Bcl-2 overexpression does not protect neurons from mutant neurofilament-mediated motor neuron degeneration.
(17/3329)
Transgenic mice with a point mutation in the light neurofilament gene develop amyotrophic lateral sclerosis-like motor neuron disease characterized by selective spinal motor neuron loss, neurofilamentous accumulations, and severe muscle atrophy. To test whether the large motor neurons at risk in this disease could be protected from mutant neurofilament-mediated killing, these mice were bred to mice overexpressing the human Bcl-2 proto-oncogene. Elevated levels of Bcl-2 increased the numbers of motor and sensory axons surviving after the developmental period of naturally occurring cell death but did not greatly reduce the number of degenerating axons or protect the large motor neurons from mutant neurofilament-mediated death. (+info)
The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans.
(18/3329)
Longevity is regulated by the daf-2 gene network in Caenorhabditis elegans. Mutations in the daf-2 gene, which encodes a member of the insulin receptor family, confer the life extension (Age) phenotype and the constitutive dauer (a growth-arrested larval form specialized for dispersal) formation phenotype. The Age phenotype is mutually potentiated by two life extension mutations in the daf-2 gene and the clk-1 gene, a homologue of yeast CAT5/COQ7 known to regulate ubiquinone biosynthesis. In this study, we demonstrated that the daf-2 mutation also conferred an oxidative stress resistance (Oxr) phenotype, which was also enhanced by the clk-1 mutation. Similar to the Age phenotype, the Oxr phenotype was regulated by the genetic pathway of insulin-like signaling from daf-2 to the daf-16 gene, a homologue of the HNF-3/forkhead transcription factor. These findings led us to examine whether the insulin-like signaling pathway regulates the gene expression of antioxidant defense enzymes. We found that the mRNA level of the sod-3 gene, which encodes Mn-superoxide dismutase (SOD), was much higher in daf-2 mutants than in the wild type. Moreover, the increased sod-3 gene expression phenotype is regulated by the insulin-like signaling pathway. Although the clk-1 mutant itself did not display Oxr and the increased sod-3 expression phenotypes, the clk-1 mutation enhanced them in the daf-2 mutant, suggesting that clk-1 is involved in longevity in two ways: clk-1 composes the original clk-1 longevity program and the daf-2 longevity program. These observations suggest that the daf-2 gene network controls longevity by regulating the Mn-SOD-associated antioxidant defense system. This system appears to play a role in efficient life maintenance at the dauer stage. (+info)
Genetic maternal effects on human life span through the inheritance of mitochondrial DNA.
(19/3329)
Ageing consists of an accumulation of changes with time both at the molecular and cellular levels, accompanying an increased susceptibility to diseases and death. If maternally inherited mitochondrial genes are involved in defining the nature and timing of ageing, and if there are genetic differences in their susceptibility to damage, a maternal contribution could be found in the inheritance of life span. The present study explores the inheritance pattern of longevity and discovers a significant genetic maternal component in human life span. (+info)
IL-4-transduced tumor cell vaccine induces immunoregulatory type 2 CD8 T lymphocytes that cure lung metastases upon adoptive transfer.
(20/3329)
Vaccinations with tumor cells engineered to produce IL-4 prolonged survival and cured 30% of mice bearing pulmonary metastases, an effect abrogated by in vivo depletion of T cells. Vaccination induced type 2 T cell polarization in both CD4 and CD8 T lymphocyte subsets. We focused on the antitumor activity exerted by type 2 CD8+ T cells (Tc2) activated by IL-4 tumor cell vaccination. Tc2 lymphocytes lacked in vitro tumor cytotoxicity, but released IL-4 upon stimulation with tumor cells, as shown by limiting dilution analysis of the frequencies of tumor-specific pCTL and of CD8 cells producing the cytokine. In vivo fresh purified CD8+ T lymphocytes from IL-4-vaccinated mice eliminated 80-100% of lung metastases when transferred into tumor-bearing mice. CD8+ lymphocytes from IL-4-vaccinated IFN-gamma knockout (KO), but not from IL-4 KO, mice cured lung metastases, thus indicating that IL-4 produced by Tc2 cells was instrumental for tumor rejection. The antitumor effect of adoptively transferred Tc2 lymphocytes needed host CD8 T cells and AsGM1 leukocyte populations, and partially granulocytes. These data indicate that Tc2 CD8+ T cells exert immunoregulatory functions and induce tumor rejection through the cooperation of bystander lymphoid effector cells. Tumor eradication is thus not restricted to a type 1 response, but can also be mediated by a type 2 biased T cell response. (+info)
Prevention of B220+ T cell expansion and prolongation of lifespan induced by Lactobacillus casei in MRL/lpr mice.
(21/3329)
We examined the therapeutic effect of heat-killed Lactobacillus casei (LC) on MRL/lpr mice. Ingestion of a diet containing 0.05% (w/w) LC from the weaning period prolonged the lifespan and tended to reduce the proportion of B220+ T cells in the spleen and mesenteric lymph nodes (MLN) of MRL/lpr mice. When LC was intraperitoneally injected once a week after the age of 8 weeks, I-A- macrophages accumulated in the spleen as well as the peritoneum and macrophage progenitors increased in the bone marrow. Moreover, the amount of IL-6 mRNA in peritoneal macrophages was reduced by LC injection. Splenocytes from LC-injected MRL/lpr mice exhibited lower proliferative responses to mitogens than those from control MRL/lpr mice and the increase in number of B220+ T cells in the spleen and MLN was prevented by LC injection. However, LC injection affected neither expression of interferon-gamma (IFN-gamma) and IL-4 mRNAs nor proliferative capacities of splenic T cells. Our findings demonstrate that LC injection accelerates macrophage recruitment and prevents the expansion of B220+ T cells without affecting the functions of T cells in MRL/lpr mice. These immunological modulations induced by LC may lead to prolongation of the lifespan of MRL/lpr mice. (+info)
Functional integrity of NMDA-dependent LTP induction mechanisms across the lifespan of F-344 rats.
(22/3329)
Previous studies have reported a lack of an age effect in the induction of long-term potentiation (LTP) at CA1 synapses, using robust (supramaximal) stimulation parameters, but an apparent age effect on the induction threshold of LTP using less robust stimulation, in the perithreshold region. These findings have led to the suggestion that old animals may experience an alteration either in the efficacy of activation of N-methyl-D-aspartate (NMDA) receptors or in the metabolic processes subsequent to NMDA receptor activation that lead to LTP expression. An alternative explanation for the apparent threshold change in old animals is that, because of the known reduction of the intracellularly recorded, compound EPSP magnitude in old rats, equivalent electrical stimulation results in a smaller effective depolarization of the postsynaptic cells and a consequently less effective activation of NMDA receptors, which are otherwise functionally normal. To distinguish between these two hypotheses, weak orthodromic stimulation was paired with intracellularly applied current pulses, thus holding constant the degree of postsynaptic depolarization. No differences in LTP induction threshold or magnitude were observed in a large sample of rats from three age groups. It is concluded that the NMDA receptor mechanisms and associated biochemical processes leading to LTP induction are not altered in aged F-344 rats. The reduced compound EPSP in old animals was reconfirmed in the present study, and a significant correlation was found in old rats between the magnitude of the EPSP at a fixed stimulus level and their performance on a spatial memory task. (+info)
Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans.
(23/3329)
Mitochondrial DNA (mtDNA) is characterized by high variability, maternal inheritance, and absence of recombination. Studies of human populations have revealed ancestral associated polymorphisms whose combination defines groups of mtDNA types (haplogroups) that are currently used to reconstruct human evolution lineages. We used such inherited mtDNA markers to compare mtDNA population pools between a sample of individuals selected for successful aging and longevity (212 subjects older than 100 years and in good clinical condition) and a sample of 275 younger individuals (median age 38 years) carefully matched as to sex and geographic origin (northern and southern Italy). All nine haplogroups that are typical of Europeans were found in both samples, but male centenarians emerged in northern Italy as a particular sample: 1) mtDNA haplogroup frequency distribution was different between centenarians and younger individuals (P=0.017 by permutation tests); and 2) the frequency of the J haplogroup was notably higher in centenarians than in younger individuals (P=0.0052 by Fisher exact test). Since haplogroups are defined on the basis of inherited variants, these data show that mtDNA inherited variability could play a role in successful aging and longevity. (+info)
Nematode ageing: Putting metabolic theories to the test.
(24/3329)
The increased life span caused by certain mutations in the nematode Caenorhabditis elegans has been interpreted in terms of two metabolic theories of ageing: the oxidative damage theory and the rate of living theory. New findings support the former, but not the latter interpretation. (+info)