Irene P. Tzanetakou

Is obesity linked to aging? Adipose tissue and the role of telomeres

Obesity is a condition in which excess or abnormal fat accumulation may present with adverse effects on health and decreased life expectancy. Increased body weight and adipose tissue accumulation amplifies the risk of developing various age-related diseases, such as cardiovascular disease, type 2 diabetes mellitus, musculoskeletal disorders, respiratory diseases and certain types of cancer. This imbalance in body composition and body weight is now recognized as a state of increased oxidative stress and inflammation for the organism. Increasing oxidative stress and inflammation affect telomeres. Telomeres are specialized DNA-protein structures found at the ends of eukaryotic chromosomes and serve as markers of biological aging rate. They also play a critical role in maintaining genomic integrity and are involved in age-related metabolic dysfunction. Erosion of telomeres is hazardous to healthy cells, as it is a known mechanism of premature cellular senescence and loss of longevity. The association of telomeres and oxidative stress is evident in cultured somatic cells in vitro, where oxidative stress enhances the process of erosion with each cycle of replication. Shorter telomeres have been associated with increasing body mass index, increased adiposity, and more recently with increasing waist to hip ratio and visceral excess fat accumulation. Furthermore, many of the metabolic imbalances of obesity (e.g. glycemic, lipidemic, etc.) give rise to organ dysfunction in a way that resembles the accelerated aging process. This article is a non-systematic review of the evidence linking obesity and accelerated aging processes as they are regulated by telomeres.

Nutrition During Pregnancy and the Effect of Carbohydrates on the Offspring's Metabolic Profile: In Search of the "Perfect Maternal Diet"

Fetal growth and development is primarily dependent upon the nutritional, hormonal and metabolic environment provided by the mother. A wartime famine study in Holland first showed that a low food intake reduces the glucose offered to the fetus and thus produces smaller size infants at birth. Maternal glucose regulation is however affected by numerous factors including physiological changes of pregnancy (e.g. insulin resistance [IR]), pathological conditions (e.g. gestational diabetes mellitus) and maternal nutrition. Maternal glucose is substantially influenced by the type of carbohydrates in the diet through its direct effect on glycemia. The rate at which each carbohydrate raises blood glucose levels after ingestion, can be measured via the dietary glycemic index (GI). Carbohydrate type and the GI of the diet enhance or inhibit abnormal hyperglycemia during pregnancy caused by either pathological conditions or the inability of the mother to cope with the physiological IR of pregnancy. In turn, maternal gestational hyperglycemia may be involved in the pathogenesis of IR, impaired glucose tolerance, type 2 diabetes mellitus, the Metabolic Syndrome and subsequent cardiovascular diseases in adult offspring. A low GI maternal diet has been associated with measurable benefits to the offspring. These include a positive effect on altering maternal blood glucose production, insulinemia and reduced adiposity as well as fetal and placental insulin and glucose regulation, fetal growth, birth weight and offspring adiposity. We review the possible links between dietary carbohydrate in health during pregnancy and the effect of maternal carbohydrate ingestion on programming the offspring’s metabolic profile.

Ageing, longevity, exceptional longevity and related genetic and non genetics markers: panel statement.

In May 2012, a group of scientists and clinicians met in Athens (Greece) to consider the relevance of ageing, longevity, exceptional longevity and related genetic and non genetic markers. During this meeting, we firstly reviewed recent epidemiological and clinical studies on ageing, longevity and exceptional longevity, briefly analyzed the ageing theories and discussed successful and unsuccessful ageing also taking into account the evolutionary perspective. Secondly, we considered the three phenotypes based on the definition of ageing, longevity and exceptional longevity and the associated biomarkers. Third, we discussed proposed treatments suitable to counteract or slow down ageing. Finally, this panel produced a consensus statement to highlight the importance of ageing, longevity and exceptional longevity, since this is a rapidly increasing phenotype worldwide. We acknowledge that not all experts in this field may completely agree with this statement.

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.

The effect of biological age on the metabolic responsiveness of mice fed a high-fat diet

Mice are widely used in studies investigating the effect of diet on metabolic risk factors, such as lipid profiles and plasma glucose levels. An important factor that is usually not taken into account is the biological age of the experimental models. The up-to-date identified experimental confounders do not cover all the parameters that may affect the results of animal studies. The aim of this study was to investigate the effects of a high-fat diet on the metabolic profile, hepatic and renal function in mice of differing ages. For this purpose two groups of male C57BL/6J mice were used, consisting of 10-week-old mice and 54-week-old mice in each group. Both groups followed identical high-fat diets for 12 weeks. The younger mice showed smaller increases in body weight, serum total cholesterol, glucose and urea levels while they had higher increases in high-density lipoprotein cholesterol levels than the older mice. Our results indicate the necessity to consider an experimental animal’s age as a confounding factor when researching or interpreting metabolic studies. Age adjustment is warranted in all animal research while a uniform approach regarding the age of the animal models should be applied in experimental studies.

Water Soluble Vitamin E Administration in Wistar Rats with Non-alcoholic Fatty Liver Disease

Objective: A diet rich in fat is associated with hepatic fat deposition [steatosis; non-alcoholic fatty liver disease (NAFLD)]. The exact cause of NAFLD however, is still unknown. The aim of this study was to assess the effect of a water-soluble formulation of vitamin E on a dietary-induced-NAFLD animal model. Methods: Adult male Wistar rats (n=20) were allocated to 2 groups: Controls (Group A, n=6), which received a standard chow diet for 24 weeks and a High Cholesterol group (HC: n=14), which received a standard chow diet enriched with cholesterol for the first 14 weeks of the experiment (t1). At t1, the HC group was divided into: Group HC(B), which received a high-saturated-fat/high-cholesterol (HSF/HCH) diet and Group HC(C), which followed the same HSF/HCH diet but was also administered water soluble vitamin E (10 IU/kg body weight/day), for 10 more weeks. Results: At the end of the study, group HC(C) exhibited significantly lower mean total cholesterol (T-CHOL) than group HC(B) (p<0.001). No significant differences were observed between HC(C) and Control groups in blood glucose and serum lipid concentrations. Liver Function Tests did not vary between all groups at the end of the study. Animals in group HC(B) exhibited higher SGOT at the end of the study compared with the beginning of the study (p<0.05). Group HC(B) exhibited the highest scores in steatosis, and grading (according to the NAFLD scoring system) in the histopathological analysis (p≤0.001 in all cases). Conclusions: Vitamin E seems to exert a hypolipidemic and hepatoprotective role in the presence of a HSF/HCH atherogenic diet in a rat model.

Correlation between mesenteric fat thickness and serum apolipoproteins in patients with peripheral arterial occlusive disease

BackgroundVisceral fat possesses the most detrimental potential for cardiovascular morbidity through the release of adipokines, as well as metabolic and proinflammatory mediators, which adversely affect metabolic and vascular homeostasis. Among the different types of visceral adipose tissue, mesenteric fat is considered particularly detrimental, due to its close proximity to the portal circulation, affecting directly the liver, which is the main regulator of body metabolic homeostasis. Mesenteric fat can be reliably estimated using abdominal ultrasonography, the only available imaging method able to depict individual mesenteric leaves. Aim of the present study was to investigate the correlation of mesenteric fat thickness (MFT) with serum apolipoprotein levels in patients undergoing digital subtraction angiography in a single center.Methods35 male patients with peripheral arterial disease were examined. After careful examination of the periumbilical area, the mesenteric leaves were identified. The maximal distance between each pair of sequential leaves was measured, and the mean value of the three thickest leaves was determined as the mesenteric fat thickness. Six apolipoprotein fasting serum concentrations were measured using a Luminex proteomics platform (xMAP Multiplex immunoassay): apolipoprotein A-I (apoAI), apolipoprotein A-II (apoAII), apolipoprotein B (apoB), apolipoprotein C-II (apoCII), apolipoprotein C-III (apoCIII) and apolipoprotein E (apoE).ResultsMFT correlated with apoAII and apoB serum concentrations. The correlations with apoAII and apoB remained significant following correction for BMI. No correlations were noted between MFT and serum apoAI, apoCII, apoCIII or apoE levels before or after adjustment for BMI.ConclusionsOur study indicates that MFT is significantly correlated with the concentration of atherogenic low density lipoproteins particles, as well as with apoAII, a determinant of free fatty acids levels. No correlation was observed between mesenteric fat thickness and very low density lipoprotein or chylomicron particles concentration.

Short Leukocyte Telomere Length Precedes Clinical Expression of AtherosclerosisNovelty and Significance: The Blood-and-Muscle Model

Rationale: Short telomere length (TL) in leukocytes is associated with atherosclerotic cardiovascular disease (ASCVD). It is unknown whether this relationship stems from having inherently short leukocyte TL (LTL) at birth or a faster LTL attrition thereafter. LTL represents TL in the highly proliferative hematopoietic system, whereas TL in skeletal muscle represents a minimally replicative tissue. Objective: We measured LTL and muscle TL (MTL) in the same individuals with a view to obtain comparative metrics for lifelong LTL attrition and learn about the temporal association of LTL with ASCVD. Methods and Results: Our Discovery Cohort comprised 259 individuals aged 63±14 years (mean±SD), undergoing surgery with (n=131) or without (n=128) clinical manifestation of ASCVD. In all subjects, MTL adjusted for muscle biopsy site (MTLA) was longer than LTL and the LTL-MTLA gap similarly widened with age in ASCVD patients and controls. Age- and sex-adjusted LTL (P=0.005), but not MTLA (P=0.90), was shorter in patients with ASCVD than controls. The TL gap between leukocytes and muscle (LTL-MTLA) was wider (P=0.0003), and the TL ratio between leukocytes and muscle (LTL/MTLA) was smaller (P=0.0001) in ASCVD than in controls. Findings were replicated in a cohort comprising 143 individuals. Conclusions: This first study to apply the blood-and-muscle TL model shows more pronounced LTL attrition in ASCVD patients than controls. The difference in LTL attrition was not associated with age during adulthood suggesting that increased attrition in early life is more likely to be a major explanation of the shorter LTL in ASCVD patients. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02176941.

Impact of N-acetylcysteine and sesame oil on lipid metabolism and hypothalamic-pituitary-adrenal axis homeostasis in middle-aged hypercholesterolemic mice

Hyperlipidemia and stress are important factors affecting cardiovascular health in middle-aged individuals. We investigated the effects of N-acetylcysteine (NAC) and sesame oil on the lipidemic status, liver architecture and the hypothalamic-pituitary-adrenal (HPA) axis of middle-aged mice fed a cholesterol-enriched diet. We randomized 36 middle-aged C57bl/6 mice into 6 groups: a control group, a cholesterol/cholic acid diet group, a cholesterol/cholic acid diet group with NAC supplementation, a cholesterol/cholic acid diet enriched with 10% sesame oil and two groups receiving a control diet enriched with NAC or sesame oil. NAC administration prevented the onset of the disturbed lipid profile, exhibiting decreased lipid peroxidation and alkaline phosphatase (ALP) levels, restored nitric oxide bioavailability and reduced hepatic damage, compared to non-supplemented groups. High-cholesterol feeding resulted in increased hypothalamic glucocorticoid receptors (GR) levels, while NAC supplementation prevented this effect. NAC supplementation presented significant antioxidant capacity by means of preventing serum lipid status alterations, hepatic damage, and HPA axis disturbance due to high-cholesterol feeding in middle-aged mice. These findings suggest a beneficial preventive action of plant-derived antioxidants, such as NAC, on lipid metabolism and on the HPA axis.

Evaluation of Chios mastic gum on lipid and glucose metabolism in diabetic mice.

Chios mastic gum (MG), a resin produced from Pistacia lentiscus var. Chia, is reported to possess beneficial cardiovascular and hepatoprotective properties. This study investigated the effect of crude Chios MG on metabolic parameters in diabetic mice. Streptozotocin-induced diabetic 12-week-old male C57bl/6 mice were assigned to three groups: NC (n=9) control; LdM (n=9) animals receiving low dose mastic for 8 weeks (20 mg/kg body weight [BW]); and HdM (n=9) animals receiving high dose mastic (500 mg/kg BW) for the same period. Serum lipid and glucose levels were determined at baseline, at 4 and 8 weeks. Serum total protein, adiponectin, and resistin levels were also measured at the end of the experiment. Histopathological examination for liver, kidney, aorta, and heart lesions was performed. After 4 weeks, MG administration resulted in decreased serum glucose and triglyceride levels in both LdM and HdM, whereas BW levels were reduced in LdM group compared with controls. At the end of the experiment, LdM presented significantly lower serum glucose, cholesterol, low-density lipoprotein cholesterol, and triglyceride levels and improved high-density lipoprotein cholesterol levels compared with control group. HdM group had ameliorated serum triglyceride levels. Hepatic steatosis observed in control group was partially reversed in LdM and HdM groups. MG administered in low dosages improves glucose and lipid disturbances in diabetic mice while alleviating hepatic damage.