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National Library of Medicine's PubMed directory of MEDLINE citations.
Department of Adult Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Cell 1999 Mar 5;96(5):701-12
Telomere maintenance is thought to play a role in signaling cellular senescence; however, a link with organismal aging processes has not been established. The telomerase null mouse provides an opportunity to understand the effects associated with critical telomere shortening at the organismal level. We studied a variety of physiological processes in an aging cohort of mTR-/- mice. Loss of telomere function did not elicit a full spectrum of classical pathophysiological symptoms of aging. However, age-dependent telomere shortening and accompanying genetic instability were associated with shortened life span as well as a reduced capacity to respond to stresses such as wound healing and hematopoietic ablation. In addition, we found an increased incidence of spontaneous malignancies. These findings demonstrate a critical role for telomere length in the overall fitness, reserve, and well being of the aging organism.
Department of Biology, University of Miami, Coral Gables, Florida 33124-0421, USA.
J Gerontol A Biol Sci Med Sci 1999 Apr;54(4):B137-42
We have generated a life-extending mutation, yw23, in Caenorhabditis elegans. The mutation is in what appears to be a new aging gene, which we have designated age-2. When homozygous, yw23 produces an increase of mean and maximum life span of about 20% over that of the wild-type strain, N2. Strain HG23 [age-2(yw23)] was obtained by screening for longer life spans among 430 lines of nematodes two generations after exposure to the mutagen ethylmethanesulfonate. Strain HG231 [age-2(yw23)] was obtained after a single out-crossing of HG23 to N2. When compared with N2, HG231 exhibits normal motility, slightly higher swimming rates, reduced fertility (especially at higher temperatures), somewhat longer development times, and a slightly larger size at the time of first egg laying. A Gompertz analysis suggests that HG231 extends life span by reducing the initial mortality rate. In genetic crosses, yw23 complements other known aging mutants in C. elegans genes-age-1, daf-2, spe-26, clk-1, clk-2, clk-3, and gro-1. A double-mutant strain, HG284, combining mutations in age-1 and age-2, lives longer than animals with individual mutations in either age-1 or age-2, and exhibits a longer life span at 25 degrees C than at 20 degrees C.
Department of Biology, McGill University, 1205 Dr Penfield Avenue, Montreal, Quebec, Canada H3A 1B1.
EMBO J 1999 Apr 1;18(7):1783-92
Mutations in the clk-1 gene of the nematode Caenorhabditis elegans result in an average slowing of a variety of developmental and physiological processes, including the cell cycle, embryogenesis, post-embryonic growth, rhythmic behaviors and aging. In yeast, a CLK-1 homologue is absolutely required for ubiquinone biosynthesis and thus respiration. Here we show that CLK-1 is fully active when fused to green fluorescent protein and is found in the mitochondria of all somatic cells. The activity of mutant mitochondria, however, is only very slightly impaired, as measured in vivo by a dye-uptake assay, and in vitro by the activity of succinate cytochrome c reductase. Overexpression of CLK-1 activity in wild-type worms can increase mitochondrial activity, accelerate behavioral rates during aging and shorten life span, indicating that clk-1 regulates and controls these processes. These observations also provide strong genetic evidence that mitochondria are causally involved in aging. Furthermore, the reduced respiration of the long-lived clk-1 mutants suggests that longevity is promoted by the age-dependent decrease in mitochondrial function that is observed in most species.
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