Biomarker panels for frailty would be of high value and better than single markers. Based on our search we would propose a core panel of frailty biomarkers consisting of (1) CXCL10 (C-X-C motif chemokine ligand 10), IL-6 (interleukin 6), CX3CL1 (C-X3-C motif chemokine ligand 1), (2) GDF15 (growth differentiation factor 15), FNDC5 (fibronectin type III domain containing 5), vimentin (VIM), (3) regucalcin (RGN/SMP30), calreticulin, (4) PLAU (plasminogen activator, urokinase), AGT (angiotensinogen), (5) BDNF (brain derived neurotrophic factor), progranulin (PGRN), (6) α-klotho (KL), FGF23 (fibroblast growth factor 23), FGF21, leptin (LEP), (7) miRNA (micro Ribonucleic acid) panel (to be further defined), AHCY (adenosylhomocysteinase) and KRT18 (keratin 18). An expanded panel would also include (1) pentraxin (PTX3), sVCAM/ICAM (soluble vascular cell adhesion molecule 1/Intercellular adhesion molecule 1), defensin α, (2) APP (amyloid beta precursor protein), LDH (lactate dehydrogenase), (3) S100B (S100 calcium binding protein B), (4) TGFβ (transforming growth factor beta), PAI-1 (plasminogen activator inhibitor 1), TGM2 (transglutaminase 2), (5) sRAGE (soluble receptor for advanced glycosylation end products), HMGB1 (high mobility group box 1), C3/C1Q (complement factor 3/1Q), ST2 (Interleukin 1 receptor like 1), agrin (AGRN), (6) IGF-1 (insulin-like growth factor 1), resistin (RETN), adiponectin (ADIPOQ), ghrelin (GHRL), growth hormone (GH), (7) microparticle panel (to be further defined), GpnmB (glycoprotein nonmetastatic melanoma protein B) and lactoferrin (LTF). We believe that these predicted panels need to be experimentally explored in animal models and frail cohorts in order to ascertain their diagnostic, prognostic and therapeutic potential.

CD38/cyclic adenosine diphosphate ribose (cADPR) signaling plays an important role in the regulation of intracellular calcium responses to agonists in a variety of cells, including airway smooth muscle (ASM) cells. The present study was aimed at determining the effect of interleukin (IL)-13, a cytokine implicated in the pathogenesis of asthma, on CD38/cADPR signaling and to ascertain the contribution of CD38/cADPR signaling to IL-13-induced airway hyperresponsiveness. Human ASM cells maintained in culture were exposed to 50 ng/ml IL-13 for 22 h and levels of CD38 expression and intracellular calcium responses to agonists were measured. Treatment of human ASM cells with IL-13 resulted in increased CD38 expression as determined by real-time polymerase chain reaction, Western blot analysis, and indirect immunofluorescence. Increased CD38 expression was reflected as increased ADP-ribosyl cyclase activity in the ASM cell membranes. The net intracellular calcium responses to bradykinin, thrombin, and histamine were significantly (P < or = 0.05) higher in cells treated with IL-13 compared with controls. Furthermore, 8-bromo-cADPR, a cADPR antagonist, attenuated IL-13-induced augmented intracellular calcium responses to agonists in human ASM cells. These findings indicate that the CD38/cADPR-dependent pathway has a major role in IL-13-induced modulation of calcium signaling in human ASM.

It is well recognized that obesity increases the risk of various cancers, including breast malignancies in postmenopausal women. Furthermore, obesity may adversely affect tumor progression, metastasis, and overall prognosis in both pre- and postmenopausal women with breast cancer. However, the precise mechanism(s) through which obesity acts is/are still elusive and this relationship has been the subject of much investigation and speculation. Recently, adipose tissue and its associated cytokine-like proteins, adipokines, particularly leptin and adiponectin, have been investigated as mediators for the association of obesity with breast cancer. Higher circulating levels of leptin found in obese subjects could be a growth-enhancing factor as supported by in vitro and preclinical studies, whereas low adiponectin levels in obese women may be permissive for leptin's growth-promoting effects. These speculations are supported by in vitro studies which indicate that leptin promotes human breast cancer cell proliferation while adiponectin exhibits anti-proliferative actions. Further, estrogen and its receptors have a definite impact on the response of human breast cancer cell lines to leptin and adiponectin. More in-depth studies are needed to provide additional and precise links between the in vivo development of breast cancer and the balance of adiponectin and leptin.

. CD38/cyclic ADP-ribose signaling: role in the regulation of calcium homeostasis in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 288: L773-L788, 2005; doi:10.1152/ ajplung.00217.2004.-The contractility of airway smooth muscle cells is dependent on dynamic changes in the concentration of intracellular calcium. Signaling molecules such as inositol 1,4,5-trisphosphate and cyclic ADP-ribose play pivotal roles in the control of intracellular calcium concentration. Alterations in the processes involved in the regulation of intracellular calcium concentration contribute to the pathogenesis of airway diseases such as asthma. Recent studies have identified cyclic ADP-ribose as a calcium-mobilizing second messenger in airway smooth muscle cells, and modulation of the pathway involved in its metabolism results in altered calcium homeostasis and may contribute to airway hyperresponsiveness. In this review, we describe the basic mechanisms underlying the dynamics of calcium regulation and the role of CD38/cADPR, a novel pathway, in the context of airway smooth muscle function and its contribution to airway diseases such as asthma. ryanodine receptor; calcium oscillations; inflammatory cytokines; muscarinic receptors; 12.6-kDa FK506-binding protein CYCLIC ADP-RIBOSE (cADPR), a nucleotide metabolite, mobilizes calcium from the intracellular stores through ryanodine receptors (RyRs). CD38, a membrane-bound glycoprotein, catalyzes the synthesis and degradation of cADPR. Studies from our laboratory and others have demonstrated that CD38/cADPRmediated calcium signaling and calcium release through RyR channels play a vital role in the regulation of calcium homeostasis in airway smooth muscle cells. Furthermore, the role of CD38/cADPR-mediated calcium signaling has been investigated in disease conditions such as asthma, diabetes, and pulmonary vasoconstriction. The review describes the evidence for the physiological and pathophysiological role of CD38/cADPR/RyR signaling in airway smooth muscle cells.

Ageing is a process that gradually increases the organism's vulnerability to death. It affects different biological pathways, and the underlying cellular mechanisms are complex. In view of the growing disease burden of ageing populations, increasing efforts are being invested in understanding the pathways and mechanisms of ageing. We review some mouse models commonly used in studies on ageing, highlight the advantages and disadvantages of the different strategies, and discuss their relevance to disease susceptibility. In addition to addressing the genetics and phenotypic analysis of mice, we discuss examples of models of delayed or accelerated ageing and their modulation by caloric restriction.

Introduction Obesity is a risk factor for postmenopausal breast cancer and is associated with shortened mammary tumor (MT) latency in MMTV-TGF-α mice with dietary-induced obesity. One link between obesity and breast cancer is the adipokine, leptin. Here, the focus is on diet-induced obesity and MT and mammary fat pad (MFP) leptin and apoptotic signaling proteins.

Abstract. calorie restriction prevents mammary tumor (Mt) development in rodents. Usually, chronic calorie restriction (ccr) has been implemented. In contrast, intermittent calorie restriction (Icr) has been less frequently used. recent studies indicate that when a direct comparison of the same degree of ccr vs. Icr was made using MMtV-tgF-α mice which develop Mts in the second year of life, Icr provided greater protection than ccr in delaying Mt detection and reducing tumor incidence. Adiponectin and leptin are two adipocytokines secreted from adipose tissue which have opposite effects on many physiological functions, including proliferation of human breast cancer cells. A recent study indicated that a low adiponectin/leptin ratio was associated with breast cancer. We evaluated the relationship of adiponectin and leptin to Mt development in MMtV-tgF-α calorie-restricted mice at several ages. Mice were enrolled at 10 weeks of age and subjected to 25% caloric reduction implemented either chronically or intermittently. Mice were euthanized at designated time points up to 74 weeks of age. serum samples were collected to measure adiponectin and leptin concentrations. Both ccr and ICR mice had significantly reduced MT incidence. For the groups studied, serum leptin increased over time, while there was a trend for an increase in serum adiponectin levels in ad libitum and Icr mice, with no change in ccr mice between 10 and 74 weeks of age. the adiponectin/leptin ratio was significantly reduced as mice aged, but this ratio in ICR mice was significantly higher than that for ad libitum and ccr mice. no correlation was noted between serum adiponectin and leptin. These findings demonstrate that intermittent calorie restriction delays the early development of Mts. this delay was associated with reduced serum leptin levels following the restriction phases of the protocol. Additionally, serum leptin levels correlated with body weight and body fat in the groups studied. IntroductionBreast cancer is a leading world-wide health problem, with millions of women succumbing to this disease each year. Animal studies have shown that calorie restriction is one of the most effective ways for the prevention of mammary tumor (MT) development, significantly decreasing both spontaneous and carcinogen-induced tumor incidence and tumor size (1-4). In this context, it has been reported that a 20-40% reduction in calorie intake resulted in significant decreases (up to 95%) of Mt incidence (4-8). two major types of calorie restriction protocols have been applied in mammary tumorigenesis prevention: chronic calorie restriction (ccr) and intermittent calorie restriction (Icr), which refer to the application of periods of ʻon' and ʻoff' caloric restriction. Although CCR has been studied extensively, ICR has been less well studied (9,10). Additionally, in these studies direct comparisons of the two restriction methods (ccr vs. Icr) were not made.We directly compared the roles of the two calorie restriction interventions on Mt development in long-term...

There is lack of information concerning how the ratio of adiponectin to leptin in serum affects breast cancer (Brca) proliferation. It is possible that the link between obesity and increased risk for aggressive Brca is in part due to the milieu of cytokines synthesized and released by the adipose tissue [1]. Adiponectin (also known as adipocyte complement-related protein of 30 kDa (Acrp30)) and leptin are two specific cytokines secreted by the adipose tissue. Acrp30 serum levels decrease with increasing fatness while leptin levels increase. Functionally, they appear to oppose each other's actions. Acrp30 can block proliferation of Brca cells [2]. In vitro assays have shown that a number of different Brca cell lines express one or both of the Acrp30 receptors and show reduced growth and/or increased apoptosis in response to Acrp30 [3]. Leptin has been implicated as a growth-promoting factor for Brca [1]. Animal studies also support a role for leptin in mammary tumor development as evidenced by the fact that mice deficient in leptin, Lep ob Lep ob [4], or with non-functioning leptin receptors, Lepr db Lepr db [5], did not develop transgene-induced mammary tumors. It is possible that the levels of adiponectin and leptin receptors, as well as the balance of serum adiponectin and leptin, are critical factors in mammary tumorigenesis.We investigated the effects of Acrp30 and a naturally truncated form known as globular Acrp30 [6] (gAcrp30) in the presence or absence of leptin. There are two different Acrp30 receptors, designated as AdipoR1 and AdipoR2 [7]. Full-length Acrp30 binds with highest affinity to AdipoR2, and gAcrp30 binds with highest affinity to AdipoR1 [7]. The serum levels of gAcrp30 in women with Brca have not yet been fully investigated, nor has the role of gAcrp30 in Brca development. We performed proliferation assays with the MDA-MB-231 (MDA-wt) ERα negative Brca cell line and the MDA-ERα7 cell line which we developed by stably integrating the ERα gene such that it now exhibits increased growth in vivo in the presence of exogenous estradiol [8]. Leptin is present in the serum of almost all humans in the range of 5-50 ng/ ml [9]. However, in obese individuals levels in excess of 100 ng/ml are common. The addition of leptin (50 ng/ml) to these two cell lines caused a slight increase in proliferation ( Figure 1A) for both the MDA-wt and MDA-ERα7 cells after 48 h. Acrp30 is measured in human serum in the range of 2-20 μg/ml and is negatively correlated with body weight, BMI, body fat and serum leptin in women [10]. When these two cell lines were treated with Acrp30 and gAcrp30 there was a reduction in proliferation of the MDA-wt and MDA-ERα7 cells as compared to leptintreated cells. To investigate how changes in the ratio of leptin and Acrp30 or gAcrp30 affect cell growth, we performed proliferation assays using ratios of Acrp30 to leptin that simulate the physiological balance found with increasing body weight, i.e., by decreasing adiponectin and increasing leptin. A high ratio of Acrp30 to leptin caused...