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Old Mice (old + mouse)

Distribution by Scientific Domains

Life Sciences	65%
Medical Sciences	34%

Distribution within Life Sciences

Anatomy & Physiology	15%

Selected Abstracts

Purple Sweet Potato Color Alleviates D-galactose-induced Brain Aging in Old Mice by Promoting Survival of Neurons via PI3K Pathway and Inhibiting Cytochrome C-mediated Apoptosis

BRAIN PATHOLOGY, Issue 3 2010
Jun Lu
Abstract Purple sweet potato color (PSPC), a class of naturally occurring anthocyanins, protects brain function against oxidative stress induced by D-galactose (D-gal) (Sigma-Aldrich, St. Louis, MO, USA). Our data showed that PSPC enhanced open-field activity, decreased step-through latency, and improved spatial learning and memory ability in D-gal-treated old mice by decreasing advanced glycation end-products' (AGEs) formation and the AGE receptor (RAGE) expression, and by elevating Cu,Zn-superoxide dismutase (Cu,Zn-SOD) (Sigma-Aldrich) and catalase (CAT) expression and activity. Cleavage of caspase-3 and increased terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end-labeling (TUNEL)-positive cells in D-gal-treated old mice were inhibited by PSPC, which might be attributed to its antioxidant property. PSPC also suppressed the activation of c-Jun NH2 -terminal kinase (JNK) and the release of cytochrome c from mitochondria that counteracted the onset of neuronal apoptosis in D-gal-treated old mice. Furthermore, it was demonstrated that phosphoinositide 3-kinase (PI3K) activation was required for PSPC to promote the neuronal survival accompanied with phosphorylation and activation of Akt and p44/42 mitogen-activated protein kinase (MAPK) by using PI3K inhibitor LY294002 (Cell Signaling Technology, Inc., Beverly, MA, USA), implicating a neuronal survival mechanism. The present results suggest that neuronal survival promoted by PSPC may be a potentially effective method to enhance resistance of neurons to age-related disease. [source]

Defective DNA methylation and CD70 overexpression in CD4+ T cells in MRL/lpr lupus-prone mice

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2007

Abstract We have determined that abnormal DNA methylation in T cells coincides with the development of autoimmunity, using a mouse model that exhibits an age-dependent lupus-like disease (MRL/lpr mice). Splenic CD4+ T cells were isolated from these mice at 5 and 16,wk of age (before and after autoimmunity is established) and the expression of DNA methyltransferase,1 (Dnmt1) and the methylation-sensitive gene Tnfsf7 (CD70) was measured. Bisulfite DNA sequencing was used to monitor the methylation status of the Tnfsf7 gene. We found that Dnmt1 steady-state mRNA levels were significantly lower in 16-wk-old MRL/lpr mice, which had established autoimmunity, compared to the 5-wk-old MRL/lpr mice. Furthermore, the expression of CD70 was higher in MRL/lpr mice at 16,wk. CD70 was overexpressed in MRL/lpr mice compared to age- and sex-matched MRL+/+ controls. Bisulfite DNA sequencing of the Tnfsf7 gene in MRL/lpr mice revealed that at 16,wk, CG pairs were hypomethylated compared to 5-wk-old mice, and that Tnfsf7 from MRL/lpr mice was hypomethylated at 16,wk relative to age-matched MRL+/+ controls. Our data indicate that decreased expression of Dnmt1 and the corresponding T cell DNA hypomethylation correlate with the development of age-dependent autoimmunity in MRL/lpr mice. [source]

Cellular and molecular studies of B cells exhibiting reverse somatic mutation throughout life

GENES TO CELLS, Issue 11 2004
Takao Kodera
Somatic mutation of immunoglobulin (Ig) genes plays an important role in generating antibody diversity. The frequency of somatic mutation appears to vary throughout life. However, this process has been difficult to study in vivo because the DNA in and around rearranged V genes undergoes random mutation, causing silent or replacement mutations. Therefore, we have developed a transgenic mouse model for studying the frequency of B cells exhibiting mutation in young and old mice. The system is based on a reporter transgene (HuG-X) that encodes a chimeric Ig heavy chain composed of a murine VDJ segment and a human IgG1 constant region. The VDJ has been mutated to contain a TAG stop codon in the D segment. Therefore, the transgene is transcribed but not translated. Point mutation of the stop codon results in expression of the chimeric H chain, which is readily detected as human IgG1 expression. In vivo, we found that the transgene undergoes spontaneous reverse somatic mutation at a low frequency. Treatment of HuG-X mice with anti-IgD greatly increases the frequency of somatic mutation. The observed mutation frequency in anti-IgD-treated mice increases with age until adulthood, then plateaux and finally declines in aged mice. The mutations in the stop codon were associated with increased double-stranded DNA breaks (DSB) within and around the TAG site. Our results demonstrate that the rate of frequency of spontaneous reverse mutation is very low in vivo, yet it is significantly increased after stimulation with anti-IgD antibodies. The frequency of point mutation is age dependent and correlates with increased DSB. [source]

Functional alterations of liver innate immunity of mice with aging in response to CpG-oligodeoxynucleotide,

HEPATOLOGY, Issue 5 2008
Toshinobu Kawabata
Immune functions of liver natural killer T (NKT) cells induced by the synthetic ligand ,-galactosylceramide enhanced age-dependently; hepatic injury and multiorgan dysfunction syndrome (MODS) induced by ligand-activated NKT cells were also enhanced. This study investigated how aging affects liver innate immunity after common bacteria DNA stimulation. Young (6 weeks) and old (50-60 weeks) C57BL/6 mice were injected with CpG oligodeoxynucleotides (CpG-ODN), and the functions of liver leukocytes were assessed. A CpG-ODN injection into the old mice remarkably increased tumor necrosis factor (TNF) production in Kupffer cells, and MODS and lethal shock were induced, both of which are rarely seen in young mice. Old Kupffer cells showed increased Toll-like receptor-9 expression, and CpG-ODN challenge augmented TNF receptor and Fas-L expression in liver NKT cells. Experiments using mice depleted of natural killer (NK) cells by anti-asialoGM1 antibody (Ab), perforin knockout mice, and mice pretreated with neutralizing interferon (IFN)-, Ab demonstrated the important role of liver NK cells in antitumor immunity. The production capacities of old mice for IFN-,, IFN-,, and perforin were much lower than those of young mice, and the CpG-induced antitumor cytotoxicity of liver NK cells lessened. Lethal shock and MODS greatly decreased in old mice depleted/deficient in TNF, FasL, or NKT cells. However, depletion of NK cells also decreased serum TNF levels and FasL expression of NKT cells, which resulted in improved hepatic injury and survival, suggesting that NK cells are indirectly involved in MODS/lethal shock induced by NKT cells. Neutralization of TNF did not reduce the CpG-induced antitumor effect in the liver. Conclusion: Hepatic injury and MODS mediated by NKT cells via the TNF and FasL-mediated pathway after CpG injection increased, but the antitumor activity of liver NK cells decreased with aging. (HEPATOLOGY 2008.) [source]

T cells developing in fetal thymus of T-cell receptor ,-chain transgenic mice colonize ,, T-cell-specific epithelial niches but lack long-term reconstituting potential

IMMUNOLOGY, Issue 1 2006
Karin Leandersson
Summary The ,, T cells generated during mouse fetal development are absolutely dependent on their invariant T-cell receptors (TCRs) for their function. However, there is little information on whether the epithelial homing properties of fetal T cells might also be developmentally induced by factors unrelated to TCR specificity. We have previously described TCR ,-chain transgenic (2B4 TCR-, TG) mice, in which the transgenic TCR ,-chain is expressed early, already at embryonic day 14 (E14). These mice have a large population of ,,, T-cell-like' CD4, CD8, (double-negative; DN) ,, T cells, some of which develop during E14,E18 contemporarily to intraepithelial lymphocytes (IELs) expressing invariant TCR-,,. Using the 2B4 TCR-, TG mouse model we have been able to more precisely study the impact of a variant TCR expression on IEL development and homing. In this study we show that TCR-, TG and TCR-, TG crossed to TCR-,-deficient mice (TCR-, TG × TCR-,,/,) carry TG TCR-,+ dendritic epidermal T cells (DETCs) and TCR-, TG+ IELs in the small intestine. The TG+ DETCs develop and seed the epidermis with similar kinetics as V,5+ DETCs of normal mice, in contrast to the TCR-,,+ DETCs found in TCR-,,/, mice. However, whereas the intestinal TCR-, TG+ IELs persist in old mice (> 20 months), the TCR-, TG+ DETCs do not. The data in this study indicate that the timing of TCR expression and thereby development during ontogeny regulates the specific homing potential for fetal T cells but not their subsequent functions and properties. [source]

Age-dependent variation in the proportion and number of intestinal lymphocyte subsets, especially natural killer T cells, double-positive CD4+ CD8+ cells and B220+ T cells, in mice

IMMUNOLOGY, Issue 3 2004
Yuiko Ishimoto
Summary The age-dependent variation in the proportion and number of lymphocyte subsets was examined at various extrathymic sites, including the liver, small intestine, colon and appendix in mice. In comparison with young mice (4 weeks of age), the number of total lymphocytes yielded by all tested organs was greater in adult (9 weeks) and old (40 weeks) mice. The major lymphocyte subset that expanded with age was interleukin-2 receptor (IL-2R) ,+ CD3int cells (50% of them expressed NK1.1) in the liver, whereas it was CD3+ IL-2R,, NK1.1, cells at all intraepithelial sites in the intestine. Although NK1.1+ CD3+ cells were present at intraepithelial sites in the intestine, the proportion of this subset was rather low. The ratio of CD4 to CD8 tended to decrease among natural killer T (NKT) cells and T cells at all intraepithelial sites in the intestine with age. A unique population of double-positive CD4+ CD8+ cells in the small intestine increased in old mice. B220+ T cells were found mainly in the appendix and colon, and the proportion of these T cells decreased in old mice. Conventional NKT cells were very few in J,281,/, and CD1d,/, mice in the liver, while NKT cells which existed in the appendix remained unchanged even in these mice. This was because unconventional CD8+ NKT cells were present in the intestine. The present results suggest that despite the fact that both the liver and intraepithelial sites in the intestine carry many extrathymic T cells, the distribution of lymphocyte subsets and their age-associated variation are site-specific. [source]

Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1/,PD-L1 pathway

AGING CELL, Issue 5 2010
Celine S. Lages
Summary Programmed cell death-1 (PD-1) is a newly characterized negative regulator of immune responses. The interaction of PD-1 with its ligands (PD-L1 and PD-L2) inhibits T-cell proliferation and cytokine production in young mice. Increased PD-1 expression has been described during chronic infections, inducing chronic activation of the immune system to control it. As aging is associated with chronic immune activation, PD-1 may contribute to age-associated T-cell dysfunction. Our data showed the following results in aged mice: (i) the number of PD-1-expressing T cells and the level of expression of PD-Ls was increased on dendritic cell subsets and T cells; (ii) PD-1+ T cells were exhausted effector memory T cells, as shown by their lower level of CD127, CD25 and CD28, as well as their limited proliferative and cytokine-producing capacity; (iii) the expression of PD-1 was up-regulated after T-cell receptor-mediated activation of CD8+ T cells, but not of CD4+ T cells; (iv) blockade of the PD-1/PD-L1 pathway moderately improved the cytokine production of T cells from old mice but did not restore their proliferation; and (v) blockade of the PD-1/PD-L1 pathway did not restore function of PD-1+ T cells; its effect appeared to be exclusively mediated by increased functionality of the PD-1, T cells. Our data thus suggest that blockade of the PD-1/PD-L1 is not likely to be efficient at restoring exhausted T-cell responses in aged hosts, although improving the responses of PD-1, T cells may prove to be a helpful strategy in enhancing primary responses. [source]

Decreased oxidative stress and greater bone anabolism in the aged, when compared to the young, murine skeleton with parathyroid hormone administration

AGING CELL, Issue 5 2010
Robert L. Jilka
Summary Because of recent insights into the pathogenesis of age-related bone loss, we investigated whether intermittent parathyroid hormone (PTH) administration antagonizes the molecular mechanisms of the adverse effects of aging on bone. Parathyroid hormone produced a greater increase in vertebral trabecular bone mineral density and bone volume as well as a greater expansion of the endocortical bone surface in the femur of 26- when compared to 6 -month-old female C57BL/6 mice. Moreover, PTH increased trabecular connectivity in vertebrae, and the toughness of both vertebrae and femora in old, but not young, mice. Parathyroid hormone also increased the rate of bone formation and reduced osteoblast apoptosis to a greater extent in the old mice. Most strikingly, PTH reduced reactive oxygen species, p66Shc phosphorylation, and expression of the lipoxygenase Alox15, and it increased glutathione and stimulated Wnt signaling in bone of old mice. Parathyroid hormone also antagonized the effects of oxidative stress on p66Shc phosphorylation, Forkhead Box O transcriptional activity, osteoblast apoptosis, and Wnt signaling in vitro. In contrast, administration of the antioxidants N -acetyl cysteine or pegylated catalase reduced osteoblast progenitors and attenuated proliferation and Wnt signaling. These results suggest that PTH has a greater bone anabolic efficacy in old age because in addition to its other positive actions on bone formation, it antagonizes the age-associated increase in oxidative stress and its adverse effects on the birth and survival of osteoblasts. On the other hand, ordinary antioxidants cannot restore bone mass in old age because they slow remodeling and attenuate osteoblastogenesis by interfering with Wnt signaling. [source]

Epigenetic changes play critical role in age-associated dysfunctions of the liver

AGING CELL, Issue 5 2010
Jingling Jin
Summary CCAAT/Enhancer Binding Proteins family proteins are important regulators of liver functions. Here, we show the critical role of C/EBP,-mediated chromatin remodeling in the age-associated dysfunctions of the liver and in the maintenance of physiological homeostasis. Because ph-S193 isoform of C/EBP, is increased in livers of old mice, we have generated C/EBP,-S193D knockin mice, which mimic the ph-S193 isoform of C/EBP,. Analyses of these mice showed that the S193D mutation causes chromatin remodeling leading to histological appearance of ,foci-like' nodules, which are also observed in livers of old mice. These ,foci-like' structures contain K9 trimethylated histone H3, a marker of heterochromatin. The increase of heterochromatin regions in S193D mice correlates with the elevation of S193D-C/EBP,-HDAC1 complexes and with dys-regulation of gene expression including epigenetic silencing of cyclin D1 and D2 promoters and the inhibition of liver proliferation. The elimination of C/EBP,-HDAC1 complexes in S193D mice by inhibition of HDAC1 corrects chromatin structure and normalizes expression of cyclin D1 and D2. We found that epigenetic dys-regulation is also associated with the elevation of C/EBP, and with the increase of C/EBP,/, heterodimers in S193D mice. The C/EBP,/, heterodimers activate transcription of Glut4 and increase the levels of Glut4. As the result, S193D livers have accelerated uptake of glucose and accumulation of glycogen in the liver. Thus, this study demonstrates that the phosphorylation of C/EBP, at S193 leads to the appearance of heterochromatin regions, which correlates with the development of age-related dysfunctions of the liver. [source]

Short-term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress

AGING CELL, Issue 3 2010
Catarina Rippe
Summary To determine if short-term calorie restriction reverses vascular endothelial dysfunction in old mice, old (O, n = 30) and young (Y, n = 10) male B6D2F1 mice were fed ad libitum (AL) or calorie restricted (CR, approximately 30%) for 8 weeks. Ex vivo carotid artery endothelium-dependent dilation (EDD) was impaired in old ad libitum (OAL) vs. young ad libitum (YAL) (74 ± 5 vs. 95 ± 2% of maximum dilation, P < 0.05), whereas old calorie-restricted (OCR) and YCR did not differ (96 ± 1 vs. 94 ± 3%). Impaired EDD in OAL was mediated by reduced nitric oxide (NO) bioavailability associated with decreased endothelial NO synthase expression (aorta) (P < 0.05), both of which were restored in OCR. Nitrotyrosine, a cellular marker of oxidant modification, was markedly elevated in OAL (P < 0.05), whereas OCR was similar to Y. Aortic superoxide production was 150% greater in OAL vs. YAL (P < 0.05), but normalized in OCR, and TEMPOL, a superoxide dismutase (SOD) mimetic that restored EDD in OAL (to 97 ± 2%), had no effect in Y or OCR. OAL had increased expression and activity of the oxidant enzyme, NADPH oxidase, and its inhibition (apocynin) improved EDD, whereas NADPH oxidase in OCR was similar to Y. Manganese SOD activity and sirtuin1 expression were reduced in OAL (P < 0.05), but restored to Y in OCR. Inflammatory cytokines were greater in OAL vs. YAL (P < 0.05), but unaffected by CR. Carotid artery endothelium-independent dilation did not differ among groups. Short-term CR initiated in old age reverses age-associated vascular endothelial dysfunction by restoring NO bioavailability, reducing oxidative stress (via reduced NADPH oxidase,mediated superoxide production and stimulation of anti-oxidant enzyme activity), and upregulation of sirtuin-1. [source]

Reduced EBF expression underlies loss of B-cell potential of hematopoietic progenitors with age

AGING CELL, Issue 3 2010
Chloé Lescale
Summary Aging is accompanied by a reduction in the generation of B lymphocytes leading to impaired immune responses. In this study, we have investigated whether the decline in B lymphopoiesis is due to age-related defects in the hematopoietic stem cell compartment. The ability of hematopoietic stem cells from old mice to generate B cells, as measured in vitro, is decreased 2,5-fold, while myeloid potential remains unchanged. This age-related decrease in B-cell potential is more marked in common lymphoid progenitors (CLP) and was associated with reduced expression of the B-lineage specifying factors, EBF and Pax5. Notably, retrovirus-mediated expression of EBF complemented the age-related loss of B-cell potential in CLP isolated from old mice. Furthermore, transduction of CLP from old mice with a constitutively active form of STAT5 restored both EBF and Pax5 expression and increased B-cell potential. These results are consistent with a mechanism, whereby reduced expression of EBF with age decreases the frequency with which multipotent hematopoietic progenitors commit to a B-cell fate, without altering their potential to generate myeloid cells. [source]

Generation of pluripotent stem cells from eggs of aging mice

AGING CELL, Issue 2 2010
Junjiu Huang
Summary Oocytes can reprogram genomes to form embryonic stem (ES) cells. Although ES cells largely escape senescence, oocytes themselves do senesce in the ovaries of most mammals. It remains to be determined whether ES cells can be established using eggs from old females, which exhibit reproductive senescence. We attempted to produce pluripotent stem cell lines from artificial activation of eggs (also called pES) from reproductive aged mice, to determine whether maternal aging affects pES cell production and pluripotency. We show that pES cell lines were generated with high efficiency from reproductive aged (old) mice, although parthenogenetic embryos from these mice produced fewer ES clones by initial two passages. Further, pES cell lines generated from old mice showed telomere length, expression of pluripotency molecular markers (Oct4, Nanog, SSEA1), alkaline phosphatase activity, teratoma formation and chimera production similar to young mice. Notably, DNA damage was reduced in pES cells from old mice compared to their progenitor parthenogenetic blastocysts, and did not differ from that of pES cells from young mice. Also, global gene expression differed only minimally between pES cells from young and old mice, in contrast to marked differences in gene expression in eggs from young and old mice. These data demonstrate that eggs from old mice can generate pluripotent stem cells, and suggest that the isolation and in vitro culture of ES cells must select cells with high levels of DNA and telomere integrity, and/or with capacity to repair DNA and telomeres. [source]

Relative roles of TGF-,1 and Wnt in the systemic regulation and aging of satellite cell responses

AGING CELL, Issue 6 2009
Morgan E. Carlson
Summary Muscle stem (satellite) cells are relatively resistant to cell-autonomous aging. Instead, their endogenous signaling profile and regenerative capacity is strongly influenced by the aged P-Smad3, differentiated niche, and by the aged circulation. With respect to muscle fibers, we previously established that a shift from active Notch to excessive transforming growth factor-beta (TGF-,) induces CDK inhibitors in satellite cells, thereby interfering with productive myogenic responses. In contrast, the systemic inhibitor of muscle repair, elevated in old sera, was suggested to be Wnt. Here, we examined the age-dependent myogenic activity of sera TGF-,1, and its potential cross-talk with systemic Wnt. We found that sera TGF-,1 becomes elevated within aged humans and mice, while systemic Wnt remained undetectable in these species. Wnt also failed to inhibit satellite cell myogenicity, while TGF-,1 suppressed regenerative potential in a biphasic fashion. Intriguingly, young levels of TGF-,1 were inhibitory and young sera suppressed myogenesis if TGF-,1 was activated. Our data suggest that platelet-derived sera TGF-,1 levels, or endocrine TGF-,1 levels, do not explain the age-dependent inhibition of muscle regeneration by this cytokine. In vivo, TGF-, neutralizing antibody, or a soluble decoy, failed to reduce systemic TGF-,1 and rescue myogenesis in old mice. However, muscle regeneration was improved by the systemic delivery of a TGF-, receptor kinase inhibitor, which attenuated TGF-, signaling in skeletal muscle. Summarily, these findings argue against the endocrine path of a TGF-,1-dependent block on muscle regeneration, identify physiological modalities of age-imposed changes in TGF-,1, and introduce new therapeutic strategies for the broad restoration of aged organ repair. [source]

DNA damage response and cellular senescence in tissues of aging mice

AGING CELL, Issue 3 2009
Chunfang Wang
Summary The impact of cellular senescence onto aging of organisms is not fully clear, not at least because of the scarcity of reliable data on the mere frequency of senescent cells in aging tissues. Activation of a DNA damage response including formation of DNA damage foci containing activated H2A.X (,-H2A.X) at either uncapped telomeres or persistent DNA strand breaks is the major trigger of cell senescence. Therefore, ,-H2A.X immunohistochemistry (IHC) was established by us as a reliable quantitative indicator of senescence in fibroblasts in vitro and in hepatocytes in vivo and the age dependency of DNA damage foci accumulation in ten organs of C57Bl6 mice was analysed over an age range from 12 to 42 months. There were significant increases with age in the frequency of foci-containing cells in lung, spleen, dermis, liver and gut epithelium. In liver, foci-positive cells were preferentially found in the centrilobular area, which is exposed to higher levels of oxidative stress. Foci formation in the intestine was restricted to the crypts. It was not associated with either apoptosis or hyperproliferation. That telomeres shortened with age in both crypt and villus enterocytes, but telomeres in the crypt epithelium were longer than those in villi at all ages were confirmed by us. Still, there was no more than random co-localization between ,-H2A.X foci and telomeres even in crypts from very old mice, indicating that senescence in the crypt enterocytes is telomere independent. The results suggest that stress-dependent cell senescence could play a causal role for aging of mice. [source]

Influence of cardiac-specific overexpression of insulin-like growth factor 1 on lifespan and aging-associated changes in cardiac intracellular Ca2+ homeostasis, protein damage and apoptotic protein expression

AGING CELL, Issue 6 2007
Qun Li
Summary A fall in circulating levels of cardiac survival factor insulin-like growth factor 1 (IGF-1) contributes to cardiac aging. To better understand the role of IGF-1 in cardiac aging, we examined the influence of cardiac IGF-1 overexpression on lifespan, cardiomyocyte intracellular Ca2+ homeostasis, protein damage, apoptosis and expression of pro- and anti-apoptotic proteins in young and old mice. Mouse survival rate was constructed by the Kaplan,Meier curve. Intracellular Ca2+ was evaluated by fura-2 fluorescence. Protein damage was determined by protein carbonyl formation. Apoptosis was assessed by caspase-8 expression, caspase-3 and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) assay. Pro- and anti-apoptotic proteins including Bax, p53, pp53, Bcl2, Omi/HtrA2, apoptosis repressor with caspase recruitment domain (ARC) and X-linked inhibitor of apoptosis protein (XIAP) were assessed by Western blot. Aging decreased plasma in IGF-1 levels, elevated myocyte resting intracellular Ca2+ levels, reduced electrically stimulated rise in intracellular Ca2+ and delayed intracellular Ca2+ decay associated with enhanced protein carbonyl formation, caspase-8 expression and caspase-3 activity in FVB mice, all of which with the exception of elevated resting intracellular Ca2+ were attenuated by IGF-1. Aging up-regulated expression of Bax, Bcl2 and ARC, down-regulated XIAP expression and did not affect p53, pp53 and Omi/HtrA2. The IGF-1 transgene attenuated or nullified aging-induced changes in Bax, Bcl2 and XIAP. Our data suggest a beneficial role for IGF-1 in aging-induced survival, cardiac intracellular Ca2+ homeostasis, protein damage and apoptosis possibly related to pro- and anti-apoptotic proteins. [source]

,Accelerated aging': a primrose path to insight?

AGING CELL, Issue 2 2004
Richard A. Miller
Summary Organism envy afflicts most researchers who work on aging in mice; how frustrating it is to see the worm and fly biologists nail down milestone after milestone, citation after citation! Surely genetic trickery can produce mice that age in a comparable jiffy? Alas, our near-total ignorance of what times the aging process makes it hard to guess what genes to tweak, if indeed aging can be mimicked a presto. Building a case that a given short-lived mutant ages quickly is a steep and thorny path, requiring more than just plucking a symptom here and there from a list of things that sometimes go wrong in old people or old mice. The hallmark of aging is that a lot goes wrong more or less at the same time, in 2-year-old mice, 10-year-old dogs and 70-year-old people. Finding ways to damage one or two systems in a 6-week or 6-month-old mouse is not too hard to do, but the implications of such studies for improved understanding of aging per se are at best indirect and at worst imaginary and distracting. [source]

Sleep and Rest Regulation in Young and Old Oestrogen-Deficient Female Mice

JOURNAL OF NEUROENDOCRINOLOGY, Issue 8 2006
V. V. Vyazovskiy
The effect of circulating oestrogen deficiency on sleep regulation and locomotor activity was investigated in aromatase cytochrome P450 deficient mice (ArKO) and wild-type (WT) controls. Sleep was recorded in 3-month old mice during a 24-h baseline day, 6-h sleep deprivation (SD) and 18-h recovery, and activity was recorded at the age of 3, 9 and 12 months. In mice deficient of oestrogen, the total amount of sleep per 24 h was the same as in WT controls. However, in ArKO mice, sleep was enhanced in the dark period at the expense of sleep in the light phase, and was more fragmented than sleep in WT mice. This redistribution of sleep resulted in a damped amplitude of slow-wave activity (SWA; power between 0.75,4.0 Hz) in non-rapid eye movement sleep across 24 h. After SD, the rebound of sleep and SWA was similar between the genotypes, suggesting that oestrogen deficiency does not affect the mechanisms maintaining the homeostatic balance between the amount of sleep and its intensity. Motor activity decreased with age in both genotypes and was lower in ArKO mice compared to WT at all three ages. After SD, the amount of rest in 3-month old WT mice increased above baseline and was more consolidated. Both effects were less pronounced in ArKO mice, reflecting the baseline differences between the genotypes. The results indicate that despite the pronounced redistribution of sleep and motor activity in oestrogen deficient mice, the basic homeostatic mechanisms of sleep regulation in ArKO mice remain intact. [source]

EGF and NGF injected into the brain of old mice enhance BDNF and ChAT in proliferating subventricular zone

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 5 2003
Paola Tirassa
Abstract The response of cells localized in the brain subventricular zone (SVZ) to growth factor stimulation has been largely described for development and adult life, whereas no information on their behavior during aging is available. To address the question of whether the cells in the SVZ of old mice respond to the intracerebroventricular administration of epidermal growth factor (EGF) and nerve growth factor (NGF), we studied the distribution of proliferating cells and the effects on ChAT and brain-derived neurotrophic factor (BDNF) synthesis in forebrain and SVZ. It was found that the conjoint administration of EGF + NGF produced a major increase in ChAT expression in both forebrain and SVZ. The ChAT mRNA levels and the number of ChAT positive cells localized in the ventricular border and in the parenchyma of SVZ area were also increased significantly in the mice receiving EGF + NGF. Enhanced numbers of SVZ cells expressing proliferative markers were also discovered in EGF + NGF treated mice and some of these cells expressed cholinergic markers, as demonstrated by double immunostaining. In addition, EGF and NGF treatments significantly upregulate BDNF protein and mRNA levels in this brain region. The present study demonstrates that cells localized in SVZ of aged mouse brain retain the capacity to respond to EGF and NGF and that after stimulation with these two growth factors, the synthesis of ChAT and BDNF also increases. The implication that cells of the SVZ remain a reservoir of cholinergic and BDNF-positive neurons in aged brain opens a new perspective for understanding the role of growth factors during neurodegenerative disorders associated with aging. © 2003 Wiley-Liss, Inc. [source]

Simultaneous measurement of serotonin and melatonin from the intestine of old mice: the effects of daily melatonin supplementation

JOURNAL OF PINEAL RESEARCH, Issue 1 2010
P. P. Bertrand
Abstract:, Ageing is associated with important changes in gastrointestinal function and in the levels of intestinal hormones secreted. Enterochromaffin (EC) cells containing serotonin (5-HT) and melatonin may play a major role in maintaining gut function during ageing. Our aim was to characterise the mucosal availability of 5-HT and melatonin in the ileum and colon of a mouse model of ageing. Female young mice (2,5 month; n = 6), aged mice (22,24 months; n = 6) and aged mice treated with melatonin (n = 6; 10 mg/kg/day) were examined. Electrochemical methods were used to measure 5-HT and melatonin concentrations near the mucosal surface of ileum and distal colon. Amperometry studies showed that steady state levels of 5-HT from ileum and colon were decreased in aged mice treated with melatonin when compared to aged mice, while compression-evoked 5-HT release was unchanged. Differential pulse voltammetry studies showed that young mice had concentrations of 5-HT of 4.8 ± 0.8 ,m in the ileum and 4.9 ± 1.0 ,m in the colon. Concentrations of melatonin were 5.7 ± 1.4 ,m in the ileum and 5.6 ± 1.9 ,m in the colon. Compared to young mice, the levels of 5-HT and melatonin were increased in aged mice (combined ileum and colon: 5-HT = 130% and melatonin = 126% of young mice) and decreased in melatonin-treated mice (5-HT = 94% and melatonin = 82%). In conclusion, our data show that the availability of gut 5-HT and melatonin is increased in aged mice and melatonin treatment suppresses natural gastrointestinal production of 5-HT and melatonin in the aged mouse intestine. [source]

Recovery from fatigue in fast and slow single intact skeletal muscle fibers from aging mouse

MUSCLE AND NERVE, Issue 9 2001
Estela González MS
Abstract In the present work, we studied the recovery from fatigue (RF) of single intact fast- and slow-twitch muscle fibers from young (age 5,7 months) and old (age 22,24 months) mice. To examine whether differences in RF underlie decreases in muscle strength and endurance with aging, we performed in vitro experiments in manually dissected extensor digitorum longus (EDL) and soleus muscle fibers. We measured the recovery of the maximum force every 5 min for a total period of 30 min after inducing fiber fatigue. Fibers were classified, according to the fatigue index, into the following three groups: 0.75,0.99, 0.5,0.74, and <0.5. Although the tetanic tension of EDL and soleus fibers from young and old mice recovered significantly, no statistically significant difference in tension or recovery time was observed between age groups. These data support the concept that the reported decline in muscle force and endurance with aging is not related to changes in RF of individual muscles fibers. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 1219,1224 [source]

Contributions of Mouse Genetic Background and Age on Anterior Lens Capsule Thickness

THE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 12 2008
Brian P. Danysh
Abstract Accurate lens capsule thickness measurements are necessary for studies investigating mechanical characteristics of the capsule. Confocal Z -axis imaging was used to measure the anterior lens capsule thickness of living intact lenses with minimal tissue manipulation. Measurements of the anterior capsule thickness is reported for the first time in young and old mice from four inbred strains, BALB/c, FVB/N, C57BL/6, and 129X1, and the outbred strain ICR. Our data demonstrates that the mouse anterior lens capsule continues to grow postnatally similar to that described in other mammals. It is also shown there is a significant difference in anterior lens capsule thickness between unrelated mouse strains, suggesting that capsule thickness is a quantitative trait shared by strains with common ancestry. Measurements, taken from other regions of FVB/N capsules revealed the anterior pole to be the thickest, followed by the equatorial region and posterior pole. In addition to mouse, anterior capsule measurements taken from intact cattle, rabbit, rat lenses, and human capsulotomy specimens correlated with the overall size of the animal. Anat Rec, 2008. © 2008 Wiley-Liss, Inc. [source]

Endothelium-derived hyperpolarizing factor as an in vivo back-up mechanism in the cutaneous microcirculation in old mice

THE JOURNAL OF PHYSIOLOGY, Issue 2 2007
Marie Line Gaubert
There is now strong evidence that an endothelium-derived hyperpolarizing factor (EDHF), other than nitric oxide (NO) or prostaglandin (PG), exists for dilating arteries and arterioles. In vitro studies on isolated vessels pointed out a role for EDHF as a back-up mechanism when the NO pathway is impaired, but there was a lack of in vivo studies showing a functional role for EDHF. Ageing has pronounced effects on vascular function and particularly on endothelium-dependent relaxation, providing a novel situation in which to assess the contributions of EDHF. The purpose of the present study was thus to determine if, in vivo, there was a functional role for EDHF as a back-up mechanism in the cutaneous microcirculation in the ageing process. We investigated in vivo the contribution of each endothelial factor (NO, PG and EDHF) in the cutaneous vasodilatation induced by iontophoretic delivery of acetylcholine and local pressure application in young adult (6,7 months) and old (22,25 months) mice, using pharmacological inhibitors. The cutaneous vasodilator responses induced by acetylcholine and local pressure application were dependent upon NO and PG pathways in young adult mice, whereas they were EDHF-dependent in old mice. EDHF appears to serve as a back-up mechanism when ageing reaches pathological states in terms of the ability for NO and PG to relax cutaneous microvessels, allowing for persistent cutaneous vasodilatator responses in old mice. However, as a back-up mechanism, EDHF did not completely restore cutaneous vasodilatation, since endothelial responses were reduced in old mice compared to young adult mice. [source]

Age and energy intake interact to modify cell stress pathways and stroke outcome

ANNALS OF NEUROLOGY, Issue 1 2010
Thiruma V. Arumugam PhD
Objective Age and excessive energy intake/obesity are risk factors for cerebrovascular disease, but it is not known if and how these factors affect the extent of brain damage and outcome in ischemic stroke. We therefore determined the interactions of age and energy intake on the outcome of ischemic brain injury, and elucidated the underlying mechanisms. Methods We utilized a novel microchip-based immunoaffinity capillary electrophoresis technology to measure a panel of neurotrophic factors, cytokines, and cellular stress resistance proteins in brain tissue samples from young, middle-aged, and old mice that had been maintained on control or energy-restricted diets prior to middle cerebral artery occlusion and reperfusion. Results Mortality from focal ischemic stroke was increased with advancing age and reduced by an intermittent fasting (IF) diet. Brain damage and functional impairment were reduced by IF in young and middle-aged mice, but not in old mice. The basal and poststroke levels of neurotrophic factors (brain-derived neurotrophic factor and basic fibroblast growth factor), protein chaperones (heat shock protein 70 and glucose regulated protein 78), and the antioxidant enzyme heme oxygenase-1 were decreased, whereas levels of inflammatory cytokines were increased in the cerebral cortex and striatum of old mice compared with younger mice. IF coordinately increased levels of protective proteins and decreased inflammatory cytokines in young, but not in old mice. Interpretation Reduction in dietary energy intake differentially modulates neurotrophic and inflammatory pathways to protect neurons against ischemic injury, and these beneficial effects of IF are compromised during aging, resulting in increased brain damage and poorer functional outcome. ANN NEUROL 2010;67:41,52 [source]

Enhancement of immunity and resistance in mice by pig IL-6 gene and CpG motifs encapsulated in chitosan nanoparticle

BIOTECHNOLOGY JOURNAL, Issue 2 2008
Qian Chen
Abstract This study was conducted to explore the synergetic effect of a novel plasmid containing a porcine IL-6 gene and CpG motifs on immunity of mice in order to develop an effective adjuvant to boost resistance against infection. The synthetic oligodeoxynucleotide containing 11 CpG motifs was inserted into the reconstructed VR1020 plasmid containing the pig IL-6 gene (VRPIL6), designated VRIL6C, and then encapsulated in chitosan nanoparticles (CNP) prepared by ionic cross linkage, designated VRIL6C-CNP. The 3-week old mice were injected, respectively, with VRIL6C-CNP, VRIL6-CNP, CpG-CNP and VR1020-CNP to detect the changes of immunity. At 28 days post inoculation, the mice were challenged with virulent hemolytic serotype 2 Streptococcus to test their resistance against infection. The results showed that there was a significant increase in immunoglobulins and interleukins in mice receiving VRIL6C-CNP compared with the control groups, as well as an increase in the lymphocytes and monocytes in the inoculated mice, so that the immunity was remarkably improved in the VRIL6C-CNP group. The challenge provoked stronger immunity and protection against infection in the VRIL6C-CNP group than in the control mice that manifested severe symptoms and lesions. This suggests that VRIL6C-CNP could remarkably enhance the nonspecific immunity of mice, and facilitate the development of an effective immunopotentiator to promote the resistance of the animals against infection. [source]

Angiogenic gene modification of skeletal muscle cells to compensate for ageing-induced decline in bioengineered functional muscle tissue

BJU INTERNATIONAL, Issue 7 2008
Dawn M. Delo
OBJECTIVE To explore the effects of ageing on the viability of bioengineered striated muscle tissue in vivo, and if this viability can be enhanced by concurrent neovascularization, as its utility for the treatment of stress urinary incontinence (SUI) might be reduced if muscle cells are derived from old patients. MATERIALS AND METHODS Myoblasts were obtained and expanded in culture from young (2 weeks), mature (3 months) and old (24 months) mice, and were engineered to express vascular endothelial growth factor (VEGF) to stimulate neovascularization. Myoblasts were injected subcutaneously into male nude mice and after 2 and 4 weeks, the engineered muscle tissues were harvested. RESULTS Bioengineered muscle tissues were formed in all groups, but the engineered muscles formed by myoblasts from old mice were smaller and less contractile. However, the bioengineered muscles expressing VEGF had a greater mass and better contractility in all age groups. CONCLUSION This pilot study showed that there was an age-related decline in the size and function of bioengineered muscle; however, there was an improvement in volume and function when the muscle cells were expressing VEGF. [source]

Purple Sweet Potato Color Alleviates D-galactose-induced Brain Aging in Old Mice by Promoting Survival of Neurons via PI3K Pathway and Inhibiting Cytochrome C-mediated Apoptosis