Senescent adipocytes as potential effectors of muscle cells dysfunction: An in vitro model.

Recently, there has been a growing body of evidence showing a negative effect of the white adipose tissue (WAT) dysfunction on the skeletal muscle function and quality. However, little is known about the effects of senescent adipocytes on muscle cells. Therefore, to explore potential mechanisms involved in age-related loss of muscle mass and function, we performed an in vitro experiment using conditioned medium obtained from cultures of mature and aged 3 T3-L1 adipocytes, as well as from cultures of dysfunctional adipocytes exposed to oxidative stress or high insulin doses, to treat C2C12 myocytes. The results from morphological measures indicated a significant decrease in diameter and fusion index of myotubes after treatment with medium of aged or stressed adipocytes. Aged and stressed adipocytes presented different morphological characteristics as well as a different gene expression profile of proinflammatory cytokines and ROS production. In myocytes treated with different adipocytes' conditioned media, we demonstrated a significant reduction of gene expression of myogenic differentiation markers as well as a significant increase of genes involved in atrophy. Finally, a significant reduction in protein synthesis as well as a significant increase of myostatin was found in muscle cells treated with medium of aged or stressed adipocytes compared to controls. In conclusion, these preliminary results suggest that aged adipocytes could influence negatively trophism, function and regenerative capacity of myocytes by a paracrine network of signaling.

Fibrogenesis Marker PRO-C3 Is Higher in Advanced Liver Fibrosis and Improves in Patients Undergoing Bariatric Surgery.

CONTEXT: Serum propeptides of type III and type VI collagen (PRO-C3 and PRO-C6) are elevated in advanced nonalcoholic fatty liver disease (NAFLD), but their value in patients with severe obesity and their evolution after bariatric surgery (BS) is unknown. It is unclear if these markers of fibrogenesis are affected by adipose tissue fibrosis (ATF). OBJECTIVE: We studied the association of PRO-C3 and PRO-C6 with liver fibrosis before BS, examined their evolution after BS, and evaluated how much patients' ATF contribute to their levels. METHODS: Serum PRO-C3 and PRO-C6 were measured in 158 BS patients and compared with liver, subcutaneous, and omental adipose tissue histology obtained during surgery. PRO-C3 and PRO-C6 levels of 63 patients were determined in follow-up at 3 and 12 months post-BS. RESULTS: Patients in the highest quartile of PRO-C3 had a higher risk of advanced liver fibrosis (stage F3-4; odds ratio 5.8; 95% CI [1.5-29.9]; P = 0.017) vs the lowest quartile (adjustment for age, gender, and BMI). PRO-C3 was positively correlated with markers of insulin resistance and liver enzymes. After BS, PRO-C3 levels decreased in patients with high baseline liver fibrosis. This decrease correlated with improvement of metabolic and liver parameters. PRO-C6 was not related to stage of liver fibrosis. ATF did not correlate with PRO-C3 or PRO-C6 levels at baseline or after BS. CONCLUSION: PRO-C3 was associated with advanced liver fibrosis in patients with severe obesity, and decreased after BS, without being affected by ATF. These data suggest that BS prominently eliminates drivers of hepatic fibrogenesis in NAFLD.

Senolytic effects of quercetin in an in vitro model of pre-adipocytes and adipocytes induced senescence.

The dysfunction of adipose tissue with aging and the accumulation of senescent cells has been implicated in the pathophysiology of chronic diseases. Recently interventions capable of reducing the burden of senescent cells and in particular the identification of a new class of drugs termed senolytics have been object of extensive investigation. We used an in vitro model of induced senescence by treating both pre-adipocytes as well as mature adipocytes with hydrogen peroxide (H2O2) at a sub-lethal concentration for 3 h for three consecutive days, and hereafter with 20 uM quercetin at a dose that in preliminary experiments resulted to be senolytic without cytotoxicity. H2O2 treated pre-adipocytes and adipocytes showed typical senescence-associated features including increased beta-galactosidase activity (SA-ß-gal) and p21, activation of ROS and increased expression of pro-inflammatory cytokines. The treatment with quercetin in senescent pre-adipocytes and adipocytes was associated to a significant decrease in the number of the SA-ß-gal positive cells along with the suppression of ROS and of inflammatory cytokines. Besides, quercetin treatment decreased miR-155-5p expression in both models, with down-regulation of p65 and a trend toward an up-regulation of SIRT-1 in complete cell extracts. The senolytic compound quercetin could affect AT ageing by reducing senescence, induced in our in vitro model by oxidative stress. The downregulation of miRNA-155-5p, possibly through the modulation of NF-κB and SIRT-1, could have a key role in the effects of quercetin on both pre-adipocytes and adipocytes.

The Mini Sarcopenia Risk Assessment (MSRA) Questionnaire score as a predictor of skeletal muscle mass loss.

BACKGROUND: Previous studies showed a strong relationship between reduction of appendicular muscle mass and worsening disability; hence, accuracy in assessing muscle mass is considered a key feature for a sarcopenia screening tool. AIM: The aim of the study was to evaluate if the 7 items of Mini Sarcopenia Risk Assessment (MSRA) questionnaire predict muscle mass loss in a population of community-dwelling elderly subjects over a 5.5-y follow-up. METHODS: The study included 159 subjects, 92 women and 67 men aged 71.5 ± 2.2 years and with mean body mass index of 26.7 ± 4.0 kg/m2. Appendicular skeletal muscle mass (ASMM) as measured with Dual-Energy X-ray absorptiometry (DXA), was obtained at baseline and after 2 and 5.5 years of follow-up where the skeletal muscle index (SMI) was calculated. RESULTS: A significant reduction of ASMM and SMI was observed at two and 5.5 years of follow-up, in both, men and women. Repeated-measures analysis of variance (ANOVA) found a significant time effect on ASMM for both subjects with MSRA > 30 and ≤ 30 (P < 0.01 and P < 0.001). The group × time interaction was significant (P < 0.001), after even considering separately subjects with normal muscle mass and low muscle mass at baseline (P < 0.05 and P = 0.005). Similar results were obtained for SMI. Considering only the subjects with normal SMI at baseline, subjects with MSRA questionnaire ≤ 30 showed 5.7 (95% CI 1.73-19.03) higher risk of exceeding the low muscle mass threshold. CONCLUSION: In a population of community-dwelling elderly men and women, MSRA score of 30 is predictive of a steeper decline in ASMM and SMI and of a higher risk of exceeding the low muscle mass EWGSOP threshold.

How does adipose tissue contribute to inflammageing?

Across aging, white adipose tissue (WAT) undergoes significant changes in quantity and distribution, with an increase in visceral adipose tissue, ectopic fat deposition and a decline in gluteofemoral subcutaneous depot. In particular, WAT becomes dysfunctional with an increase in production of inflammatory peptides and a decline of those with anti-inflammatory activity and infiltration of inflammatory cells. Moreover, dysfunction of WAT is characterized by preadipocyte differentiation decline, increased oxidative stress and mitochondrial dysfunction, reduction in vascularization and hypoxia, increased fibrosis and senescent cell accumulation. WAT changes represent an important hallmark of the aging process and may be responsible for the systemic pro-inflammatory state ("inflammageing") typical of aging itself, leading to age-related metabolic alterations. This review focuses on mechanisms linking age-related WAT changes to inflammageing.

Worsening Disability and Hospitalization Risk in Sarcopenic Obese and Dynapenic Abdominal Obese: A 5.5 Years Follow-Up Study in Elderly Men and Women.

Background/Objectives: A general lack of studies comparing the effect of both dynapenic abdominal obesity and sarcopenic obesity on worsening disability and hospitalization risk should be recognized. The aim of the current study was to evaluate, with a 5.5-year follow-up, the prognostic value of sarcopenic obesity and dynapenic abdominal obesity definitions on worsening disability and hospitalization risk in a sample of older adults. Subjects/Methods: In 177 women and 97 men aged 68-78 years, the following outcomes were evaluated at baseline: appendicular skeletal muscle mass (ASMM), percent fat mass (FM%), leg isometric strength, body mass index (BMI), lipid profile, vitamin D3, albumin, fibrinogen, glycemia, physical activity level, income, smoking status, and comorbidities. The rate of reported disabilities and hospitalization were also assessed at baseline, 1, 2, 3, and 5.5-years follow-up. The study population was classified into: (i) non-sarcopenic/obese (NS/O), sarcopenic/non-obese (S/NO), sarcopenic/obese (S/O), non-sarcopenic/non-obese (NS/NO, reference category) according to relative ASMM/FM% tertiles; (ii) non-dynapenic/abdominal obese (ND/AO), dynapenic/non-abdominal obese (D/NAO), dynapenic/abdominal obese (D/AO), non-dynapenic/non-abdominal obese (ND/NAO, reference category) according to muscle strength/waist circumference tertiles. Results: The prevalence of D/AO and S/O was 12.0 and 8.0%, respectively. Only 2 subjects were both D/NAO and S/O (0.8%). D/NAO subjects showed a worsening disability risk of 1.69 times (95% CI: 1.11-2.57), ND/AO subjects showed a 2-fold increased risk (95% CI: 1.34-2.98), while being D/AO more than trebled the risk, even after adjustment for confounding factors (HR: 3.39, 95%; CI: 1.91-6.02). By dividing the study population according to the relative ASMM/FM% tertiles, no groups showed an increased risk of worsening disability. The hospitalization risk, even after adjustment for potential confounders, was 1.84 (95% CI: 1.06-3.19) for D/AO. Dividing the study population according to the relative ASMM/FM% tertiles, no groups showed increased risk of hospitalization. Conclusions: Our results showed that dynapenic abdominal obesity and sarcopenic obesity seem to indicate two distinct phenotypes associated with different health risk profiles. The distribution of participants in waist circumference and muscle strength tertiles allowed for a more accurate risk stratification for worsening disability and hospitalization.

Brown and Beige Adipose Tissue and Aging.

Across aging, adipose tissue (AT) changes its quantity and distribution: AT becomes dysfunctional with an increase in production of inflammatory peptides, a decline of those with anti-inflammatory activity and infiltration of macrophages. Adipose organ dysfunction may lead to age-related metabolic alterations. Aging is characterized by an increase in adiposity and a decline in brown adipose tissue (BAT) depots and activity, and UCP1 expression. There are many possible links to age-associated involution of BAT, including the loss of mitochondrial function, impairment of the sympathetic nervous system, age-induced alteration of brown adipogenic stem/progenitor cell function and changes in endocrine signals. Aging is also associated with a reduction in beige adipocyte formation. Beige adipocytes are known to differentiate from a sub-population of progenitors resident in white adipose tissue (WAT); a defective ability of progenitor cells to proliferate and differentiate has been hypothesized with aging. The loss of beige adipocytes with age may be caused by changes in trophic factors in the adipose tissue microenvironment, which regulate progenitor cell proliferation and differentiation. This review focuses on possible mechanisms involved in the reduction of BAT and beige activity with aging, along with possible targets for age-related metabolic disease therapy.

Predictors of self-reported adherence to direct oral anticoagulation in a population of elderly men and women with non-valvular atrial fibrillation.

There is a general lack of studies evaluating medication adherence with self-report scales for elderly patients in treatment with direct oral anticoagulants (DOACs). The aim of the study was to assess the degree of adherence to DOAC therapy in a population of elderly outpatients aged 65 years or older affected by non-valvular atrial fibrillation (NVAF), using the 4-item Morisky Medication Adherence Scale, and to identify potential factors, including the geriatric multidimensional evaluation, which can affect adherence in the study population. A total of 103 subjects, anticoagulated with DOACs for NVAF in primary or secondary prevention, were eligible; 76 showed adequate adhesion to anticoagulant therapy, while 27 showed inadequate adherence. Participants underwent biochemical assessment and Morisky Scale, Instrumental Activities of Daily Living, CHA2DS2-VASc, HAS-BLED, mental status and nutritional evaluations were performed. 2% of subjects assumed Dabigatran at low dose, while 7.8% at standard dose, 9.7% assumed low-dose of Rivaroxaban and 30.1% at standard dose, 6.8% assumed Apixaban at low dose and 39.7% at standard dose, and finally 1% assumed Edoxaban at low dose and 2.9% at standard dose. Most subjects took the DOACs without help (80.6%), while 16 subjects were helped by a family member (15.5%) and 4 were assisted by a caregiver (3.9%). Binary logistic regression considered inappropriate adherence as a dependent variable, while age, male sex, polypharmacotherapy, cognitive decay, caregiver help for therapy assumption, duration of DOAC therapy and double daily administration were considered as independent variables. The double daily administration was an independent factor, determining inappropriate adherence with an OR of 2.88 (p = 0.048, CI 1.003-8.286).

Association between intestinal permeability and faecal microbiota composition in Italian children with beta cell autoimmunity at risk for type 1 diabetes.

BACKGROUND: Pancreatic organ-specific autoimmunity in subjects at risk for type 1 diabetes (T1D) is associated with increased intestinal permeability and an aberrant gut microbiota, but these factors have not yet been simultaneously investigated in the same subjects. Thus, the aim of this study was to assess both intestinal permeability and gut microbiota composition in an Italian sample of children at risk for T1D. METHODS: Ten Italian children with beta cell autoimmunity at risk for T1D and 10 healthy children were involved in a case-control study. The lactulose/mannitol test was used to assess intestinal permeability. Analysis of microbiota composition was performed using polymerase chain reaction followed by denaturing gradient gel electrophoresis, based on the 16S rRNA gene. RESULTS: Intestinal permeability was significantly higher in children at risk for T1D than in healthy controls. Moreover, the gut microbiota of the former differed from that of the latter group: Three microorganisms were detected - Dialister invisus, Gemella sanguinis and Bifidobacterium longum - in association with the pre-pathologic state. CONCLUSIONS: The results of this study validated the hypothesis that increased intestinal permeability together with differences in microbiota composition are contemporaneously associated with the pre-pathological condition of T1D in a sample of Italian children. Further studies are necessary to confirm the microbial markers identified in this sample of children as well as to clarify the involvement of microbiota modifications in the mechanisms leading to increased permeability and the autoimmune mechanisms that promote diabetes onset. Copyright © 2016 John Wiley & Sons, Ltd.