Postnatal growth failure, short life span, and early onset of cellular senescence and subsequent immortalization in mice lacking the xeroderma pigmentosum group G gene.
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The xeroderma pigmentosum group G (XP-G) gene (XPG) encodes a structure-specific DNA endonuclease that functions in nucleotide excision repair (NER). XP-G patients show various symptoms, ranging from mild cutaneous abnormalities to severe dermatological impairments. In some cases, patients exhibit growth failure and life-shortening and neurological dysfunctions, which are characteristics of Cockayne syndrome (CS). The known XPG protein function as the 3' nuclease in NER, however, cannot explain the development of CS in certain XP-G patients. To gain an insight into the functions of the XPG protein, we have generated and examined mice lacking xpg (the mouse counterpart of the human XPG gene) alleles. The xpg-deficient mice exhibited postnatal growth failure and underwent premature death. Since XPA-deficient mice, which are totally defective in NER, do not show such symptoms, our data indicate that XPG performs an additional function(s) besides its role in NER. Our in vitro studies showed that primary embryonic fibroblasts isolated from the xpg-deficient mice underwent premature senescence and exhibited the early onset of immortalization and accumulation of p53. (+info)
Another set of responses and correlated responses to selection on age at reproduction in Drosophila melanogaster.
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Ageing is the decline in survival probability and fertility later in adult life. It can evolve through mutation accumulation and pleiotropy. Artificial selection by age at reproduction is a useful method for detecting the effects of pleiotropy, and for producing lines that differ in their rate of ageing for further analysis. However, the approach has encountered difficulties from gene-environment interaction and inadvertent selection. We have produced a new set of selection lines in Drosophila melanogaster, breeding from either 'young' or 'old' adults, and avoiding some of the difficulties present in previous studies. Breeding from older adults resulted in an evolutionary increase in survival but, contrary to all previous studies using this method, in no increase in late-life fertility. The increase in survival was accompanied by an evolutionary decline in fertility early in adult life, confirming the importance of pleiotropy in the evolution of ageing. Contrary to previous studies, there were no correlated responses to selection in the pre-adult period; development time, larval competitive ability and adult size achieved did not differ between the lines from the two selection regimes. (+info)
Prospective study of intentional weight loss and mortality in overweight white men aged 40-64 years.
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Although 25% of US men indicate that they are trying to lose weight, the association between intentional weight loss and longevity in men is unknown. The authors analyzed prospective data from 49,337 overweight (initial body mass index > or =27) white men aged 40-64 years who, in 1959-1960, answered questions on weight change direction, amount, time interval, and intent. Vital status was determined in 1972. Proportional hazards regression estimated mortality rate ratios for men who intentionally lost weight compared with men with no weight change. Analyses were stratified by health status and adjusted for age, initial body mass index, smoking status, alcohol intake, education, physical activity, health history, and physical symptoms. Among men with no reported health conditions (n = 36,280), intentional weight loss was not associated with total, cardiovascular (CVD), or cancer mortality, but diabetes-associated mortality was increased 48% (95% confidence interval (CI) -7% to +133%) among those who lost 20 pounds (9.1 kg) or more; this increase was largely related to non-CVD mortality. Among men with reported health conditions (n = 13,057), intentional weight loss had no association with total or CVD mortality, but cancer mortality increased 25% (95% confidence interval -4% to +63%) among those who lost 20 pounds or more. Diabetes-associated mortality was reduced 32% (95% confidence interval -52% to -5%) among those who lost less than 20 pounds and 36% (95% confidence interval -49% to -20%) among those who lost more than 20 pounds. These results and those from our earlier study in women (Williamson et al., Am J Epidemiol 1995;141:1128-41) suggest that intentional weight loss may reduce the risk of dying from diabetes, but not from CVD. In observational studies, however, it is difficult to separate intentional weight loss from unintentional weight loss due to undiagnosed, underlying disease. Well-designed observational studies, as well as randomized controlled trials, are needed to determine whether intentional weight loss reduces CVD mortality. (+info)
Longevity, stress response, and cancer in aging telomerase-deficient mice.
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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. (+info)
Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice.
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An3 1 KAL I MutL homologue 1 (MLH1) is a member of the family of proteins required for DNA mismatch repair. Germ-line mutations in MLH1 lead to the cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). We generated mice carrying a null mutation in the Mlh1 gene. We showed that mice heterozygous and homozygous for the Mlh1 gene are predisposed to developing tumors of the gastrointestinal (GI) tract, lymphomas, and a number of other tumor types. We also examined the role of adenomatous polyposis coli gene (Apc) gene mutations in the GI tumors of Mlh1 mutant mice by different methods and showed that the GI tumors in Mlh1 mice express little or no adenomatous polyposis coli protein. When an Apc gene mutation was bred into the Mlh1 mutant mice, the GI tumor incidence increased 40-100-fold. The wild-type Apc allele in these tumors was found to contain mutations. Together, these results show that we have developed two mouse models for human HNPCC and that the mechanisms of tumor development in the GI tract of these mice involve loss of Apc gene function in a manner very similar to that seen in the GI tumors of HNPCC. (+info)
Health of the elderly in a community in transition: a survey in Thiruvananthapuram City, Kerala, India.
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Results of a survey to assess the health and functional status of the elderly (defined as those who are 60 years or older) in Thiruvananthapuram city, the capital of Kerala state, India, are discussed. As the process of development results in longevity without concomitant economic success, traditional support systems break down. The differences in status of the elderly dependent on gender and socioeconomic class are highlighted. Women are poorer and generally suffer more morbidity than men in old age, even though their death rates are lower. The better-off among the elderly enjoy a quality of life much superior to their poor brethren. Thus, in transitional societies such as Kerala, socioeconomic status and gender play a significant role in determining the quality of life of the elderly, a finding which may have some policy implications. (+info)
Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice.
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Dietary manipulations to prevent cancer and other diseases of aging have drawn broad public and scientific attention. One indicator of this interest is that dehydroepiandrosterone (DHEA) supplements are widely consumed by those who hope that this hormone may keep them "younger longer." However, key data to support this belief are lacking. For example, the influence of DHEA treatment on spontaneous cancer and life span in healthy, long-lived strains of mice or rats is unknown. This is in contrast to the situation for caloric restriction (CR), which is known to oppose cancer development and increase maximum life span in rodents. To address this issue, we assigned 300 middle age (12-month-old) male C57BL/6 mice to one of four groups (n = 75 for each group) and evaluated them for longevity and spontaneous disease patterns. Two groups were fed a normal diet (ND), and two others were fed a calorie-restricted diet (RD). One ND group and one RD group were also given 25 microg/ml DHEA sulfate (DHEAS) in their drinking water. Although urine samples from DHEAS-treated mice contained 10-fold more DHEA and DHEAS than did samples from unsupplemented mice, DHEAS administration did not affect body weight, life span, or cancer patterns. The RD lowered body weight by 26% and increased maximum life span by approximately 15%. The incidence of the most prevalent cancer, plasma cell neoplasm, was higher in RD mice (66%) than in ND mice (41%). Thus, DHEAS, as administered here, influenced neither cancer nor longevity at two caloric intakes. In contrast, CR from middle age increased longevity, the age at which tumor-bearing mice died, and the percentage of mice dying with cancers, suggesting that CR may retard promotion and/or progression of existing lymphoid cancers. (+info)
Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN.
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The tumour suppressor gene PTEN (also called MMAC1 or TEP1) is somatically mutated in a variety of cancer types [1] [2] [3] [4]. In addition, germline mutation of PTEN is responsible for two dominantly inherited, related cancer syndromes called Cowden disease and Bannayan-Ruvalcaba-Riley syndrome [4]. PTEN encodes a dual-specificity phosphatase that inhibits cell spreading and migration partly by inhibiting integrin-mediated signalling [5] [6] [7]. Furthermore, PTEN regulates the levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3) by specifically dephosphorylating position 3 on the inositol ring [8]. We report here that the dauer formation gene daf-18 is the Caenorhabditis elegans homologue of PTEN. DAF-18 is a component of the insulin-like signalling pathway controlling entry into diapause and adult longevity that is regulated by the DAF-2 receptor tyrosine kinase and the AGE-1 PI 3-kinase [9]. Others have shown that mutation of daf-18 suppresses the life extension and constitutive dauer formation associated with daf-2 or age-1 mutants. Similarly, we show that inactivation of daf-18 by RNA-mediated interference mimics this suppression, and that a wild-type daf-18 transgene rescues the dauer defect. These results indicate that PTEN/daf-18 antagonizes the DAF-2-AGE-1 pathway, perhaps by catalyzing dephosphorylation of the PIP3 generated by AGE-1. These data further support the notion that mutations of PTEN contribute to the development of human neoplasia through an aberrant activation of the PI 3-kinase signalling cascade. (+info)