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PubMed2001

Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling.

The lifespan of Caenorhabditis elegans is regulated by the insulin/insulin-like growth factor (IGF)-1 receptor homolog DAF-2, which signals through a conserved phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Mutants in this pathway remain youthful and active much longer than normal animals and can live more than twice as long. This lifespan extension requires DAF-16, a forkhead/winged-helix transcription factor. DAF-16 is thought to be the main target of the DAF-2 pathway. Insulin/IGF-1 signaling is thought to lead to phosphorylation of DAF-16 by AKT activity, which in turn shortens lifespan. Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei. Disrupting Akt-consensus phosphorylation sites in DAF-16 causes nuclear accumulation in wild-type animals, but, surprisingly, has little effect on lifespan. Thus the DAF-2 pathway must have additional outputs. Lifespan in C. elegans can be extended by perturbing sensory neurons or germ cells. In both cases, lifespan extension requires DAF-16. We find that both sensory neurons and germline activity regulate DAF-16 accumulation in nuclei, but the nuclear localization patterns are different. Together these findings reveal unexpected complexity in the DAF-16-dependent pathways that regulate aging.

Animals↗
PubMed1990

Longevity in small cell lung cancer. A report to the Lung Cancer Subcommittee of the United Kingdom Coordinating Committee for Cancer Research.

An analysis of the long-term results of treatment of 3,681 patients with small cell lung cancer (SCLC) is presented. The data were obtained from major centres in the UK who were conducting treatment trials during the period 1978-1986 and for whom complete computer records and follow-up were available. A total of 217 (5.9%) survived 2 years or more. Two year survival for patients presenting with limited disease (LD) was 8.5% and for extensive disease (ED) 2.2%. Death from SCLC continued until 7 years after diagnosis but not thereafter. At this point overall survival was 3% (3.6% LD, 1.1% ED). Survival after 2 years was not affected by initial disease extent, sex, thoracic radiotherapy or prophylactic cranial irradiation. Death from causes other than SCLC continued throughout the period of observation. Vascular disease, respiratory failure and second tumours were the main other causes of death. The better survival in younger patients was mainly attributable to few deaths from these other causes. These results indicate that only a small proportion of patients with SCLC are cured by current treatment. Although shorter term improvement in survival has been obtained with current treatment, the poor overall long-term results support studies exploring new approaches to cure and to palliation.

Carcinoma, Small Cell↗
PubMed1990

The role of glucose-6-phosphate dehydrogenase in the evolution of longevity in Drosophila melanogaster.

Different polymorphic elements of the enzyme glucose-6-phosphate dehydrogenase (G6PD) are favoured under selection for long versus short life span. Replicate independently selected populations of short-lived individuals exhibit a more rapidly migrating and less actively staining allozyme, while long-lived populations have a slower migrating and more active allozyme. These correspond to the common ZwA and ZwB variants of the G6PD locus Zw. In vitro measurements show G6PD activity varies with allozymes and life span. Long-lived males have 64 per cent greater activity in G6PD, while females of long-lived strains are 108 per cent higher than those of short-lived strains. Previous studies of these strains have repeatedly demonstrated additivity of life span in F1 crosses. Activity of G6PD in reciprocal F1 populations is additive and intermediate between parents.

Adaptation, Physiological↗
PubMed2001

Larger hip circumference independently predicts health and longevity in a Swedish female cohort.

OBJECTIVE: The waist circumference is widely viewed as a simple but effective measure for assessing obesity-related health risks, whereas measurement of the hip circumference is not currently prioritized. This study examines health risks associated specifically with hip circumference in a cohort of Swedish women, to determine whether information may be lost by excluding the hip circumference from health surveys. RESEARCH METHODS AND PROCEDURES: The subjects described in this report constitute a population-based sample of 38- to 60-year-old women who underwent anthropometric examinations in 1968. The 24-year incidence rates have been ascertained for myocardial infarction, combined cardiovascular diseases, and diabetes. All-cause, cardiovascular, and myocardial infarction mortality also were evaluated. RESULTS: Hip circumference was a significant independent inverse risk estimator for all endpoints studied. Using Cox regression with adjustment for age, smoking, body mass index, and waist circumference, the remaining variability associated with larger hips was associated with significantly fewer adverse health outcomes. The hip circumference became statistically informative after body mass index adjustment. The strongest protective associations were observed for cardiovascular disease and diabetes endpoints, although significant trends were also seen for total mortality. Considering hip and waist simultaneously, the strength of the inverse association for large hips generally exceeded the positive association for waist. DISCUSSION: Recent interest in the waist circumference as an effective screening tool has taken the focus off of the hip circumference. The present results suggest that collection of hip measurements should not be discontinued in assessment of obesity-related risk status and health promotion.

Adult↗
PubMed2004

Caloric restriction and body weight independently affect longevity in Wistar rats.

OBJECTIVE: To evaluate the independent effects of caloric restriction (CR) and body weight (BW) on mortality rate (MR) and the extent to which BW may mediate the effect of CR on MR. DESIGN AND SUBJECTS: Data were from the Biosure Study, a randomized, controlled, prospective intervention study of diet regimens in 1200 Wistar rats. Animals were followed until they died spontaneously, were euthanized because of illness, or reached age 30 months. STATISTICAL ANALYSIS: Cox regression was performed to evaluate the effects of CR and BW on MR. Bootstrap procedures were used to test the contribution of BW to the effect of CR on MR. RESULTS: CR initiated after age 13 weeks decreased the rate of subsequent mortality. The MR increased with higher BW in early adulthood (21 weeks) and this effect persisted even after adjustment for CR. After adjustment for BW in early adulthood, we did not find a similar relation between mortality and BW in late adulthood (105 weeks). Mediation analysis indicated that low BW associated with CR appeared to mediate some of the mortality-reducing effects of CR, but CR clearly had effects independent of BW. The reductions in BW appeared to account for approximately 11% of the effect of CR. CONCLUSION: CR and BW have independent effects on MR in Wistar rats. BW may mediate a small part of the CR effects on MR.

Aging↗
PubMed1999

Sugar meals and longevity of the sandfly Phlebotomus papatasi in an arid focus of Leishmania major in the Jordan Valley.

The sugar diet and life-span of Phlebotomus papatasi were studied in a typical zoonotic focus of Leishmania major in an arid area of the Jordan Valley during 1996-1997. Plant-tissue residues (cellulose particles) were identified in the stained guts of 23% of P. papatasi and significant amounts of sugar were found in the gut of 16%. Feeding on different plants was demonstrated by using their branches, suffused with cellulose stain, as baits in the field. Ingested, stained cellulose was detected in 10% of the sandflies (6% of males, 12.5% of females) caught near bait-branches of common local plants, mostly Chenopodiaceae. The similar rates of plant and sugar feeding, with the observed absence of aphids (ruling out the availability of honeydew), implied that the sugar meals of sandflies were obtained directly from plants. The relative paucity of sugar meals in P. papatasi coincided with a short life-span, evaluated by daily growth lines in the cuticle. The age of the oldest females was estimated to be 8 days, and 6 days for males. Under local conditions, the first gonotrophic cycle can be completed in 6 days and the usual transmission of L. major is apparently afterwards, when females ingest blood to initiate another cycle. Only about 9% of P. papatasi females survived > 6 days.

Animals↗
PubMed2002

Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice.

Small body size has been associated with long life span in four stocks of mutant dwarf mice, and in two varieties of dietary restriction in rodents. In this study, small body size at ages 2-24 months was shown to be a significant predictor of life span in a genetically heterogeneous mouse population derived from four common inbred mouse strains. The association was strongest for weights measured early in adult life, and somewhat weaker, though still statistically significant, at later ages. The effect was seen both in males and females, and was replicated in an independent population of the same genetic background. Body size at ages 2-4 months was correlated with levels of serum leptin in both males and females, and with levels of IGF-I and thyroid hormone in females only. A genome scan showed the presence of polymorphic alleles on chromosomes 2, 6, 7 and 15 with significant effects on body weight at 2-4 months, at 10-12 months, or at both age ranges, showing that weight gain trajectory in this stock is under complex genetic control. Because it provides the earliest known predictor of life span, body weight may be usefully included in screens for induced mutations that alter aging. The evidence that weight in 2-month-old mice is a significant predictor of life span suggests that at least some of the lethal diseases of old age can be timed by factors that influence growth rate in juvenile rodents.

Animals↗