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

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

Learning Agile Soccer Skills for a Bipedal Robot with Deep Reinforcement Learning

We investigate whether Deep Reinforcement Learning (Deep RL) is able to synthesize sophisticated and safe movement skills for a low-cost, miniature humanoid robot that can be composed into complex behavioral strategies in dynamic environments. We used Deep RL to train a humanoid robot with 20 actuated joints to play a simplified one-versus-one (1v1) soccer game. We first trained individual skills in isolation and then composed those skills end-to-end in a self-play setting. The resulting policy exhibits robust and dynamic movement skills such as rapid fall recovery, walking, turning, kicking and more; and transitions between them in a smooth, stable, and efficient manner - well beyond what is intuitively expected from the robot. The agents also developed a basic strategic understanding of the game, and learned, for instance, to anticipate ball movements and to block opponent shots. The full range of behaviors emerged from a small set of simple rewards. Our agents were trained in simulation and transferred to real robots zero-shot. We found that a combination of sufficiently high-frequency control, targeted dynamics randomization, and perturbations during training in simulation enabled good-quality transfer, despite significant unmodeled effects and variations across robot instances. Although the robots are inherently fragile, minor hardware modifications together with basic regularization of the behavior during training led the robots to learn safe and effective movements while still performing in a dynamic and agile way. Indeed, even though the agents were optimized for scoring, in experiments they walked 156% faster, took 63% less time to get up, and kicked 24% faster than a scripted baseline, while efficiently combining the skills to achieve the longer term objectives. Examples of the emergent behaviors and full 1v1 matches are available on the supplementary website.Comment: Project website: https://sites.google.com/view/op3-socce

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Studio del cross-talk tra il tessuto adiposo ed il tessuto muscolare in un modello in vitro

Il tessuto adiposo (TA) bianco ha degli effetti negativi sulla funzione e sulla qualità del muscolo scheletrico ma si hanno poche informazioni sugli effetti degli adipociti senescenti e disfunzionali sulle cellule muscolari. Il TA e quello muscolare, possono comunicare tra loro attraverso le extra-vescicole (EV) che possono regolare la sensibilità all’insulina. Abbiamo realizzato un modello in vitro utilizzando un terreno di coltura condizionato ottenuto da adipociti murini 3T3-L1 maturi, invecchiati, insulino-resistenti ed esposti a stress ossidativo per trattare miociti C2C12. Dal medium sono state inoltre estratte e caratterizzate le EV mediante microscopia elettronica e tecnica del rilevamento di impulsi resistivi sintonizzabili (TRPS). Le analisi hanno indicato una significativa diminuzione del diametro dei miociti e dell’indice di fusione dopo il trattamento con medium di adipociti invecchiati o sottoposti a stress ossidativo o resi insulino-resistenti.Inoltre, in queste cellule, si riduce l’espressione genica dei marcatori di differenziazione miogenica (MyHC-Iib, MyoD) ed è stato osservato una tendenza verso un’aumentata espressione di geni coinvolti nella fibrosi (CCN-2, COL1A1) e nell’atrofia muscolare (Atrogin-1, MuRF1) nei miociti trattati con medium di adipociti invecchiati o stressati. Esiste una tendenziale riduzione della sintesi proteica ed un significativo aumento dell’espressione della miostatina nelle cellule C2C12 trattate con medium di adipociti invecchiati rispetto ai controlli e c’è concentrazione di EV maggiore nel gruppo insulino-resistente rispetto al controllo. Questi risultati preliminari suggeriscono che gli adipociti invecchiati o disfunzionali potrebbero influenzare negativamente il trofismo, la funzione e la capacità rigenerativa dei miociti attraverso una rete paracrina di segnalazione e le EV potrebbero essere coinvolte in questi processi

Studio del cross-talk tra il tessuto adiposo ed il tessuto muscolare in un modello in vitro

Il tessuto adiposo (TA) bianco ha degli effetti negativi sulla funzione e sulla qualità del muscolo scheletrico ma si hanno poche informazioni sugli effetti degli adipociti senescenti e disfunzionali sulle cellule muscolari. Il TA e quello muscolare, possono comunicare tra loro attraverso le extra-vescicole (EV) che possono regolare la sensibilità all’insulina. Abbiamo realizzato un modello in vitro utilizzando un terreno di coltura condizionato ottenuto da adipociti murini 3T3-L1 maturi, invecchiati, insulino-resistenti ed esposti a stress ossidativo per trattare miociti C2C12. Dal medium sono state inoltre estratte e caratterizzate le EV mediante microscopia elettronica e tecnica del rilevamento di impulsi resistivi sintonizzabili (TRPS). Le analisi hanno indicato una significativa diminuzione del diametro dei miociti e dell’indice di fusione dopo il trattamento con medium di adipociti invecchiati o sottoposti a stress ossidativo o resi insulino-resistenti.Abbiamo osservato che nei miociti trattati col terreno ottenuto da adipociti invecchiati e/o disfunzionali, si riduce l’espressione genica dei marcatori di differenziazione miogenica (MyHC-Iib, MyoD) e si osserva una tendenza verso un’aumentata espressione di geni coinvolti nella fibrosi (CCN-2, COL1A1) e nell’atrofia muscolare (Atrogin-1, MuRF1) nei miociti trattati con medium di adipociti invecchiati o stressati. Esiste una tendenziale riduzione della sintesi proteica ed un significativo aumento dell’espressione della miostatina nelle cellule C2C12 trattate con medium di adipociti invecchiati rispetto ai controlli e c’è concentrazione di EV maggiore nel gruppo insulino-resistente rispetto al controllo. Questi risultati preliminari suggeriscono che gli adipociti invecchiati o disfunzionali potrebbero influenzare negativamente il trofismo, la funzione e la capacità rigenerativa dei miociti attraverso una rete paracrina di segnalazione e le EV potrebbero essere coinvolte in questi processi

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

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

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. 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. 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. 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

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)