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Humans and orcas are among the very rare species that have a prolonged post-reproductive lifespan (PRLS), during which the aging process continues. Reactive oxygen species (ROS) derived from mitochondria and from the NADPH oxidase (NOX) enzymes of innate immune cells are known to contribute to aging, with the former thought to be dominant. CD33-related-Siglecs are immune receptors that recognize self-associated-molecular-patterns and modulate NOX-derived-ROS. We herewith demonstrate a strong correlation of lifespan with CD33rSIGLEC gene number in 26 species, independent of body weight or phylogeny. The correlation is stronger when considering total CD33rSIGLEC gene number rather than those encoding inhibitory and activating subsets, suggesting that lifetime balancing of ROS is important. Combining independent lines of evidence including the short half-life and spontaneous activation of neutrophils, we calculate that even without inter-current inflammation, a major source of lifetime ROS exposure may actually be neutrophil NOX-derived. However, genomes of human supercentenarians (>110 years) do not harbor a significantly higher number of functional CD33rSIGLEC genes. Instead, lifespan correlation with CD33rSIGLEC gene number was markedly strengthened by excluding the post-reproductive lifespan of humans and orcas (R2  = 0.83; P

Blood pressure (BP) is a highly heritable trait and a major cardiovascular disease risk factor. Genome wide association studies (GWAS) have implicated a number of susceptibility loci for systolic (SBP) and diastolic (DBP) blood pressure. However, a large portion of the heritability cannot be explained by the top GWAS loci and a comprehensive understanding of the underlying molecular mechanisms is still lacking. Here, we utilized an integrative genomics approach that leveraged multiple genetic and genomic datasets including (a) GWAS for SBP and DBP from the International Consortium for Blood Pressure (ICBP), (b) expression quantitative trait loci (eQTLs) from genetics of gene expression studies of human tissues related to BP, (c) knowledge-driven biological pathways, and (d) data-driven tissue-specific regulatory gene networks. Integration of these multidimensional datasets revealed tens of pathways and gene subnetworks in vascular tissues, liver, adipose, blood, and brain functionally associated with DBP and SBP. Diverse processes such as platelet production, insulin secretion/signaling, protein catabolism, cell adhesion and junction, immune and inflammation, and cardiac/smooth muscle contraction, were shared between DBP and SBP. Furthermore, "Wnt signaling" and "mammalian target of rapamycin (mTOR) signaling" pathways were found to be unique to SBP, while "cytokine network", and "tryptophan catabolism" to DBP. Incorporation of gene regulatory networks in our analysis informed on key regulator genes that orchestrate tissue-specific subnetworks of genes whose variants together explain ~20% of BP heritability. Our results shed light on the complex mechanisms underlying BP regulation and highlight potential novel targets and pathways for hypertension and cardiovascular diseases.

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

Aging is characterized by a decline in neuronal function in all animal species investigated so far. Functional changes are accompanied by and may be in part caused by, structurally visible degenerative changes in neurons. In the mammalian brain, normal aging shows abnormalities in dendrites and axons, as well as ultrastructural changes in synapses, rather than global neuron loss. The analysis of the structural features of aging neurons, as well as their causal link to molecular mechanisms on the one hand, and the functional decline on the other hand is crucial in order to understand the aging process in the brain. Invertebrate model organisms like Drosophila and C. elegans offer the opportunity to apply a forward genetic approach to the analysis of aging. In the present review, we aim to summarize findings concerning abnormalities in morphology and ultrastructure in invertebrate brains during normal aging and compare them to what is known for the mammalian brain. It becomes clear that despite of their considerably shorter life span, invertebrates display several age-related changes very similar to the mammalian condition, including the retraction of dendritic and axonal branches at specific locations, changes in synaptic density and increased accumulation of presynaptic protein complexes. We anticipate that continued research efforts in invertebrate systems will significantly contribute to reveal (and possibly manipulate) the molecular/cellular pathways leading to neuronal aging in the mammalian brain.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2008.05.044 Byline: Yelena V. Budovskaya (1), Kendall Wu (1)(3), Lucinda K. Southworth (2), Min Jiang (1), Patricia Tedesco (4), Thomas E. Johnson (4), Stuart K. Kim (1)(2) Keywords: CELLBIO; HUMDISEASE; RNA Abstract: To define the C. elegans aging process at the molecular level, we used DNA microarray experiments to identify a set of 1294 age-regulated genes and found that the GATA transcription factors ELT-3, ELT-5, and ELT-6 are responsible for age regulation of a large fraction of these genes. Expression of elt-5 and elt-6 increases during normal aging, and both of these GATA factors repress expression of elt-3, which shows a corresponding decrease in expression in old worms. elt-3 regulates a large number of downstream genes that change expression in old age, including ugt-9, col-144, and sod-3. elt-5(RNAi) and elt-6(RNAi) worms have extended longevity, indicating that elt-3, elt-5, and elt-6 play an important functional role in the aging process. These results identify a transcriptional circuit that guides the rapid aging process in C. elegans and indicate that this circuit is driven by drift of developmental pathways rather than accumulation of damage. Author Affiliation: (1) Department of Developmental Biology, Stanford University Medical Center, Stanford, CA 94305, USA (2) Stanford Medical Informatics, Stanford University Medical Center, Stanford, CA 94305, USA (3) Affymetrix, Inc., 3420 Central Expressway, Santa Clara, CA 95051, USA (4) Institute for Behavioral Genetics, Department of Integrative Physiology, University of Colorado, Boulder, Box 447, Boulder, CO 80309, USA Article History: Received 23 October 2007; Revised 13 February 2008; Accepted 21 May 2008 Article Note: (miscellaneous) Published: July 24, 2008

Author(s): Yun Zhang [1]; Charles Ma [1]; Thomas Delohery [2, 3]; Brian Nasipak [1]; Barrett C. Foat [1]; Alexander Bounoutas [1]; Harmen J. Bussemaker [1]; Stuart K. Kim [4]; Martin [...]

In Caenorhabditis elegans, let-60 Ras controls many cellular processes, such as differentiation of vulval epithelial cells, function of chemosensory neurons, and meiotic progression in the germ line. Although much is known about the let-60 Ras signaling pathway, relatively little is understood about the target genes induced by let-60 Ras signaling that carry out terminal effector functions leading to morphological change. We have used DNA microarrays to identify 708 genes that change expression in response to activated let-60 Ras. Key Words: Ras signaling; vulval development; DNA microarray; C. elegans.

The Caenorhabditis elegans APC-related gene apr-1 is necessary for epithelial cell migration and Hox gene expression. The human APC tumor suppressor gene is mutated in most inherited colorectal cancer cases. APR-1 may positively regulate activity of the the beta-Catenin/Armadillo-related proteins HMP-2 in migrating epithelial cells and BAR-1 in the vulval precursor cells.

LIN-7 binds to LET-23 receptor tyrosine kinase (RTK) in vivo. This binding is required for LET-23 basolateral localization and for vulval induction. LIN-2 and LIN-10 form a protein complex with LIN-7, showing that all three proteins are directly involved in basolateral localization of LET-23 RTK. It has been possible to identify a mechanism for basolateral localization of the LET-23 RTK in C. elegans vulval epithelia. A similar mechanism could be involved in basolateral localization of other transmembrane proteins in polarized epithelial cells in all animals.

The PDZ protein LIN-10 is needed for localizing GLR-1 to the ASH-to-interneuron synapses. It has been established that LIN-10 is a shared component of the polarized protein-sorting pathways in epithelia and neurons. Furthermore, it has been shown that PDZ proteins are needed for localization of a neurotransmitter receptor to central synapses in vivo. It is possible that different neurotransmitter receptors are recruited to the ASH-to-interneuron synapses through the action of distinct PDZ proteins.

The Caenorhabditis elegans mpk-1 gene encodes a MAP kinase protein that plays an important role in Ras-mediated induction of vulval cell fates. We show that mutations that eliminate mpk-1 activity result in a highly penetrant, vulvaless phenotype. A double mutant containing a gain-of-function mpk-1 mutation and a gain-of-function mek mutation (MEK phosphorylates and activates MPK-1) exhibits a multivulva phenotype. These results suggest that mpk-1 may transduce most or all of the anchor cell signal. Epistasis analysis suggests that mpk-1 acts downstream of mek-2 (encodes a MEK homolog) and upstream of lin-1 (encodes an Ets transcription factor) in the anchor cell signaling pathway. Finally, mpk-1 may act together with let-60 ras in multiple developmental processes, as mpk-1 mutants exhibit nearly the same range of developmental phenotypes as let-60 ras mutants.

Vulval development in Caenorhabditis elegans is mediated by the protein LIN-31. If this protein is bound by LIN-1, the resulting complex inhibits vulval induction. Phosphorylation of LIN-31 by a membrane-associated protein (MAP) kinase liberates it from its complex with LIN-1 and relieves the genetic repression. LIN-31 phosphorylation is also important for the differentiation of cells destined to become the vulva. The expression of both LIN-1 and LIN-31 is under the control of MPK-1.

The Caenorhabditis elegans let-60 gene encodes a Ras protein that mediates induction of the hermaphrodite vulva. To better understand how mutations constitutively activate Ras and cause unregulated cell division, we have characterized ga89, a temperature-sensitive, gain-of-function mutation in let-60 ras. At 25 [degrees], ga89 increases let-60 activity resulting in a multivulva phenotype. At 15 [degrees], ga89 decreases let-60 activity resulting in a vulvaless phenotype in let-60(ga89)/Df animals. The ga89 mutation causes a leucine (L) to phenylalanine (F) substitution at amino acid 19, a residue conserved in all Ras proteins. We introduced the L19F change into human H-Ras protein and found that the in vitro GTPase activity of H-Ras became temperature-dependent. Genetic experiments suggest that LET-60(L19F) interacts with GAP and GNEF, since mutations that decrease GAP and GNEF activity affect the multivulva phenotype of let-60(ga89) animals. These results suggest that the L19F mutation primarily affects the intrinsic rate of GTP hydrolysis by Ras, and that this effect may be sufficient to account for the activated-Ras phenotype caused by let-60(ga89). Our results suggest that a mutation in a human ras gene analogous to ga89 might contribute to oncogenic transformation.

We describe a genetic mosaic analysis procedure in which Caenorhabditis elegans mosaics are generated by spontaneous loss of an extrachromosomal array. This technique allows almost any C. elegans gene that can be used in germline transformation experiments to be used in mosaic analysis experiments. We identified a cosmid clone that rescues the mutant phenotype of ncl-1, so that this cell-autonomous marker could be used to analyze mosaic animals. To determine the sites of action for unc-29 and lin-31, an extrachromosomal array was constructed containing the ncl-1 (+) cosmid linked to lin-31 (+) and unc-29 (+) cosmids. This array is mitotically unstable and can be lost to produce a clone of mutant cells. The specific cell division at which the extrachromosomal array had been lost was deduced by scoring the Ncl phenotypes of individual cells in genetic mosaics. The Unc-29 and Lin-31 phenotypes were then scored in these animals to determine in which cells these genes are required. This analysis showed that unc-29, which encodes a subunit of the acetylcholine receptor, acts in the body muscle cells. Furthermore, lin-31, which specifies cell fates during vulval induction and encodes a putative transcription factor similar to HNF-3/fork head, acts in the Pn.p cells.

LIN-7, a cell junction-associated protein, is required for the proper localization of LET-23 receptor tyrosine kinase to epithelial precursor (Pn.p) cell junctions during C. elegans vulval induction. LET-23 normally colocalizes with LIN-7 at the basal side of the cell junctions in Pn.p cells and LET-23 is mislocalized in lin-7 and lin-2 mutants. Proper localization of LET-23 appears to be required for LET-23 signaling activity, as lin-7 and lin-2 mutants exhibit a vulvaless phenotype.

During the induction of the caenohabditis elegans vulval induction, anchor-cell signal transduction is not required for the expression of the secondary cell fate. Observation of genetic mosaic animals in which precursor cells (P5.p, P6.p, P7.p) were defective in the anchor cell signal transduction pathway showed that these cells adopted a secondary cell path. The data proving that this pattern of cell fates can be generated by sequential signals has been given in detail.

Supplemental digital content is available in the text. Purpose: This study aimed to screen the entire genome for genetic markers associated with risk for concussion. Methods: A genome-wide association analyses was performed using data from the Kaiser Permanente Research Bank and the UK Biobank. Concussion cases were identified based on electronic health records from the Kaiser Permanente Research Bank and the UK Biobank from individuals of European ancestry. Genome-wide association analyses from both cohorts were tested for concussion using a logistic regression model adjusting for sex, height, weight, and race/ethnicity using allele counts for single nucleotide polymorphisms. Previously identified genes within the literature were also tested for association with concussion. Results: There were a total of 4064 cases of concussion and 291,472 controls within the databases, with two single nucleotide polymorphisms demonstrating a genome-wide significant association with concussion. The first polymorphism, rs144663795 (P = 9.7 × 10−11; OR = 2.91 per allele copy), is located within the intron of SPATA5. Strong, deleterious mutations in SPATA5 cause intellectual disability, hearing loss, and vision loss. The second polymorphism, rs117985931 (P = 3.97 × 10−9; OR = 3.59 per allele copy), is located within PLXNA4. PLXNA4 plays a key role is axon outgrowth during neural development, and DNA variants in PLXNA4 are associated with risk for Alzheimer's disease. Previous investigations have identified five candidate genes that may be associated with concussion, but none showed a significant association in the current model (P < 0.05). Conclusion: Two genetic markers were identified as potential risk factors for concussion and deserve further validation and investigation of molecular mechanisms. [ABSTRACT FROM AUTHOR]