Replicatively senescent human fibroblasts reveal a distinct intracellular metabolic profile with alterations in NAD+ and nicotinamide metabolism.

Cellular senescence occurs by proliferative exhaustion (PEsen) or following multiple cellular stresses but had not previously been subject to detailed metabolomic analysis. Therefore, we compared PEsen fibroblasts with proliferating and transiently growth arrested controls using a combination of different mass spectroscopy techniques. PEsen cells showed many specific alterations in both the NAD+ de novo and salvage pathways including striking accumulations of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) in the amidated salvage pathway despite no increase in nicotinamide phosphoribosyl transferase or in the NR transport protein, CD73. Extracellular nicotinate was depleted and metabolites of the deamidated salvage pathway were reduced but intracellular NAD+ and nicotinamide were nevertheless maintained. However, sirtuin 1 was downregulated and so the accumulation of NMN and NR was best explained by reduced flux through the amidated arm of the NAD+ salvage pathway due to reduced sirtuin activity. PEsen cells also showed evidence of increased redox homeostasis and upregulated pathways used to generate energy and cellular membranes; these included nucleotide catabolism, membrane lipid breakdown and increased creatine metabolism. Thus PEsen cells upregulate several different pathways to sustain their survival which may serve as pharmacological targets for the elimination of senescent cells in age-related disease

Online continuing medical education as a key link for successful noncommunicable disease self-management: the CASALUD™ Model

Héctor Gallardo-Rincón,1 Rodrigo Saucedo-Martínez,1 Ricardo Mujica-Rosales,1 Evan M Lee,2 Amy Israel,2 Braulio Torres-Beltran,3 Úrsula Quijano-González,3 Elena Rose Atkinson,3 Pablo Kuri-Morales,4 Roberto Tapia-Conyer1 1Fundación Carlos Slim, Mexico City, Mexico; 2Lilly Global Health, Eli Lilly and Company, Vernier, Switzerland; 3C230 Consultores, Mexico City, Mexico; 4Mexican Ministry of Health, Mexico City, Mexico Purpose: The purpose of this study is to evaluate how the benefits of online continuing medical education (CME) provided to health care professionals traveled along a patient “educational chain”. In this study, the educational chain begins with the influence that CME can have on the quality of health care, with subsequent influence on patient knowledge, disease self-management, and disease biomarkers. Methods: A total of 422 patients with at least one noncommunicable disease (NCD) treated in eight different Mexican public health clinics were followed over 3 years. All clinics were participants in the CASALUD Model, an NCD care model for primary care, where all clinic staff were offered CME. Data were collected through a questionnaire on health care, patient disease knowledge, and self-management behaviors; blood samples and anthropometric measurements were collected to measure patient disease biomarkers. Results: Between 2013 and 2015, the indexes measuring quality of health care, patient health knowledge, and diabetes self-management activities rose moderately but significantly (from 0.54 to 0.64, 0.80 to 0.84, and 0.62 to 0.67, respectively). Performing self-care activities – including owning and using a glucometer and belonging to a disease support group – saw the highest increase (from 0.65 to 0.75). A1C levels increased between 2013 and 2015 from 7.95 to 8.41% (63–68 mmol/mol) (P<0.001), and blood pressure decreased between 2014 and 2015 from 143.7/76.8 to 137.5/74.4 (systolic/diastolic reported in mmHg) (P<0.001). The mean levels of other disease biomarkers remained statistically unchanged, despite the improvements seen in the previous “links” of the educational chain. Conclusion: Online CME can effect certain changes in the educational chain linking quality of health care, patient knowledge, and self-management behaviors. However, in order to assure adequate NCD control, the entire health care system must be improved in tandem. Online CME programs, such as CASALUD’s, are feasible strategies for impacting changes in disease self-management at a clinic level throughout a country. Keywords: chronic disease, health education, type 2 diabetes mellitus, Mexico, continuing medical education, primary care&nbsp

FASN activity is important for the initial stages of the induction of senescence

Senescent cells accumulate in several tissues during ageing and contribute to several pathological processes such as ageing and cancer. Senescence induction is a complex process not well defined yet and is characterized by a series of molecular changes acquired after an initial growth arrest. We found that fatty acid synthase (FASN) levels increase during the induction of senescence in mouse hepatic stellate cells and human primary fibroblasts. Importantly, we also observed a significant increase in FASN levels during ageing in mouse liver tissues. To probe the central role of FASN in senescence induction, we used a small-molecule inhibitor of FASN activity, C75. We found that C75 treatment prevented the induction of senescence in mouse and human senescent cells. Importantly, C75 also reduced the expression of the signature SASP factors interleukin 1α (IL-1α), IL-1β and IL-6, and suppressed the secretion of small extracellular vesicles. These findings were confirmed using a shRNA targeting FASN. In addition, we find that FASN inhibition induces metabolic changes in senescent cells. Our work underscores the importance of C75 as a pharmacological inhibitor for reducing the impact of senescent cell accumulationChildren with Cancer UK (Number: 14–178)BBSRC (BB/P000223/1)The Royal Society (RG170399)Nacional Health Institute Carlos IIIMiguel-Servet (CP13-00234)MINECO (SAF2016-78666 R