with BD. Importantly, augmented peripheral cell apoptosis, which may be a consequence of augmented turn-over secondary to chronic stress, has been reported in BD. Thus, during chronic stress, cells with shorter telomeres might have already been eliminated, selecting for medium to large telomeres. Second, quantification of telomere length by quantitative PCR (qPCR) provides a measure of the mean LTL present in a given cell population. A major limitation of this technique is its sensitivity, as qPCR does not detect short telomeres. Because short but not average LTL determines pathological phenotypes and drives cell fate, our results must be interpreted with caution. In addition, LTL is a mosaic trait, and reflects the replicative history of the analyzed tissue. Granulocytes have longer telomeres than any other leukocyte subset and are present in higher numbers in BD patients. LTL from patients with late-stage BD could be enriched in the granulocyte population, leading to overestimation and misinterpretation of the real impact of LTL. Finally, we could also argue that similar LTL could be a consequence of pharmacotherapy. Lithium therapy is associated with neuroprotective properties. This effect could explain why euthymic patients in late-stage BD under longer lithium therapy might have similar LTL to early-stage BD patients. Two recently published reports from our group address telomere shortening and familial traits in BD and SZ. Our findings show a significant negative trend for shorter LTL among patients with BD when compared to their healthy siblings, and similar and shorter LTL among patients with SZ and their unaffected siblings. More importantly, in both studies, LTL was shorter in unaffected siblings than in healthy nonrelated controls (HCs). Because HCs and unaffected siblings of BD patients had significant differences in LTL, we might speculate that telomere shortening is not influenced by medication and is indeed a neurobiological change with a clear genetic background. Furthermore, we might consider that genetic background in unaffected siblings could be seen as a susceptibility or vulnerability trait, and that resilience mechanisms may inhibit the appearance of pathological BD. In this study, we indeed failed to address important confounders, such as comorbidities, physical activity, smoking, and lifestyle factors. We also did not include data regarding familial history of major psychiatric disorders, nor did we quantify LTL in participants’ parents. Both of our studies had cross-sectional designs, thus precluding inference of any causal associations. Prospective epidemiological studies with adequately calculated sample sizes should be designed and conducted in newly diagnosed, therapy-naive BD patients to evaluate specific mechanisms potentially associated with lithium neuroprotection in telomere homeostasis.

Effects of previous physical exercise to chronic stress on long-term aversive memory and oxidative stress in amygdala and hippocampus of rats

Since stressful situations are considered risk factors for the development of depression and there are few studies evaluating prevention therapies for this disease, in the present study we evaluated the effect of previous physical exercise in animals subjected to chronic variable stress (CVS), an animal model of depression, on behavior tasks. We also investigated some parameters of oxidative stress and Na+, K+‐ATPase activity, immunocontent and gene expression of alpha subunits in amygdala and hippocampus of rats. Young male rats were randomized into four study groups (control, exercised, stressed, exercised + stressed). The animals were subjected to controlled exercise treadmill for 20 min,three times a week, for two months prior to submission to the CVS (40 days). Results show that CVS impaired performance in inhibitory avoidance at 24 h and 7 days after training session. CVS induced oxidative stress, increasing reactive species, lipoperoxidation and protein damage, and decreasing the activity of antioxidant enzymes. The activity of Na+, K+‐ATPase was decreased, but the immunocontents and gene expression of catalytic subunits were not altered. The previous physical exercise was able to improve performance in inhibitory avoidance at 24 h after training; additionally, exercise prevented oxidative damage, but was unable to reverse completely the changes observed on the enzymatic activities. Our findings suggest that physical exercise during the developmental period may protect against aversive memory impairment and brain oxidative damage caused by chronic stress exposure later in life.

Guarana (Paullinia cupana Mart.) alters gut microbiota and modulates redox status, partially via caffeine in Wistar rats: GUARANA ALTERS GUT MICROBIOTA AND MODULATES REDOX STATUS

Microbiota alterations are observed in pathological conditions, and their regulation is a subject of great interest. Gut microbes are affected by diet, and plant polyphenols may have positive effect on gut microbiota; however, plant‐derived extracts may have toxic effects. Guarana (Paullinia cupana Mart.) is a nontraditional medicinal plant applied worldwide. Guarana yields an alkaloid and polyphenol‐rich seed with antimicrobial, antioxidant, and anti‐inflammatory properties, where caffeine is the major compound. We evaluated the effects of guarana seed powder (GSP) and purified caffeine on gut microbial composition and redox and inflammatory parameters in Wistar rats after 21 days of treatment. Fecal microbiota was analyzed utilizing 16S rDNA sequencing. Antioxidant enzymes activities from liver, kidney, and colon, as well as oxidative damage markers, were evaluated. Total nonenzymatic antioxidant potential was also evaluated. Microbiota was altered by both treatments, GSP and caffeine, without loss of diversity. In the liver, the kidney, and the colon, we observed a decrease in the antioxidant enzymes activities in the GSP group with no increase in the expression of oxidative damage markers, although some enzymes were also regulated by caffeine. Taken together, these results suggested that GSP ameliorates redox parameters but negatively affected gut microbiota, partially via caffeine.

Immunosenescence induced by plasma from individuals with obesity caused cell signaling dysfunction and inflammation

To evaluate the consequences of plasma from individuals with obesity on parameters associated with immunosenescence in unrelated healthy peripheral blood mononuclear cells (PBMC).

Effects of Achyrocline satureioides Inflorescence Extracts against Pathogenic Intestinal Bacteria: Chemical Characterization, In Vitro Tests, and In Vivo Evaluation

Three Achyrocline satureioides (AS) inflorescences extracts were characterized: (i) a freeze-dried extract prepared from the aqueous extractive solution and (ii) a freeze-dried and (iii) a spray-dried extract prepared from hydroethanol extractive solution (80% ethanol). The chemical profile, antioxidant potential, and antimicrobial activity against intestinal pathogenic bacteria of AS extracts were evaluated. In vitro antioxidant activity was determined by the total reactive antioxidant potential (TRAP) assay. In vivo analysis and characterization of intestinal microbiota were performed in male Wistar rats (saline versus treated animals with AS dried extracts) by high-throughput sequencing analysis: metabarcoding. Antimicrobial activity was tested in vitro by the disc diffusion tests. Moisture content of the extracts ranged from 10 to 15% and 5.7 to 17 mg kg−1 of fluorine. AS exhibited antioxidant activity, especially in its freeze-dried form which also exhibited a wide spectrum of antimicrobial activity against intestinal pathogenic bacteria greater than those observed by the antibiotic, amoxicillin, when tested against Bacillus cereus and Staphylococcus aureus. Antioxidant and antimicrobial activities of AS extracts seemed to be positively correlated with the present amount of flavonoids. These findings suggest a potential use of AS as a coadjuvant agent for treating bacterial-induced intestinal diseases with high rates of antibiotic resistance.