Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.

Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions.pre-print5,92 M

Protective role of chaperone-mediated autophagy against atherosclerosis

Chaperone-mediated autophagy (CMA) contributes to regulation of energy homeostasis by timely degradation of enzymes involved in glucose and lipid metabolism. Here, we report reduced CMA activity in vascular smooth muscle cells and macrophages in murine and human arteries in response to atherosclerotic challenges. We show that in vivo genetic blockage of CMA worsens atherosclerotic pathology through both systemic and cell-autonomous changes in vascular smooth muscle cells and macrophages, the two main cell types involved in atherogenesis. CMA deficiency promotes dedifferentiation of vascular smooth muscle cells and a proinflammatory state in macrophages. Conversely, a genetic mouse model with up-regulated CMA shows lower vulnerability to proatherosclerotic challenges. We propose that CMA could be an attractive therapeutic target against cardiovascular diseases

Increased CD74 expression in human atherosclerotic plaques: contribution to inflammatory responses in vascular cells

AIMS: The purpose of this study was to analyse the expression of CD74 in human atherosclerotic plaques and peripheral blood mononuclear cells (PBMC) as well as its potential participation in proinflammatory responses in cultured human vascular smooth muscle cells (VSMC). METHODS AND RESULTS: CD74 expression was analysed in human atherosclerotic plaques (immunohistochemistry), PBMC (real-time PCR), and human aortic VSMC (real-time PCR and western blotting). Nuclear factor-kappaB (NF-kappaB) activation was assessed by southwestern histochemistry and electrophoretic mobility shift assay. Monocyte chemoattractant protein-1 (MCP-1) levels were studied by both real-time PCR and enzyme-linked immunosorbent assay. CD74 immunostaining was increased in the inflammatory vs. the fibrous region of atherosclerotic plaques (n = 70, 18.2 +/- 1.3 vs. 7.8 +/- 0.6% positive staining/mm2, P < 0.001). CD74 colocalized with the transcription factor NF-kappaB in both VSMC and macrophages. In cultured VSMC, CD74 expression was induced by interferon gamma (IFNgamma). Incubation with an agonistic anti-CD74 antibody or with IFNgamma elicited MCP-1 expression, which was prevented by AKT and gamma-secretase inhibitors. Moreover, CD74 small-interfering RNA decreased NF-kappaB activation and MCP-1 production induced by IFNgamma in VSMC. Finally, CD74 mRNA levels in PBMC from patients with carotid stenosis were higher than in healthy subjects (n = 20, 3 +/- 0.5 vs. 2 +/- 0.5 AU, P < 0.001). Additionally, a linear trend between CD74 mRNA expression tertiles and intima-media thickness (IMT) was observed in PBMC from asymptomatic subjects (n = 185, P < 0.001). CONCLUSION: CD74 levels are increased in plaques and PBMC from patients with carotid stenosis and are associated with IMT in subjects free from clinical cardiovascular diseases. CD74 could be a novel therapeutic target to decrease the inflammatory response in atherosclerosis

Protective role of chaperone-mediated autophagy against atherosclerosis

Significance Cardiovascular diseases remain the leading cause of death worldwide, with atherosclerosis being the most common source of clinical events. Metabolic changes with aging associate with concurrent increased risk of both type 2 diabetes and cardiovascular disease, with the former further raising the risk of the latter. The activity of a selective type of autophagy, chaperone-mediated autophagy (CMA), decreases with age or upon dietary excesses. Here we study whether reduced CMA activity increases risk of atherosclerosis in mouse models. We have identified that CMA is up-regulated early in response to proatherogenic challenges and demonstrate that reduced systemic CMA aggravates vascular pathology in these conditions. We also provide proof-of-concept support that CMA up-regulation is an effective intervention to reduce atherosclerosis severity and progression

Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice

Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlated with lifespan extension, though it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

non present