Mechano growth factor, a splice variant of IGF-1, promotes neurogenesis in the aging mouse brain.

Mechano growth factor (MGF) is a splice variant of IGF-1 first described in skeletal muscle. MGF induces muscle cell proliferation in response to muscle stress and injury. In control mice we found endogenous expression of MGF in neurogenic areas of the brain and these levels declined with age.

Survival of irradiated recipient mice after transplantation of bone marrow from young, old and "early aging" mice.

Bone marrow transplantation is used to examine survival, hematopoietic stem cell function and pathology in recipients of young and old wild type bone marrow derived stem cells (BMDSCs) as well as cells from p53-based models of premature aging. There is no difference in the long term survival of recipients of 8 week-old p53+/m donor cells compared to recipients of 8 week-old wild-type (WT) donor cells (70 weeks) or of recipients of 16-18 weeks-old donor cells from either p53+/m or WT mice. There is shorter survival in recipients of older versus younger WT donor bone marrow, but the difference is only significant when comparing 8 and 18 week-old donors.

P44, the 'longevity-assurance' isoform of P53, regulates tau phosphorylation and is activated in an age-dependent fashion.

p44 is a short isoform of p53 with 'longevity-assurance' activity. Overexpression of p44 in the mouse (p44(+/+) transgenic mice) causes a progeroid phenotype that mimics an accelerated form of aging. The phenotype includes abnormal phosphorylation of the microtubule-binding protein tau, synaptic deficits, and cognitive decline.

Development of a Positive-readout Mouse Model of siRNA Pharmacodynamics.

Development of RNAi-based therapeutics has the potential to revolutionize treatment options for a range of human diseases. However, as with gene therapy, a major barrier to progress is the lack of methods to achieve and measure efficient delivery for systemic administration. We have developed a positive-readout pharmacodynamic transgenic reporter mouse model allowing noninvasive real-time assessment of siRNA activity.

Dominant effects of Δ40p53 on p53 function and melanoma cell fate.

The TP53 gene encodes 12 distinct isoforms, some of which can alter p53 activity in the absence of genomic alteration. Endogenous p53 isoforms have been identified in cancers; however, the function of these isoforms remains unclear. In melanoma, the frequency of TP53 mutations is relatively low compared with other cancers, suggesting that these isoforms may have a larger role in regulating TP53 activity.

Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging.

Oxidative stress is a determining factor of cellular senescence and aging and a potent inducer of the tumour-suppressor p53. Resistance to oxidative stress correlates with delayed aging in mammals, in the absence of accelerated tumorigenesis, suggesting inactivation of selected p53-downstream pathways. We investigated p53 regulation in mice carrying deletion of p66, a mutation that retards aging and confers cellular resistance and systemic resistance to oxidative stress.

Glucose Tolerance in Mice is Linked to the Dose of the p53 Transactivation Domain.

Aim: To test the transactivation domain-mediated control of glucose homeostasis by the tumor suppressor p53.

Background: The tumor suppressor p53 has a critical role in maintenance of glucose homeostasis. Phosphorylation of Ser18 in the transaction domain of p53 controls the expression of Zpf385a, a zinc finger protein that regulates adipogenesis and adipose function.

p53 isoform profiling in glioblastoma and injured brain.

The tumor suppressor p53 has been found to be the most commonly mutated gene in human cancers; however, the frequency of p53 mutations varies from 10 to 70% across different cancer types. This variability can partly be explained by inactivating mechanisms aside from direct genomic polymorphisms. The p53 gene encodes 12 isoforms, some of which can modulate full-length p53 activity in cancer.

Impersonalized medicine.

Research reported in this issue of Science Translational Medicine illustrates the benefits of short-term food withdrawal (fasting) in the treatment of cancer. Fasting exploited fundamental differences in the way tumor cells and normal cells respond to stress, simultaneously strengthening normal cell function and weakening tumor cell survival in the presence of toxic doses of chemotherapeutic drugs.

Δ40 Isoform of p53 controls β-cell proliferation and glucose homeostasis in mice.

Objective: Investigating the dynamics of pancreatic β-cell mass is critical for developing strategies to treat both type 1 and type 2 diabetes. p53, a key regulator of the cell cycle and apoptosis, has mostly been a focus of investigation as a tumor suppressor. Although p53 alternative transcripts can modulate p53 activity, their functions are not fully understood.

Delta40p53 controls the switch from pluripotency to differentiation by regulating IGF signaling in ESCs.

Δ40p53 is a transactivation-deficient isoform of the tumor suppressor p53. We discovered that Δ40p53, in addition to being highly expressed in embryonic stem cells (ESCs), is the major p53 isoform during early stages of embryogenesis in the mouse. By altering the dose of Δ40p53 in ESCs, we identified a critical role for this isoform in maintaining the ESC state.

Fat tissue, aging, and cellular senescence.

Fat tissue, frequently the largest organ in humans, is at the nexus of mechanisms involved in longevity and age-related metabolic dysfunction. Fat distribution and function change dramatically throughout life. Obesity is associated with accelerated onset of diseases common in old age, while fat ablation and certain mutations affecting fat increase life span.

Anxiety and the aging brain: stressed out over p53?

We propose a model in which cell loss in the aging brain is seen as a root cause of behavioral changes that compromise quality of life, including the onset of generalized anxiety disorder, in elderly individuals. According to this model, as stem cells in neurogenic regions of the adult brain lose regenerative capacity, worn-out, dead, or damaged neurons fail to be replaced, leaving gaps in function. As most replacement involves inhibitory interneurons, either directly or indirectly, the net result is the acquisition over time of a hyper-excitable state.

Phosphorylation regulates SIRT1 function.

Background: SIR2 is an NAD(+)-dependent deacetylase [1]-[3] implicated in the regulation of lifespan in species as diverse as yeast [4], worms [5], and flies [6]. We previously reported that the level of SIRT1, the mammalian homologue of SIR2 [7], [8], is coupled to the level of mitotic activity in cells both in vitro and in vivo[9]. Cells from long-lived mice maintained SIRT1 levels of young mice in tissues that undergo continuous cell replacement by proliferating stem cells.

Immunity and cognition: what do age-related dementia, HIV-dementia and 'chemo-brain' have in common?

Until recently, dogma dictated that the immune system and the central nervous system (CNS) live mostly separate, parallel lives, and any interactions between the two were assumed to be limited to extreme cases of pathological insult. It was only a decade ago that T cells in the injured brain were shown to play a protective rather than a destructive role. In this article, we explore the role of the immune system in the healthy brain, focusing on the key function that T lymphocytes have in the regulation of cognition.

Antagonistic pleiotropy and p53.

George Williams' antagonistic pleiotropy theory of aging proposes that cellular damage and organismal aging are caused by pleiotrophic genes, or genes with multiple phenotypic effects [Williams, G.C., 1957.

Running on empty: how p53 controls INS/IGF signaling and affects life span.

In higher organisms dependent on the regenerative ability of tissue stem cells to maintain tissue integrity throughout adulthood, the failure of stem cells to replace worn out, dead, or damaged cells is seen as one mechanism that limits life span. In these organisms, tumor suppressors such as p53 are central participants in the control of longevity because they regulate stem cell proliferation. Several recent reports have identified p53 as a longevity gene in organisms such as Caenorhabditis elegans and Drosophila melanogaster, which lack proliferative stem cells in all but the germline and have relatively short life spans.

Egr-1 and Hipk2 are required for the TrkA to p75(NTR) switch that occurs downstream of IGF1-R.

The aging program mediated by IGF1-R is responsible for a naturally occurring TrkA to p75(NTR) switch that leads to activation of the second messenger ceramide and increased production of the Alzheimer's disease amyloid beta-peptide. Biochemical and genetic approaches that target IGF1-R signaling, p75(NTR), or ceramide are able to block the above events. Here, we show that the transcription factors Egr-1 and Hipk2 are required elements for the TrkA to p75(NTR) switch downstream of IGF1-R signaling.

Mutant alleles of HD improve the life span of p53(-/-) mice.

Loss of function mutations in the p53 tumor suppressor gene predispose mice and humans to cancer, resulting in abbreviated life spans. A dominant mutation in the murine HD gene, similar to mutations that cause Huntington's disease in humans, reverses some of the effects of p53 mutations on longevity. We attribute this to the enhanced apoptotic effect of the expanded polyglutamine region in the HD protein on proliferating cells lacking p53.

Hbo1 Links p53-dependent stress signaling to DNA replication licensing.

Hbo1 is a histone acetyltransferase (HAT) that is required for global histone H4 acetylation, steroid-dependent transcription, and chromatin loading of MCM2-7 during DNA replication licensing. It is the catalytic subunit of protein complexes that include ING and JADE proteins, growth regulatory factors and candidate tumor suppressors. These complexes are thought to act via tumor suppressor p53, but the molecular mechanisms and links between stress signaling and chromatin, are currently unknown.

Regenerative capacity of neural precursors in the adult mammalian brain is under the control of p53.

The question of whether or not stem cell loss drives aging in the brain has not been fully resolved. Here, we used mice over-expressing the short isoform of p53 (DeltaNp53 or p44) as a model of aging to gain insight into the cellular mechanisms underlying age-related functional deficits in the brain. By BrdU labeling, we observed an accelerated decline in the number of subventricular zone proliferating cells with age in p44Tg mice compared to mice with normal p53 expression.

Genetic interaction between expanded murine Hdh alleles and p53 reveal deleterious effects of p53 on Huntington's disease pathogenesis.

Huntingtin, the protein product of the Huntington's disease (HD) gene, is known to interact with the tumor suppressor p53. It has recently been shown that activation of p53 upregulates the level of huntingtin, both in vitro and in vivo, whereas p53 deficiency in HD-transgenic flies and mice has been found to be beneficial. To explore further the involvement of p53 in HD pathogenesis, we generated mice homozygous for a mutant allele of Hdh (HdhQ140) and with zero, one, or two functional alleles of p53.

Progressive loss of SIRT1 with cell cycle withdrawal.

Sir2 is an NAD+-dependent deacetylase that regulates lifespan in yeast, worms and flies. The mammalian orthologs of Sir2 include SIRT1 in humans and mice. In this study, we analyzed the level of SIRT1 in human lung fibroblasts (IMR90) and mouse embryonic fibroblasts (MEFs) from mice with normal, accelerated, and delayed aging.

An aging pathway controls the TrkA to p75NTR receptor switch and amyloid beta-peptide generation.

Aging of the brain is characterized by marked changes in the expression levels of the neurotrophin receptors, TrkA and p75(NTR). An expression pattern in which TrkA predominates in younger animals switches to one in which p75(NTR) predominates in older animals. This TrkA-to-p75(NTR) switch is accompanied by activation of the second messenger ceramide, stabilization of beta-site amyloid precursor protein-cleaving enzyme-1 (BACE1), and increased production of amyloid beta-peptide (Abeta).