SummaryA diet deficient in the amino acid methionine has previously been shown to extend lifespan in several stocks of inbred rats. We report here that a methionine-deficient (Meth-R) diet also increases maximal lifespan in (BALB/ cJ × × × × C57BL/6 J)F1 mice. Compared with controls, Meth-R mice have significantly lower levels of serum IGF-I, insulin, glucose and thyroid hormone. Meth-R mice also have higher levels of liver mRNA for MIF (macrophage migration inhibition factor), known to be higher in several other mouse models of extended longevity. Meth-R mice are significantly slower to develop lens turbidity and to show age-related changes in T-cell subsets. They are also dramatically more resistant to oxidative liver cell injury induced by injection of toxic doses of acetaminophen. The spectrum of terminal illnesses in the Meth-R group is similar to that seen in control mice. Studies of the cellular and molecular biology of methionine-deprived mice may, in parallel to studies of calorie-restricted mice, provide insights into the way in which nutritional factors modulate longevity and late-life illnesses.

To gain insight into the pathways by which caloric restriction (CR) slows aging, gene expression levels were assessed for each of 2,352 genes in the livers of 9-month-old CR and control mice. A total of 352 genes were found to be significantly increased or decreased by CR. The distribution of affected genes among functional classes was similar to the distribution of genes within the test set. Surprisingly, a disruption or knockout of the gene for the GH receptor (GHR-KO), which also produces life extension, had a much smaller effect on gene expression, with no more than 10 genes meeting the selection criterion. There was, however, an interaction between the GHR-KO mutation and the CR diet: the effects of CR on gene expression were significantly lower in GHR-KO mice than in control mice. Of the 352 genes altered significantly by CR, 29 had shown a significant and parallel alteration in expression in a previous study of liver gene expression that compared mice of the long-lived Snell dwarf stock (dw/dw) to controls. These 29 genes, altered both by CR and in dwarf mice, provide a list of biochemical features common to both models of delayed aging, and thus merit confirmation and more detailed study.

Idiopathic pneumonia syndrome (IPS) is a significant cause of mortality after allogeneic bone marrow transplantation (allo-BMT), and tumor necrosis factor-␣ (TNF-␣) is a significant effector molecule in this process. However, the relative contribution of donor-versus host-derived TNF-␣ to the development of IPS has not been elucidated. Using a lethally irradiated parent 3 F1 mouse IPS model, we showed that 5 weeks after transplantation allo-BMT recipients developed significant lung injury compared with syngeneic controls, which was associated with increased bronchoalveolar lavage (BAL) fluid levels of TNF-␣, elevated numbers of donorderived TNF-␣-secreting T cells, and increased pulmonary macrophage production of TNF-␣ to lipopolysaccharide (LPS) stimulation. Allo-BMT with TNF-␣ ؊/؊ donor cells resulted in significantly reduced IPS severity, whereas utilization of TNF-␣-deficient mice as BMT recipients had no effect on IPS. We next determined that TNF-␣ secretion from both donor accessory cells (monocytes/macrophages) and T cells significantly contributed to the development of IPS. Importantly, the absence of donor T-cell-derived TNF-␣ resulted in a significant decrease in inflammatory chemokine production in the lung and near complete abrogation of IPS.Collectively, these data demonstrate that donor TNF-␣ is critical to the development of IPS and reveal a heretofore unknown mechanism for T-cell-derived TNF-␣ in the evolution of this process.

Previous studies have shown that dermal fibroblast cell lines derived from young adult mice of the long-lived Snell dwarf (dw/dw), Ames dwarf (df/df) and growth hormone receptor knockout (GHR-KO) mouse stocks are resistant, in vitro, to the cytotoxic effects of hydrogen peroxide, cadmium, ultraviolet light, paraquat, and heat. Here we show that, in contrast, fibroblasts from mice on low-calorie (CR) or low methionine (Meth-R) diets are not stress resistant in culture, despite the longevity induced by both dietary regimes. A second approach, involving induction of liver cell death in live animals using acetaminophen (APAP), documented hepatotoxin resistance in the CR and Meth-R mice, but dw/dw and GHR-KO mutant mice were not resistant to this agent, and were in fact more susceptible than littermate controls to the toxic effects of APAP. These data thus suggest that while resistance to stress is a common characteristic of experimental life span extension in mice, the cell types showing resistance may differ among the various models of delayed or decelerated aging.

To gain further insight into the basis for the extended longevity and delayed aging of Snell dwarf (dw/dw) mice, we have measured levels of expression of 2352 genes in liver of mice at 6 months of age. We find 60 genes for the which the Student's t statistic meets the arbitrary criterion of p <.001, and among these 17 meet the Bonferroni-adjusted significance criterion at p <.05, which corresponds to a nominal value of p <.00002. Using the Bonferroni criterion, we find that dwarf mice show increases in liver mRNA for two mannose-binding lectins, two DNA binding proteins, serum amyloid P component, corticosteroid-binding globulin, and insulin-like growth factor-binding protein 2, as well as decreases in a two phosphodiesterases, a pheromone-binding urinary protein, insulin-like growth factor-I (IGF-I), a calcium-binding protein calgranulin B, a deubiquitinating enzyme, a hydroxysteroid dehydrogenase, a DNA methyltransferase, a glycine transporter, and a placental lactogen. We also use this data set to compare the results of different suggested criteria for evaluating intergroup differences in gene expression. Of the 2352 genes examined, 524 (22%) showed a twofold difference between dwarf and normal mice, but most of these fail to meet the conventional significance criterion of p <.05, let alone criteria that have been adjusted to compensate for multiple comparison artifacts. The list of genes that show reliable differences between dwarf and control animals provides new insights into the range of changes induced by deficiencies in growth hormone, thyroid-stimulating hormone, and prolactin, and it will help to guide further studies of the pathways by which these hormone deficiencies contribute to delayed aging in these mutant mice.

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Background To investigate the effectiveness and safety of withholding or restarting antithrombotic agents, and different antithrombotic therapies among patients with atrial fibrillation post‐intracranial hemorrhage. Methods and Results This is a nationwide retrospective cohort study involving patients with atrial fibrillation receiving antithrombotic therapies who subsequently developed intracranial hemorrhage between January 1, 2011 and December 31, 2017. The risk of ischemic stroke (IS), recurrent intracerebral hemorrhage (ICH), and all‐cause mortality were investigated between patients receiving no treatment versus patients reinitiating oral anticoagulants (OACs) or antiplatelet agents, and warfarin versus non‐vitamin K antagonist OACs. We applied inverse probability of treatment weighting to balance the baseline characteristics and Cox proportional hazards model to estimate the hazard ratios (HRs) of different outcomes of interest. Compared with no treatment, OACs reduced the risk of IS (HR, 0.61; 0.42–0.89), without increase in the risk of ICH (1.15, 0.66–2.02); antiplatelet agent users showed a similar risk of IS (1.13, 0.81–1.56) and increased risk of ICH (1.81, 1.07–3.04). Use of OACs or antiplatelet agents did not reduce the risk of all‐cause mortality (0.85, 0.72–1.01; and 0.88, 0.75–1.03, respectively). Compared with warfarin, non‐vitamin K antagonist OAC users showed a similar risk of IS (0.92, 0.50–1.70), non‐significantly reduced risk of ICH (0.53, 0.22–1.30), and significantly reduced all‐cause mortality (0.60, 0.43–0.84). Conclusions OACs are recommended in patients with atrial fibrillation and intracranial hemorrhage because they reduced the risk of IS with no increase in the risk of subsequent ICH. Non‐vitamin K antagonist OACs are recommended over warfarin owing to their survival benefits.

Internalization of macromolecules and membrane into cells through endocytosis is critical for cellular growth, signaling and plasma membrane (PM) tension homeostasis. Although endocytosis is responsive to both biochemical and physical stimuli, how physical cues modulate endocytic pathways is less understood. Contrary to the accumulating discoveries on the effects of increased PM tension on endocytosis, less is known about how a decrease of PM tension impacts on membrane trafficking. Here, we reveal that an acute decrease of PM tension results in phosphatidic acid (PA) production, F-actin and phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P 2 ]enriched dorsal membrane ruffling and subsequent macropinocytosis in myoblasts. The PA production induced by decreased PM tension depends on phospholipase D2 (PLD2) activation via PLD2 nanodomain disintegration. Furthermore, the 'decreased PM tension-PLD2-macropinocytosis' pathway is prominent in myotubes, reflecting a potential mechanism of PM tension homeostasis upon intensive muscle stretching and relaxation. Together, we identify a new mechanotransduction pathway that converts an acute decrease in PM tension into PA production and then initiates macropinocytosis via actin and PI(4,5)P 2 -mediated processes.