Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

Rather than being a passive, haphazard process of wear and tear, lifespan can be modulated actively by components of the insulin/insulin-like growth factor I (IGFI) pathway in laboratory animals. Complete or partial loss-of-function mutations in genes encoding components of the insulin/IGFI pathway result in extension of life span in yeasts, worms, flies, and mice. This remarkable conservation throughout evolution suggests that altered signaling in this pathway may also influence human lifespan.

Suh, Yousin
Atzmon, Gil
Cho, Mi-Ook
Hwang, David
Liu, Bingrong
Leahy, Daniel J.
Barzilai, Nir
Cohen, Pinchas
Publication Title: 

Mitochondrial dysfunction has been a hallmark of cancer. However, whether it has a causative role awaits to be elucidated. Here, using an animal model derived from inactivation of SUV3, a mitochondrial helicase, we demonstrated that mSuv3+/- mice harbored increased mitochondrial DNA (mtDNA) mutations and decreased mtDNA copy numbers, leading to tumor development in various sites and shortened lifespan. These phenotypes were transmitted maternally, indicating the etiological role of the mitochondria.

Chen, P.-L.
Chen, C.-F.
Chen, Y.
Guo, X. E.
Huang, C.-K.
Shew, J.-Y.
Reddick, R. L.
Wallace, D. C.
Lee, W.-H.
Publication Title: 
PloS One

The immune response is essential for survival by destroying microorganisms and pre-cancerous cells. However, inflammation, one aspect of this response, can result in short- and long-term deleterious side-effects. Mclk1?/? mutant mice can be long-lived despite displaying a hair-trigger inflammatory response and chronically activated macrophages as a result of high mitochondrial ROS generation. Here we ask whether this phenotype is beneficial or simply tolerated. We used models of infection by Salmonella serovars and found that Mclk1?/?

Wang, Dantong
Wang, Ying
Argyriou, Catherine
CarriËre, Audrey
Malo, Danielle
Hekimi, Siegfried
Publication Title: 
Annals of Internal Medicine

The complications of iron overload in hemochromatosis can be avoided by early diagnosis and appropriate management. Therapeutic phlebotomy is used to remove excess iron and maintain low normal body iron stores, and it should be initiated in men with serum ferritin levels of 300 microg/L or more and in women with serum ferritin levels of 200 microg/L or more, regardless of the presence or absence of symptoms.

Barton, J. C.
McDonnell, S. M.
Adams, P. C.
Brissot, P.
Powell, L. W.
Edwards, C. Q.
Cook, J. D.
Kowdley, K. V.
Publication Title: 
Cell Metabolism

A common thread among conserved life span regulators lies within intertwined roles in metabolism and energy homeostasis. We show that heterozygous mutations of AMP biosynthetic enzymes extend Drosophila life span. The life span benefit of these mutations depends upon increased AMP:ATP and ADP:ATP ratios and adenosine monophosphate-activated protein kinase (AMPK). Transgenic expression of AMPK in adult fat body or adult muscle, key metabolic tissues, extended life span, while AMPK RNAi reduced life span.

Stenesen, Drew
Suh, Jae Myoung
Seo, Jin
Yu, Kweon
Lee, Kyu-Sun
Kim, Jong-Seok
Min, Kyung-Jin
Graff, Jonathan M.
Publication Title: 

The amplification of ribosomal DNA during development of the somatic macronucleus in Tetrahymena thermophila was analyzed by genetic and molecular biological techniques. We have identified an alternate form of the rDNA, structurally distinguishable from the wild-type by an extra cutting site for Bam HI in its nontranscribed spacer. The altered rDNA was inherited in crosses in a simple Mendelian fashion, consistent with the presence of only one rRNA gene copy per haploid genome in the micronucleus.

Pan, W. C.
Orias, E.
Flacks, M.
Blackburn, E. H.
Publication Title: 
PloS One

Apolipoprotein-?4 (APOE-?4) is a major genetic risk factor for cognitive decline, Alzheimer's disease (AD) and early mortality. An accelerated rate of biological aging could contribute to this increased risk. Here, we determined whether APOE-?4 status impacts leukocyte telomere length (TL) and the rate of cellular senescence in healthy mid-life women and, further, whether hormone replacement therapy (HT) modifies this association. Post-menopausal women (N?=?63, Mean age?=?57.7), all HT users for at least one year, were enrolled in a randomized longitudinal study.

Jacobs, Emily G.
Kroenke, Candyce
Lin, Jue
Epel, Elissa S.
Kenna, Heather A.
Blackburn, Elizabeth H.
Rasgon, Natalie L.
Publication Title: 
Molecular and Cellular Biology

The autonomously replicating rRNA genes (rDNA) in the somatic nucleus of Tetrahymena thermophila are maintained at a copy number of approximately 10(4) per nucleus. A mutant in which the replication properties of this molecule were altered was isolated and characterized. This mutation of inbred strain C3, named rmm4, was shown to have the same effect on rDNA replication and to be associated with the same 1-base-pair (bp) deletion as the previously reported, independently derived rmm1 mutation (D. L. Larson, E. H. Blackburn, P. C. Yaeger, and E. Orias, Cell 47:229-240, 1986).

Yaeger, P. C.
Orias, E.
Shaiu, W. L.
Larson, D. D.
Blackburn, E. H.
Publication Title: 
Dementia and Geriatric Cognitive Disorders

BACKGROUND: Mutations in the presenilin-1 gene (PSEN1) have been identified in autosomal dominant early-onset cases of Alzheimer's disease (AD). AIMS: To investigate different clinical phenotypes of siblings possessing the same heterozygous P264L mutation in the PSEN1 gene. METHODS: We evaluated clinical features, neuroimaging results, and neuropsychological examinations. The PSEN1 gene and other dementia-related gene mutations were screened.

Ishizuka, Takanori
Nakamura, Masayuki
Ichiba, Mio
Fujita, Seigo
Takeuchi, Kouzo
Fujimoto, Toshiro
Sano, Akira
Publication Title: 
Cancer Research

Apurinic/apyrimidinic endonuclease is a key enzyme in the process of base excision repair, required for the repair of spontaneous base damage that arises as a result of oxidative damage to DNA. In mice, this endonuclease is coded by the Apex gene, disruption of which is incompatible with embryonic life. Here we confirm the embryonic lethality of Apex-null mice and report the phenotypic characterization of mice that are heterozygous mutants for the Apex gene (Apex+/-). We show that Apex heterozygous mutant cells and animals are abnormally sensitive to increased oxidative stress.

Meira, L. B.
Devaraj, S.
Kisby, G. E.
Burns, D. K.
Daniel, R. L.
Hammer, R. E.
Grundy, S.
Jialal, I.
Friedberg, E. C.


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