Social stress shortens lifespan in mice.

Stress and low socioeconomic status in humans confer increased vulnerability to morbidity and mortality. However, this association is not mechanistically understood nor has its causation been explored in animal models thus far. Recently, cellular senescence has been suggested as a potential mechanism linking lifelong stress to age-related diseases and shorter life expectancy in humans. Here, we established a causal role for lifelong social stress on shortening lifespan and increasing the risk of cardiovascular disease in mice. Specifically, we developed a lifelong chronic psychosocial stress model in which male mouse aggressive behavior is used to study the impact of negative social confrontations on healthspan and lifespan. C57BL/6J mice identified through unbiased cluster analysis for receiving high while exhibiting low aggression, or identified as subordinate based on an ethologic criterion, had lower median and maximal lifespan, and developed earlier onset of several organ pathologies in the presence of a cellular senescence signature. Critically, subordinate mice developed spontaneous early-stage atherosclerotic lesions of the aortic sinuses characterized by significant immune cells infiltration and sporadic rupture and calcification, none of which was found in dominant subjects. In conclusion, we present here the first rodent model to study and mechanistically dissect the impact of chronic stress on lifespan and disease of aging. These data highlight a conserved role for social stress and low social status on shortening lifespan and increasing the risk of cardiovascular disease in mammals and identify a potential mechanistic link for this complex phenomenon.

The neuropeptide TLQP-21 opposes obesity via C3aR1-mediated enhancement of adrenergic-induced lipolysis.

OBJECTIVES: Obesity is characterized by excessive fat mass and is associated with serious diseases such as type 2 diabetes. Targeting excess fat mass by sustained lipolysis has been a major challenge for anti-obesity therapies due to unwanted side effects. TLQP-21, a neuropeptide encoded by the pro-peptide VGF (non-acronymic), that binds the complement 3a receptor 1 (C3aR1) on the adipocyte membrane, is emerging as a novel modulator of adipocyte functions and a potential target for obesity-associated diseases. The molecular mechanism is still largely uncharacterized. METHODS: We used a combination of pharmacological and genetic gain and loss of function approaches. 3T3-L1 and mature murine adipocytes were used for in vitro experiments. Chronic in vivo experiments were conducted on diet-induced obese wild type, ß1, ß2, ß3-adrenergic receptor (AR) deficient and C3aR1 knockout mice. Acute in vivo lipolysis experiments were conducted on Sprague Dawley rats. RESULTS: We demonstrated that TLQP-21 does not possess lipolytic properties per se. Rather, it enhances ß-AR activation-induced lipolysis by a mechanism requiring Ca2+ mobilization and ERK activation of Hormone Sensitive Lipase (HSL). TLQP-21 acutely potentiated isoproterenol-induced lipolysis in vivo. Finally, chronic peripheral TLQP-21 treatment decreases body weight and fat mass in diet induced obese mice by a mechanism involving ß-adrenergic and C3a receptor activation without associated adverse metabolic effects. CONCLUSIONS: In conclusion, our data identify an alternative pathway modulating lipolysis that could be targeted to diminish fat mass in obesity without the side effects typically observed when using potent pro-lipolytic molecules.

The role of dorsolateral prefrontal cortex in inhibition mechanism: A study on cognitive reflection test and similar tasks through neuromodulation.

The main characteristic of the cognitive reflection test (CRT) is that it requires people to overcome a cognitive conflict. Solving this conflict requires (1) inhibitory control of prepotent but incorrect responses and (2) mental set-shifting in order to reframe the problem and reach a meaningful solution. Based on the well-known involvement of the dorsolateral prefrontal cortex (DLPFC) in inhibitory control we hypothesised that transcranial direct current stimulation (tDCS) of the DLPFC would modulate its contribution to problem-solving performance. Thirty-nine participants undergoing anodal, cathodal, or sham tDCS were asked to solve the CRT and similar mathematical problems that were structured to induce an automatic, impulsive but incorrect response. To provide a multi-dimensional picture of the processes underlying responding we assessed impulsivity traits using self-report measures and recorded physiological indices using biofeedback equipment. The results indicated that participants were more likely to provide incorrect impulsive responses after cathodal stimulation, i.e. when inhibitory control associated to the DLPFC was reduced. Baseline values of blood volume pulses predicted solution recognition, highlighting the potential role of individual physiological differences in problem solving. In conclusion, this study provides evidence supporting the role of the DLPFC in modulation of processes involved in solving CRTs and similar problems, thanks to its association to the inhibitory control mechanisms involved in suppressing impulsive responses.