The ongoing obesity pandemic generates a constant need to develop new therapeutic strategies to restore the energy balance. Therefore, the concept of activating brown adipose tissue (BAT) in order to ...increase energy expenditure has been revived. In mammals, two developmentally distinct types of brown adipocytes exist; the classical or constitutive BAT that arises during embryogenesis, and the beige adipose tissue that is recruited postnatally within white adipose tissue (WAT) in the process called browning. Research of recent years has significantly increased our understanding of the mechanisms involved in BAT activation and WAT browning. They also allowed for the identification of critical molecules and critical steps of both processes and, therefore, many new therapeutic targets. Several non-pharmacological approaches, as well as chemical compounds aiming at the induction of WAT browning and BAT activation, have been tested in vitro as well as in animal models of genetically determined and/or diet-induced obesity. The therapeutic potential of some of these strategies has also been tested in humans. In this review, we summarize present concepts regarding potential therapeutic targets in the process of BAT activation and WAT browning and available strategies aiming at them.
Flavonoids in Skin Senescence Prevention and Treatment Domaszewska-Szostek, Anna; Puzianowska-Kuźnicka, Monika; Kuryłowicz, Alina
International journal of molecular sciences,
07/2021, Volume:
22, Issue:
13
Journal Article
Peer reviewed
Open access
Skin aging is associated with the accumulation of senescent cells and is related to many pathological changes, including decreased protection against pathogens, increased susceptibility to ...irritation, delayed wound healing, and increased cancer susceptibility. Senescent cells secrete a specific set of pro-inflammatory mediators, referred to as a senescence-associated secretory phenotype (SASP), which can cause profound changes in tissue structure and function. Thus, drugs that selectively eliminate senescent cells (senolytics) or neutralize SASP (senostatics) represent an attractive therapeutic strategy for age-associated skin deterioration. There is growing evidence that plant-derived compounds (flavonoids) can slow down or even prevent aging-associated deterioration of skin appearance and function by targeting cellular pathways crucial for regulating cellular senescence and SASP. This review summarizes the senostatic and senolytic potential of flavonoids in the context of preventing skin aging.
In the elderly, chronic low-grade inflammation (inflammaging) is a risk factor for the development of aging-related diseases and frailty. Using data from several thousand Eastern Europeans aged ...65 years and older, we investigated whether the serum levels of two proinflammatory factors, interleukin-6 (IL-6) and C-reactive protein (CRP), were associated with physical and cognitive performance, and could predict mortality in successfully aging elderly.
IL-6 and CRP levels systematically increased in an age-dependent manner in the entire study group (IL-6: n = 3496 individuals, p < 0.001 and CRP: n = 3632, p = 0.003), and in the subgroup of successfully aging individuals who had never been diagnosed with cardiovascular disease, myocardial infarction, stroke, type 2 diabetes, or cancer, and had a Mini Mental State Examination (MMSE) score ≥24 and a Katz Activities of Daily Living (ADL) score ≥5 (IL-6: n = 1258, p < 0.001 and CRP: n = 1312, p < 0.001). In the subgroup of individuals suffering from aging-related diseases/disability, only IL-6 increased with age (IL-6: n = 2238, p < 0.001 and CRP: n = 2320, p = 0.249). IL-6 and CRP levels were lower in successfully aging individuals than in the remaining study participants (both p < 0.001). Higher IL-6 and CRP levels were associated with poorer physical performance (lower ADL score) and poorer cognitive performance (lower MMSE score) (both p < 0.001). This association remained significant after adjusting for age, gender, BMI, lipids, estimated glomerular filtration rate, and smoking status. Longer survival was associated with lower concentrations of IL-6 and CRP not only in individuals with aging-related diseases/disability (HR = 1.063 per each pg/mL, 95 % CI: 1.052-1.074, p < 0.001 and HR = 1.020 per each mg/L, 95 % CI: 1.015-1.025, p < 0.001, respectively) but also in the successfully aging subgroup (HR = 1.163 per each pg/mL, 95 % CI: 1.128-1.199, p < 0.001 and HR = 1.074 per each mg/L, 95 % CI: 1.047-1.100, p < 0.001, respectively). These associations remained significant after adjusting for age, gender, BMI, lipids and smoking status. The Kaplan-Meier survival curves showed similar results (all p < 0.001).
Both IL-6 and CRP levels were good predictors of physical and cognitive performance and the risk of mortality in both the entire elderly population and in successfully aging individuals.
With increased life expectancies in developed countries, cancer rates are becoming more common among the elderly. Cancer is typically driven by a combination of germline and somatic mutations ...accumulating during an individual's lifetime. Yet, many centenarians reach exceptionally old age without experiencing cancer. It was suggested that centenarians have more robust DNA repair and mitochondrial function, allowing improved maintenance of DNA stability. In this study, we applied real‐time quantitative PCR to examine the expression of ATM in lymphoblastoid cell lines (LCLs) from 15 healthy female centenarians and 24 younger female donors aged 21–88 years. We observed higher ATM mRNA expression of in LCLs from female centenarians compared with both women aged 21–48 years (FD = 2.0, p = .0016) and women aged 56–88 years (FD = 1.8, p = .0094. Positive correlation was found between ATM mRNA expression and donors age (p = .0028). Levels of hsa‐miR‐181a‐5p, which targets ATM, were lower in LCLs from centenarians compared with younger women. Our findings suggest a role for ATM in protection from age‐related diseases, possibly reflecting more effective DNA repair, thereby reducing somatic mutation accumulation during aging. Further studies are required for analyzing additional DNA repair pathways in biosamples from centenarians and younger age men and women.
In the assessment of the health risk of an obese individual, both the amount of adipose tissue and its distribution and metabolic activity are essential. In adults, the distribution of adipose tissue ...differs in a gender-dependent manner and is regulated by sex steroids, especially estrogens. Estrogens affect adipocyte differentiation but are also involved in the regulation of the lipid metabolism, insulin resistance, and inflammatory activity of the adipose tissue. Their deficiency results in unfavorable changes in body composition and increases the risk of metabolic complications, which can be partially reversed by hormone replacement therapy. Therefore, the idea of the supplementation of estrogen-like compounds to counteract obesity and related complications is compelling. Phytoestrogens are natural plant-derived dietary compounds that resemble human estrogens in their chemical structure and biological activity. Supplementation with phytoestrogens may confer a range of beneficial effects. However, results of studies on the influence of phytoestrogens on body composition and prevalence of obesity are inconsistent. In this review, we present data from in vitro, animal, and human studies regarding the role of phytoestrogens in adipose tissue development and function in the context of their potential application in the prevention of visceral obesity and related complications.
Atherosclerosis is a complex process involving endothelial dysfunction, vascular inflammation, vascular smooth muscle cell (VSMC) proliferation, angiogenesis, and calcification. One of the ...pathomechanisms of atherosclerosis is the upregulation of Wnt signaling. This study aimed to summarize the current knowledge regarding the role of Wnt signaling and sclerostin in atherosclerosis, vascular calcification, aneurysms, and mortality based on the PubMed database. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendation and identified 160 papers that were included in this systematic review. The published data highlight that the upregulation of Wnt components facilitates the initiation and progression of atherosclerosis, arterial remodeling, VSMCs proliferation and phenotypic transition to the osteoblastic lineage in the arterial wall. This results in protein secretion, cell migration, calcification, fibrosis and aneurysm formation. The transformation of VSMCs into osteoblast-like cells that is observed in atherosclerosis results in sclerostin expression inhibiting the Wnt pathway. Furthermore, it was shown that sclerostin, expressed in atherosclerotic plaques, inhibits aneurysm formation in a mouse model. However, in humans, while the antisclerostin antibody romosozumab inhibits bone resorption, biochemical parameters of endothelial activation and inflammation are not affected, and the incidence of aneurysms is not increased. It was suggested that detecting sclerostin in the calcified aortic atherosclerotic plaques reflects a defense mechanism against Wnt activation and inhibition of atherosclerosis, although this has only been shown in animal models. Moreover, an increased number of vascular cells converted to osteogenic phenotypes results in increased plasma sclerostin concentrations. Therefore, plasma sclerostin derived from bone limits its importance as a global marker of vascular calcification.
Women live longer than men; this can be attributed in part to the function of estrogens. In premenopausal women 17β-estradiol (E2) is produced mainly by the ovaries. Extra-ovarian sources of this ...hormone comprise adipose tissue, breast tissue, bone, leukocytes, heart, testes, prostate, adrenal tissues, and some brain structures. E2 exerts the majority of its biological functions by interacting with the nuclear receptors ERα and ERβ, encoded by the ESR1 and ESR2 genes, respectively. The genomic mechanism of ER action is the regulation of the activity of target genes. In addition, E2 induces rapid cellular effects in transcription-independent, non-genomic mechanisms, acting via receptors localized in the plasma membrane, in the cytoplasm, and in the mitochondria. Notably, ERα commonly serves as an extra-nuclear receptor of E2. In wild type animal models of cardiac ischemia ERα activation reduces infarct size, apoptosis of cardiomyocytes, inflammation, and oxidative stress, induces vasodilatation and increases neovascularization. The cardioprotective role of ERα in human is not fully elucidated. An individual with disruptive ESR1 mutation had dysfunctional epithelium and suffered from early cardiovascular disease. An association of the common ESR1 −397T>C and −351A>G polymorphisms and of other polymorphisms with cardiovascular disease and with myocardial infarction is still not firmly established.
► The effect of estrogens and of ERα on the cardiovascular system is described. ► E2 and ERα exert their function acting via genomic and non-genomic mechanisms. ► In animals, ERα activation reduces infarct size, inflammation, and oxidative stress. ► It also induces vasodilatation and increases neovascularization. ► The cardioprotective role of ERα in humans is not fully elucidated.
One of adipokines involved in the development of insulin resistance is retinol-binding protein 4(RBP4). The physiological role of RBP4 is transport of retinol from the liver to peripheral tissues. ...One of the first events related to the excessive visceral fat accumulation is the development of inflammation followed by hormonal adipose tissue dysfunction, including excessive RBP4 production. Reduced density of the membrane-type glucose transporter 4 (GLUT4) is considered as a direct cause for the stimulation of RBP4 release to the circulation by adipocytes. Circulating RBP4 inhibits the signal pathways stimulated by insulin in skeletal muscle cells, resulting in the development of insulin resistance. Drugs stimulating receptor peroxisome proliferator-activated gamma (PPARγ) - thiazolidinediones - inhibit the production of RBP4 by adipose tissue and increase the insulin sensitivity of the tissues. Increased secretion of RBP4 stimulates the expression of adhesion molecules in the endothelial cells, promoting development of atherosclerosis and arterial hypertension. Population studies demonstrated an association between serum RBP4 in the circulation, and the severity of atherosclerosis and risk of the cardiovascular events and type 2 diabetes. It also appears that the rbp4 gene functional polymorphisms may influence the risk of metabolic complications of obesity, including vascular injury. Therefore, the concentration of RBP4 in the circulation may be considered both as the causative factor and marker of chronic vascular injury. This article summarizes the current state of knowledge on the potential role of RBP4 in the pathogenesis of cardiovascular diseases, particularly related to insulin resistance.
Background
Identifying prognostic factors that are predictive of in-hospital mortality for patients in surgical units may help in identifying high-risk patients and developing an approach to reduce ...mortality. This study analyzed mortality predictors based on outcomes obtained from a national database of adult patients.
Materials and methods
This retrospective study design collected data obtained from the National Health Fund in Poland comprised of 2,800,069 hospitalizations of adult patients in surgical wards during one calendar year. Predictors of mortality which were analyzed included: the patient’s gender and age, diagnosis-related group category assigned to the hospitalization, length of the hospitalization, hospital type, admission type, and day of admission.
Results
The overall mortality rate was 0.8%, and the highest rate was seen in trauma admissions (24.5%). There was an exponential growth in mortality with respect to the patient’s age, and male gender was associated with a higher risk of death. Compared to elective admissions, the mortality was 6.9-fold and 15.69-fold greater for urgent and emergency admissions (
p
< 0.0001), respectively. Weekend or bank holiday admissions were associated with a higher risk of death than working day admissions. The “weekend” effect appears to begin on Friday. The highest mortality was observed in less than 1 day emergency cases and with a hospital stay longer than 61 days in any type of admission.
Conclusion
Age, male gender, emergency admission, and admission on the weekend or a bank holiday are factors associated with greater mortality in surgical units.
Sirtuin 6 (SIRT6) exerts a protective effect on health and extends the lives of model organisms. We, therefore, aimed to clarify whether age-related epigenetic drift is responsible for differences in ...SIRT6 expression in peripheral blood mononuclear cells (PBMCs) of healthy young (n = 55, mean age 27.5 ± 4.4 years), middle-aged (n = 51, 65.4 ± 3.3 years), and long-lived (n = 51, 93.9 ± 3.6 years) humans. In silico analysis was performed using the STRING network. No age-related differences were observed in the percentage of SIRT6 CpG island methylation. However, the age affected the expression of miR-34a-5p, miR-125a-5p, miR-186-5p, miR-342-5p and miR-766-3p (all p < 0.0001), miR-181-2-3p and Let-7c (both p = 0.0003), and miR-103a-3p (p = 0.0069). A negative association was observed between SIRT6 mRNA and miR-186-5p (r
s
= −0.25, p = 0.026), and a positive association was observed with miR-34a-5p (r
s
= 0.31, p = 0.0055) and miR-181a-2-3p (r
s
= 0.39, p = 0.0002). SIRT6 mRNA also negatively correlated with the expression of TP53 (r
s
= −0.41, p = 0.0126) and MYC (r
s
= −0.35, p = 0.0448). Notably, the expression of several miRNAs and genes was similar in young and long-lived groups but different from the middle-aged group. We conclude that age-related epigenetic changes can affect the expression of SIRT6 in PBMCs and, in this way, possibly influence immunosenescence. Moreover, molecular events could differentiate 'normal' ageing from that of long-lived individuals.
PDF
