Browsing by Subject "lifespan"

Now showing 1 - 4 of 4

Open Access
Molecular characterization of numr-1 and numr-2: genes that increase both resistance to metal-induced stress and lifespan in Caenorhabditis elegans
(2010) Tvermoes, Brooke E; Boyd, Windy A; Freedman, Jonathan H
To define the mechanisms involved in the molecular response to the carcinogenic metal cadmium, two novel metal-inducible genes from C. elegans were characterized: numr-1 and numr-2 (nuclear localized metal responsive). numr-1 and numr-2 sequences and cellular patterns of expression are identical, indicating that these are functionally equivalent genes. Constitutive transcription of numr-1 and numr-2 is developmentally regulated and occurs in the intestine, in head and tail neurons, and vulva muscles. Exposure to metals induces numr-1 and numr-2 transcription in pharyngeal and intestinal cells. Other environmental stressors do not affect transcription, indicating that these are metal-specific, stress-responsive genes. NUMR-1 and NUMR-2 target to nuclei and colocalize with HSF-1, suggesting that they may be components of nuclear stress granules. Nematodes overexpressing NUMR-1 and NUMR-2 are resistant to stress and live longer than control animals; likewise reducing expression increases sensitivity to metals and decreases neuromuscular functions. Upstream regulatory regions of both genes contain potential binding sites for DAF-16 and SKN-1, which are components of the insulin-IGF-like signaling pathway. This pathway regulates longevity and stress responses in C. elegans. NUMR-1 and NUMR-2 may function to promote resistance to environmental stressors and longevity, which is mediated by the insulin-IGF-like signaling pathway.
Open Access
The emergence of longevous populations.
(Proc Natl Acad Sci U S A, 2016-11-29) Colchero, Fernando; Rau, Roland; Jones, Owen R; Barthold, Julia A; Conde, Dalia A; Lenart, Adam; Nemeth, Laszlo; Scheuerlein, Alexander; Schoeley, Jonas; Torres, Catalina; Zarulli, Virginia; Altmann, Jeanne; Brockman, Diane K; Bronikowski, Anne M; Fedigan, Linda M; Pusey, Anne E; Stoinski, Tara S; Strier, Karen B; Baudisch, Annette; Alberts, Susan C; Vaupel, James W
The human lifespan has traversed a long evolutionary and historical path, from short-lived primate ancestors to contemporary Japan, Sweden, and other longevity frontrunners. Analyzing this trajectory is crucial for understanding biological and sociocultural processes that determine the span of life. Here we reveal a fundamental regularity. Two straight lines describe the joint rise of life expectancy and lifespan equality: one for primates and the second one over the full range of human experience from average lifespans as low as 2 y during mortality crises to more than 87 y for Japanese women today. Across the primate order and across human populations, the lives of females tend to be longer and less variable than the lives of males, suggesting deep evolutionary roots to the male disadvantage. Our findings cast fresh light on primate evolution and human history, opening directions for research on inequality, sociality, and aging.
Open Access
The NKI-Rockland Sample: A Model for Accelerating the Pace of Discovery Science in Psychiatry.
(Front Neurosci, 2012) Nooner, Kate Brody; Colcombe, Stanley J; Tobe, Russell H; Mennes, Maarten; Benedict, Melissa M; Moreno, Alexis L; Panek, Laura J; Brown, Shaquanna; Zavitz, Stephen T; Li, Qingyang; Sikka, Sharad; Gutman, David; Bangaru, Saroja; Schlachter, Rochelle Tziona; Kamiel, Stephanie M; Anwar, Ayesha R; Hinz, Caitlin M; Kaplan, Michelle S; Rachlin, Anna B; Adelsberg, Samantha; Cheung, Brian; Khanuja, Ranjit; Yan, Chaogan; Craddock, Cameron C; Calhoun, Vincent; Courtney, William; King, Margaret; Wood, Dylan; Cox, Christine L; Kelly, AM Clare; Di Martino, Adriana; Petkova, Eva; Reiss, Philip T; Duan, Nancy; Thomsen, Dawn; Biswal, Bharat; Coffey, Barbara; Hoptman, Matthew J; Javitt, Daniel C; Pomara, Nunzio; Sidtis, John J; Koplewicz, Harold S; Castellanos, Francisco Xavier; Leventhal, Bennett L; Milham, Michael P
The National Institute of Mental Health strategic plan for advancing psychiatric neuroscience calls for an acceleration of discovery and the delineation of developmental trajectories for risk and resilience across the lifespan. To attain these objectives, sufficiently powered datasets with broad and deep phenotypic characterization, state-of-the-art neuroimaging, and genetic samples must be generated and made openly available to the scientific community. The enhanced Nathan Kline Institute-Rockland Sample (NKI-RS) is a response to this need. NKI-RS is an ongoing, institutionally centered endeavor aimed at creating a large-scale (N > 1000), deeply phenotyped, community-ascertained, lifespan sample (ages 6-85 years old) with advanced neuroimaging and genetics. These data will be publically shared, openly, and prospectively (i.e., on a weekly basis). Herein, we describe the conceptual basis of the NKI-RS, including study design, sampling considerations, and steps to synchronize phenotypic and neuroimaging assessment. Additionally, we describe our process for sharing the data with the scientific community while protecting participant confidentiality, maintaining an adequate database, and certifying data integrity. The pilot phase of the NKI-RS, including challenges in recruiting, characterizing, imaging, and sharing data, is discussed while also explaining how this experience informed the final design of the enhanced NKI-RS. It is our hope that familiarity with the conceptual underpinnings of the enhanced NKI-RS will facilitate harmonization with future data collection efforts aimed at advancing psychiatric neuroscience and nosology.
Open Access
Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart-related traits.
(Aging Cell, 2017-02) Kulminski, Alexander M; Kernogitski, Yelena; Culminskaya, Irina; Loika, Yury; Arbeev, Konstantin G; Bagley, Olivia; Duan, Matt; Arbeeva, Liubov; Ukraintseva, Svetlana V; Wu, Deqing; Stallard, Eric; Yashin, Anatoliy I
Traditionally, genomewide association studies (GWAS) have emphasized the benefits of large samples in the analyses of age-related traits rather than their specific properties. We adopted a realistic concept of genetic susceptibility to inherently heterogeneous, age-related traits driven by the elusive role of evolution in their properties. We analyzed in detail the associations of rs693 and rs562338 polymorphisms representing the Apolipoprotein B locus with endophenotypes (total cholesterol [TC] and high-density lipoprotein cholesterol) and phenotypes (myocardial infarction [MI] and survival) in four large-scale studies, which include 20 748 individuals with 2357 MI events. We showed that a strong, robust predisposition of rs693 and rs562338 to TC (β = 0.72, P = 7.7 × 10(-30) for rs693 and β = -1.08, P = 9.8 × 10(-42) for rs562338) is not translated into a predisposition to MI and survival. The rs693_A allele influences risks of MI and mortality after MI additively with lipids. This allele shows antagonistic effects-protecting against MI risks (β = -0.18, P = 1.1 × 10(-5) ) or increasing MI risks (β = 0.15, P = 2.8 × 10(-3) ) and mortality after MI, in different populations. Paradoxically, increased TC concentrations can be protective against MI for the rs693_A allele carriers. Our results uncouple the influences of the same alleles on endophenotypes and phenotypes despite potential causal relationships among the latter. Our strategy reveals virtually genomewide significance for the associations of rs693 with MI (P = 5.5 × 10(-8) ) that is contrasted with a weak estimate following the traditional, sample-size-centered GWAS strategy (P = 0.16) in the same sample. These results caution against the use of the traditional GWAS strategy for gaining profound insights into genetic predisposition to healthspan and lifespan.