Many forms of neurodegeneration are associated with oxidative stress and mitochondrial dysfunction. Mitochondria are prominent targets of oxidative damage, however, it is not clear whether mitochondrial DNA (mtDNA) damage and/or its lack of repair are primary events in the delayed onset observed in Huntington’s disease (HD). We hypothesize that an age-dependent increase in mtDNA damage contributes to mitochondrial dysfunction in HD. Two HD mouse models were studied, the 3-nitropropionic acid (3-NPA) chemically induced model and the HD transgenic mice of the R6/2 strain containing 115–150 CAG repeats in the huntingtin gene. The mitochondrial toxin 3-NPA inhibits complex II of the electron transport system and causes neurodegeneration that resembles HD in the striatum of human and experimental animals. We measured nuclear and mtDNA damage by quantitative PCR (QPCR) in striatum of 5- and 24-month-old untreated and 3-NPA treated C57BL/6 mice. Aging caused an increase in damage in both nuclear and mitochondrial genomes. 3-NPA induced 4–6 more damage in mtDNA than nuclear DNA in 5-month-old mice, and this damage was repaired by 48 h in the mtDNA. In 24-month-old mice 3NPA caused equal amounts of nuclear and mitochondrial damage and this damage persistent in both genomes for 48 h. QPCR analysis showed a progressive increase in the levels of mtDNA damage in the striatum and cerebral cortex of 7–12-week-old R6/2 mice. Striatum exhibited eight-fold more damage to the mtDNA compared with a nuclear gene. These data suggest that mtDNA damage is an early biomarker for HD-associated neurodegeneration and supports the hypothesis that mtDNA lesions may contribute to the pathogenesis observed in HD.

DNA damage activates cell cycle checkpoints that prevent progression through the cell cycle. In yeast, the DNA damage checkpoint response is regulated by a series of genes that have mammalian homologs, including rad1, rad9, hus1, and rad17. On the basis of sequence homology, yeast and human Rad1, Rad9, and Hus1 protein homologs are predicted to structurally resemble the sliding clamp PCNA. Likewise, Rad17 homologs have extensive homology with replication factor C (RFC) subunits (p36, p37, p38, p40, and p140), which form a clamp loader for PCNA. These observations predict that Rad1, Hus1, and Rad9 might interact with Rad17 as a clampclamp loader pair during the DNA damage response. In this report, we demonstrate that endogenous human Rad17 (hRad17) interacts with the PCNA-related checkpoint proteins hRad1, hRad9, and hHus1. Mutational analysis of hRad1 and hRad17 demonstrates that this interaction has properties similar to the interaction between RFC and PCNA, a well characterized clampclamp loader pair. Moreover, we show that DNA damage affects the association of hRad17 with the clamp-like checkpoint proteins. Collectively, these data provide the first experimental evidence that hRad17 interacts with the PCNA-like proteins hRad1, hHus1, and hRad9 in manner similar to the interaction between RFC and PCNA.In response to DNA damage, eukaryotic cells block cell cycle progression in a process commonly known as the DNA damageinduced checkpoint response. Studies in genetically tractable yeast model systems have identified a large number of genes, dubbed checkpoint genes, that are essential for DNA damageinducible checkpoint activation (reviewed in Refs. 1-5). Epistasis and biochemical analyses in yeasts and humans have provisionally ordered the checkpoint proteins into a signaling pathway in which DNA damage relays activating signals through the phosphatidylinositol 3-kinase-related kinases, which include spRad3, scMec1, ATR, and ATM. The phosphatidylinositol 3-kinase-related kinases regulate activation of the serine-threonine protein kinases Chk1 and Chk2 (6 -10), which phosphorylate the cell-cycle phosphatase Cdc25 (7,9,11,12). Phosphorylation of Cdc25 inhibits its activity (13,14) and its accumulation in the nucleus (15, 16), thereby preventing activation of the CyclinB-Cdc2 complex and blocking the G 2 /M transition after DNA damage.Studies in Schizosaccharomyces pombe and Saccharomyces cerevisiae demonstrated that the checkpoint proteins spRad1, spHus1, spRad9, and spRad17 (using S. pombe nomenclature) or their homologs are essential for DNA damage-activated checkpoint responses (reviewed in Refs. 1 and 3-5). Furthermore, these studies suggest that all four proteins act early in the DNA damage-induced signaling pathway. Sequence analyses provide a few clues regarding potential functions of these proteins. Yeast, human, and fly Rad1 exhibit sequence homology with Ustilago maydis Rec1 (17-23), a checkpoint protein and a 3Ј-5Јexonuclease (24), suggesting that Rad1 may also be a nuclease. However, a highly conserved D...

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Benefits of physical activity Physical activity plays an important role in the treatment of chronic diseases in older adults. Physical activity has beneficial effects for the treatment of cardiovascular disease, high blood pressure, high cholesterol, chronic lung disease, diabetes, obesity, and osteoarthritis. These beneficial effects occur in people of all ages, including the 65 and over population. Physical activity also helps to relieve symptoms of depression, helps to maintain independent living, and enhances overall quality of life [4]. Physical inactivity and functional decline among older adults According to the National Center for Health Statistics, Americans are living longer, with life expectancy for those born in 2002 at 77.3 years, up from 71.2 in 1972 [5]. However, the quality of those additional years may be somewhat compromised, with over 34% of adults age 65 or older reporting limitations with even the most basic activities of daily living (ADLs), such as bathing and dressing [6,7]. Decreased physical capacity (e.g., muscular strength and endurance, flexibility, agility, and balance) leads to impairment in functional tasks (e.g., standing up from a seated position, lifting light weights, etc.), potentially leading to difficulties maintaining personal and social roles (i.e., disability). Indeed, decreased lower body strength has been identified as a powerful predictor of disability onset in later life [4]. Because quality of life in