scholarly journals Diet-induced leukocyte telomere shortening in a baboon model for early stage atherosclerosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Genesio M. Karere ◽  
Michael C. Mahaney ◽  
Deborah E. Newman ◽  
Angelica M. Riojas ◽  
Clint Christensen ◽  
...  

AbstractReported associations between leukocyte telomere length (LTL) attrition, diet and cardiovascular disease (CVD) are inconsistent. This study explores effects of prolonged exposure to a high cholesterol high fat (HCHF) diet on LTL in a baboon model of atherosclerosis. We measured LTL by qPCR in pedigreed baboons fed a chow (n = 105) or HCHF (n = 106) diet for 2 years, tested for effects of diet on LTL, and association between CVD risk factors and atherosclerotic lesions with LTL. Though not different at baseline, after 2 years median LTL is shorter in HCHF fed baboons (P < 0.0001). Diet predicts sex- and age-adjusted LTL and LTL attrition (P = 0.0009 and 0.0156, respectively). Serum concentrations of CVD biomarkers are associated with LTL at the 2-year endpoint and LTL accounts approximately 6% of the variance in aortic lesions (P = 0.04). Although heritable at baseline (h2 = 0.27, P = 0.027) and after 2 years (h2 = 0.46, P = 0.0038), baseline LTL does not predict lesion extent after 2 years. Atherogenic diet influences LTL, and LTL is a potential biomarker for early atherosclerosis. Prolonged exposure to an atherogenic diet decreases LTL and increases LTL attrition, and shortened LTL is associated with early-stage atherosclerosis in pedigreed baboons.

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
GENESIO KARERE ◽  
Shifra Birnbaum ◽  
Clint Christensen ◽  
Michael Mahaney ◽  
John VandeBerg ◽  
...  

Introduction: Cardiovascular disease, the leading cause of death in developed countries, is commonly due to atherosclerosis. Studies have demonstrated association between leukocyte telomere shortening (LTS), extent of atherosclerotic lesions and accelerated cell senescence. Further LTS is associated with dietary intake. However, efforts to link LTS, diet and extent of lesions have been unsuccessful in humans due to difficulties controlling diet in large human population studies. To begin addressing these critical issues, we controlled dietary fat (high-fat, HF) in baboons for 2yrs - a well-developed primate model of human atherosclerosis. This is the first study in primates showing correlation of LTS with both chronic HF diet and atherosclerotic lesions. Hypothesis: We hypothesized that leukocyte telomere length decreased with chronic HF diet in baboons and is correlated with extent of atherosclerotic lesions. Methods and Results: A cohort of pedigreed baboons (n=107; females=46, males=61) was fed a HF diet for 2yrs. Absolute leukocyte telomere lengths (LTL; kb/diploid genome) were quantified by qPCR before and after diet challenge. Total telomere length was calculated by computing the ratio of telomere quantity per single copy gene quantity (baboon LIPG). Mean LTL was significantly shorter after feeding baboons a HF diet for 2 yrs (paired t test, p=0.03). Baboons (n=232) maintained on a low fat diet for 2yrs showed no significant difference in LTL (p=0.47). These findings suggest that a HF diet accelerates LTS. Further we quantified the extent of atherosclerotic lesions in baboons after 2yr HF diet and found that LTL, adjusted for age and sex, were correlated with lesions in descending aorta (Pearson correlation, r=0.19; p=0.03). Interestingly this correlation was significant in females but not in males after adjusting for age (r=0.27, p=0.03). Conclusions: LTS correlates with chronic feeding with a HF diet in baboons, is significantly correlated with arterial lesions and the correlation is sex-specific. These findings suggest that LTS may be a potential biomarker of extent of atherosclerosis.


2019 ◽  
Vol 49 (1) ◽  
pp. 3-9
Author(s):  
Genesio M. Karere ◽  
Edward J. Dick ◽  
Samuel Galindo ◽  
Jesse C. Martinez ◽  
Jacob E. Martinez ◽  
...  

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Genesio Karere ◽  
Jeremy Glenn ◽  
Samuel Galindo ◽  
Roy Garcia ◽  
Frederic Chevalier ◽  
...  

Introduction: Atherosclerosis is a progressive disease, and it’s the common cause of cardiovascular disease (CVD). CVD is the leading cause of morbidity and mortality in the US. It is important to detect early-stage asymptomatic atherosclerosis prior to progression to plaques. However, it is not feasible to obtain target tissues from humans with early-stage atherosclerosis. We tested the hypothesis that a panel of microRNAs (miRNAs) expressed in atherosclerotic lesions and expressed in plasma of the same baboons are potential biomarkers indicative of initiation and progression of atherosclerosis. Methods and Results: We used small RNA-Seq to identify miRNA expression profiles in atherosclerotic lesions and in plasma of baboons. We challenged adult baboons (n=24) with a high cholesterol, high fat (HCHF) diet for two years. After the diet challenge, common iliac arteries were harvested, fixed in 10% buffered formalin and stained with Sudan IV. We observed interesting fatty streak lesion variations, including early stage (EGES), flat (F) and raised (R) lesions, corresponding, respectively, to AHA lesion types I, II and V. We identified 45 miRNAs differentially expressed in fatty streak lesions (ES vs F=0; ES vs R =36; F vs R=9), and 43 miRNAs in plasma of the same animals (ES vs F=0; ES vs R =21; F vs R=22). Further, we observed that miR-30-5p, miR-340-5p, miR-548-5p and let-7-3p were expressed in flat lesions as well as in plasma, whereas miR-30-5p and miR-21-5p were expressed in raised lesions and in plasma. FDR < 0.05. Conclusions: We conclude that a panel of six miRNAs differentially expressed in fatty streak lesions and differentially expressed in plasma of the same animals is a potential biomarker indicative of initiation and progression of atherosclerosis in baboons. Future studies will focus on translating baboon findings to humans.


2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Fan Xia ◽  
Yonju Ha ◽  
Shuizhen Shi ◽  
Yi Li ◽  
Shengguo Li ◽  
...  

AbstractThe retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood–retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ying Zhu ◽  
Wen Xu ◽  
Wei Hu ◽  
Fang Wang ◽  
Yan Zhou ◽  
...  

Abstract Background Portal hypertension induced esophageal and gastric variceal bleeding is the main cause of death among patients of decompensated liver cirrhosis. Therefore, a standardized, biomarker-based test, to make an early-stage non-invasive risk assessment of portal hypertension, is highly desirable. However, no fit-for-purpose biomarkers have yet been identified. Methods We conducted a pilot study consisting of 5 portal hypertensive gastropathy (PHG) patients and 5 normal controls, sampling the gastric mucosa of normal controls and PHG patients before and after endoscopic cyanoacrylate injection, using label-free quantitative (LFQ) mass spectrometry, to identify potential biomarker candidates in gastric mucosa from PHG patients and normal controls. Then we further used parallel reaction monitoring (PRM) to verify the abundance of the targeted protein. Results LFQ analyses identified 423 significantly differentially expressed proteins. 17 proteins that significantly elevated in the gastric mucosa of PHG patients were further validated using PRM. Conclusions This is the first application of an LFQ-PRM workflow to identify and validate PHG–specific biomarkers in patient gastric mucosa samples. Our findings lay the foundation for comprehending the molecular mechanisms of PHG pathogenesis, and provide potential applications for useful biomarkers in early diagnosis and treatment. Trial registration and ethics approval: Trial registration was completed (ChiCTR2000029840) on February 25, 2020. Ethics Approvals were completed on July 17, 2017 (NYSZYYEC20180003) and February 15, 2020 (NYSZYYEC20200005).


Author(s):  
Jeffrey T. Howard ◽  
Jud C. Janak ◽  
Alexis R. Santos-Lozada ◽  
Sarah McEvilla ◽  
Stephanie D. Ansley ◽  
...  

A growing body of literature on military personnel and veterans’ health suggests that prior military service may be associated with exposures that increase the risk of cardiovascular disease (CVD), which may differ by race/ethnicity. This study examined the hypothesis that differential telomere shortening, a measure of cellular aging, by race/ethnicity may explain prior findings of differential CVD risk in racial/ethnic groups with military service. Data from the first two continuous waves of the National Health and Nutrition Examination Survey (NHANES), administered from 1999–2002 were analyzed. Mean telomere length in base pairs was analyzed with multivariable adjusted linear regression with complex sample design, stratified by sex. The unadjusted mean telomere length was 225.8 base shorter for individuals with prior military service. The mean telomere length for men was 47.2 (95% CI: −92.9, −1.5; p < 0.05) base pairs shorter for men with military service after adjustment for demographic, socioeconomic, and behavioral variables, but did not differ significantly in women with and without prior military service. The interaction between military service and race/ethnicity was not significant for men or women. The results suggest that military service may contribute to accelerated aging as a result of health damaging exposures, such as combat, injury, and environmental contaminants, though other unmeasured confounders could also potentially explain the results.


BMJ Open ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. e036213
Author(s):  
Tina Bonde Sorensen ◽  
Robin Wilson ◽  
John Gregson ◽  
Bhavani Shankar ◽  
Alan D Dangour ◽  
...  

ObjectivesTo explore associations of night-time light intensity (NTLI), a novel proxy for continuous urbanisation levels, with mean systolic blood pressure (SBP), body mass index (BMI), fasting serum low-density lipoprotein (LDL) and fasting plasma glucose (FPG), among adults in early-stage urbanisation in Telangana, South India.DesignCross-sectional analysis of the third wave of the Andhra Pradesh Children and Parents Study cohort.Setting28 villages representing a continuum of urbanisation levels, ranging from rural settlement to medium-sized town in Telangana, South India.ParticipantsData were available from 6944 participants, 6236 of whom were eligible after excluding pregnant women, participants younger than 18 years of age and participants missing data for age. Participants were excluded if they did not provide fasting blood samples, had implausible or missing outcome values, were medicated for hypertension or diabetes or had triglyceride levels invalidating derived LDL. The analysis included 5924 participants for BMI, 5752 participants for SBP, 5287 participants for LDL and 5328 participants for FPG.ResultsIncreasing NTLI was positively associated with mean BMI, SBP and LDL but not FPG. Adjusted mean differences across the range of village-level NTLI were 1.0 kg/m2 (95% CI 0.01 to 1.9) for BMI; 4.2 mm Hg (95% CI 1.0 to 7.4) for SBP; 0.3 mmol/L (95% CI −0.01 to 0.7) for LDL; and −0.01 mmol/L (95% CI −0.4 to 0.4) for FPG. Associations of NTLI with BMI and SBP were stronger in older age groups.ConclusionThe association of NTLI with cardiovascular disease (CVD) risk factors identify NTLI as a potentially important tool for exploring urbanisation-related health. Consistent associations of moderate increases in urbanisation levels with important CVD risk factors warrant prevention strategies to curb expected large public health impacts from continued and rapid urbanisation in India.


Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1816
Author(s):  
Laura Pelosi ◽  
Maria Grazia Berardinelli ◽  
Laura Forcina ◽  
Francesca Ascenzi ◽  
Emanuele Rizzuto ◽  
...  

IL-6 is a pleiotropic cytokine that can exert different and opposite effects. The muscle-induced and transient expression of IL-6 can act in an autocrine or paracrine manner, stimulating anabolic pathways associated with muscle growth, myogenesis, and with regulation of energy metabolism. In contrast, under pathologic conditions, including muscular dystrophy, cancer associated cachexia, aging, chronic inflammatory diseases, and other pathologies, the plasma levels of IL-6 significantly increase, promoting muscle wasting. Nevertheless, the specific physio-pathological role exerted by IL-6 in the maintenance of differentiated phenotype remains to be addressed. The purpose of this study was to define the role of increased plasma levels of IL-6 on muscle homeostasis and the mechanisms contributing to muscle loss. Here, we reported that increased plasma levels of IL-6 promote alteration in muscle growth at early stage of postnatal life and induce muscle wasting by triggering a shift of the slow-twitch fibers toward a more sensitive fast fiber phenotype. These findings unveil a role for IL-6 as a potential biomarker of stunted growth and skeletal muscle wasting.


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