Circulating blood leukocyte gene expression profiles: effects of the Ames dwarf mutation on pathways related to immunity and inflammation

Aging is associated with a decline of immune competence and an increase in markers of inflammation. There is considerable evidence that inflammatory processes play a role in aging and the determination of lifespan. Hypopituitary Ames dwarf mice have extended longevity and exhibit many symptoms of delayed aging, although various aspects of immune function are suppressed in the mutants. In the present study, the expression of genes related to immunity and inflammation was compared in peripheral blood leukocytes (PBL) from Ames dwarf and normal mice using Affymetrix GeneChip arrays. Among the more than 3000 probe sets that were differentially expressed, 273 were identified as being associated with immunity and/or inflammation. Pathway analysis revealed interactions among 91 of these probe sets, centered on casp3, bcl2, il4, prkca, mapk14 and TGFbeta1. Ames dwarf mice had reduced leukocyte expression of casp3 and TGFbeta and increased expression of Bcl2. Alterations in the expression of these genes suggest likely functional changes in apoptosis, B and T cell homeostasis, prostaglandin synthesis, humoral immunity, chemokine activity, complement activation, hemostasis and wound healing pathways. Collectively, these results suggest that activation of both anti-inflammatory pathways and an anti-clotting mechanism combined with reduced turnover of leukocytes may contribute to delayed aging and extended longevity of Ames dwarf mice. We are also aware that alterations in gene expression in PBLs can be due to different composition of PBL populations when comparing Ames dwarf to WT animals, and it will be interesting to investigate these genes in particular PBL populations in the future. However, whole leukocytes population represents the function of immune system in these organisms.     

Effects of caloric restriction on insulin pathway gene expression in the skeletal muscle and liver of normal and long-lived GHR-KO mice

Growth hormone receptor/binding protein knockout (GHR-KO) mice are characterized by resistance to growth hormone (GH), reduced insulin like growth factor 1 (IGF1) levels and enhanced insulin sensitivity and markedly increased lifespan. Findings in these and other long-lived mutant mice, and in normal animals subjected to caloric restriction (CR) indicate that insulin signaling is importantly involved in the control of longevity. We have examined the mRNA expression level of genes involved in insulin/IGF1 action in the skeletal muscle and liver of normal and GHR-KO mice fed ad libitum or subjected to long term 30% CR. The levels of IR, IRS1, IRS2, GLUT4 and IGF1 message in the skeletal muscle were reduced by CR in both normal and GHR-KO mice. In the liver, the results indicate that in GHR-KO mice mRNA expression of genes related to early steps of insulin signaling is up-regulated in the liver but not in the muscle. The results also show that improved insulin sensitivity in response to CR is not due to increased mRNA expression of the above genes in either normal or GHR-KO animals.     

Dysregulated Expression of Both the Costimulatory CD28 and Inhibitory CTLA-4 Molecules in PB T Cells of Advanced Cervical Cancer Patients Suggests Systemic Immunosuppression Related to Disease Progression

Cervical cancer (CC) occurs more frequently in women who are immunosuppressed, suggesting that both local and systemic immune abnormalities may be involved in the evolution of the disease. Costimulatory CD28 and inhibitory CTLA-4 molecules expressed in T cells play a key role in the balanced immune responses. There has been demonstrated a relation between CD28, CTLA-4, and IFN genes in susceptibility to CC, suggesting their importance in CC development. Therefore, we assessed the pattern of CD28 and CTLA-4 expression in T cells from PB of CC patients with advanced CC (stages III and IV according to FIGO) compared to controls. We also examined the ability of PBMCs to secrete IFN-gamma. We found lower frequencies of freshly isolated and ex vivo stimulated CD4 + CD28+ and CD8 + CD28+ T cells in CC patients than in controls. Loss of CD28 expression was more pronounced in the CD8+ T subset. Markedly increased proportions of CTLA-4+ T cells in CC patients before and after culture compared to controls were also observed. In addition, patients’ T cells exhibited abnormal kinetics of surface CTLA-4 expression, with the peak at 24 h of stimulation, which was in contrast to corresponding normal T cells, revealing maximum CTLA-4 expression at 72 h of stimulation. Of note, markedly higher IFN-gamma concentrations were shown in supernatants of stimulated PBMCs from CC patients. Conclusions: Our report shows the dysregulated CD28 and CTLA-4 expression in PB T cells of CC patients, which may lead to impaired function of these lymphocytes and systemic immunosuppression related to disease progression.     

Multivariate analysis as an advantageous approach for prediction of the adverse outcome in head and neck microvascular reconstructive surgery

Background

The use of a free flap has become a mainstay of reconstruction following the ablative surgery in head and neck. The success rates are about 90%, however, several factors have been described to have an adverse effect on free flap survival.

Primary screening of the immunopharmacologic activity of Filatov tissue therapy preparations

The paper presents results of primary assessment of immunopharmacologic activity of tissue preparations (peloidodistillate, FiBS, torfot, extract of aloe, placental extract) and the study of their influence on basic links of immune response (experimental investigations were carried out with mice-hybrids F1). It is found that the studied bioregulators possess immunomodulating action on primary humoral immune response and don't increase a hypersensitive reaction of a slowed type. The direction of immunotropic action of tissue preparations depends on the state of immunologic reactivity of the body and the kind of a preparation (variety of immunopharmacologic activity of the distillates groups and albumin preparations). It is expedient to work out indications to the usage of tissue preparations after V. P. Filatov to prevent and treat immunodeficient and immunopathologic conditions of the body.     

Insulin signaling cascade in the hearts of long-lived growth hormone receptor knockout mice: effects of calorie restriction

Calorie restriction (CR) improves insulin sensitivity and increases life span in normal but not in long-lived growth hormone-resistant knockout (GHRKO) mice. In this study, we examined interactive effects of GH resistance and long-term CR on cardiac insulin action. GHRKO mice exhibited marked increases in the insulin-induced phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), Akt, and ERK1/2 along with elevated insulin-stimulated IRS-1-associated regulatory subunit of phosphatidylinositol 3-kinase in the heart. These changes were associated with elevated protein levels of IR, IRS-1, and Akt and with a down-regulation of cardiac glucose transporter 4 (GLUT4). In normal mice, CR induced an important increase in the phosphorylation of cardiac Akt without elevation of Akt protein, reaching activation levels similar to those seen in GHRKO mice. This change may be cardioprotective and thus contribute to increased longevity in response to CR. Interestingly, the insulin signaling cascade in the heart of GHRKO mice was unaffected by CR.     

Growth hormone increases DNA damage in ovarian follicles and macrophage infiltration in the ovaries

GeroScience - Evidence points to an important role of the growth hormone (GH) in the aging process and longevity. GH-deficient mice are smaller, live longer than normal littermates, and females...