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- Alderman, J. McKee, et al.
(författare)
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Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice
- 2009
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Ingår i: Experimental Gerontology. - : Elsevier BV. - 0531-5565 .- 1873-6815. ; 44:1-2, s. 26-33
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Tidskriftsartikel (refereegranskat)abstract
- Pit1 null (Snell dwarf) and Proph1 null (Ames dwarf) mutant mice lack GH, PRL and TSH. Snell and Ames dwarf mice also exhibit reduced IGF-I, resistance to cancer and a longer lifespan than control mice. Endogenous glucose production during fasting is reduced in Snell dwarf mice compared to fasting control mice. In view of cancer cell dependence on glucose for energy, low endogenous glucose production may provide Snell dwarf mice with resistance to cancer. We investigated whether endogenous glucose production is lower in Snell dwarf mice during feeding. Inhibition of endogenous glucose production by glucose injection was enhanced in 12 to 14 month-old female Snell dwarf mice. Thus, we hypothesize that lower endogenous glucose production during feeding and fasting reduces cancer cell glucose utilization providing Snell dwarf mice with resistance to cancer. The elevation of circulating adiponectin, a hormone produced by adipose tissue, may contribute to the suppression of endogenous glucose production in 12 to 14 month-old Snell dwarf mice. We compared the incidence of cancer at time of death between old Snell dwarf and control mice. Only 18% of old Snell dwarf mice had malignant lesions at the time of death compared to 82% of control mice. The median ages at death for old Snell dwarf and control mice were 33 and 26 months, respectively. By contrast, previous studies showed a high incidence of cancer in old Ames dwarf mice at the time of death. Hence, resistance to cancer in old Snell dwarf mice may be mediated by neuroendocrine factors that reduce glucose utilization besides elevated adiponectin, reduced IGF-I and a lack of GH, PRL and TSH, seen in both Snell and Ames dwarf mice. Proteomics analysis of pituitary secretions from Snell dwarf mice confirmed the absence of GH and PRL, the secretion of ACTH and elevated secretion of Chromogranin B and Secretogranin II. Radioimmune assays confirmed that circulating Chromogranin B and Secretogranin II were elevated in 12 to 14 month-old Snell dwarf mice. In summary, our results in Snell dwarf mice suggest that the pituitary gland and adipose tissue are part of a neuroendocrine loop that lowers the risk of cancer during aging by reducing the availability of glucose.
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| 2. |
- Buerger, Katharina, et al.
(författare)
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Validation of Alzheimer's disease CSF and plasma biological markers: the multicentre reliability study of the pilot European Alzheimer's Disease Neuroimaging Initiative (E-ADNI).
- 2009
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Ingår i: Experimental gerontology. - : Elsevier BV. - 1873-6815 .- 0531-5565. ; 44:9, s. 579-85
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Alzheimer's Disease Neuroimaging Initiatives ("ADNI") aim to validate neuroimaging and biochemical markers of Alzheimer's disease (AD). Data of the pilot European-ADNI (E-ADNI) biological marker programme of cerebrospinal fluid (CSF) and plasma candidate biomarkers are reported. METHODS: Six academic EADC centres recruited 49 subjects (healthy controls, subjects with mild cognitive impairment (MCI) and AD). We measured CSF beta-amyloid 42 (CSF Abeta42), total tau-protein (t-tau), phosphorylated tau-proteins (P-tau181, P-tau231), plasma beta-amyloid 40 and 42 (Abeta40/Abeta42). Immediate fresh shipment was compared to freezing and later shipment on dry ice. RESULTS: CSF T-tau (fresh samples) was increased in AD versus controls (p=0.049), CSF Abeta42 (frozen samples) was decreased in MCI and AD (p=0.02), as well as plasma Abeta40 (fresh and frozen samples) in AD (p=0.049 and p=0.016). Pooled values of neurochemical parameters and ratios thereof were different between centres (p<0.005). Analysis of frozen samples yielded higher diagnostic accuracy than immediate fresh shipment with 100% (fresh: 100%) correctly classified in control subjects, 100% (78%) in MCI, 91% (91%) in AD. CONCLUSION: The use of frozen rather than fresh samples renders higher diagnostic accuracy within a multicentre context. We confirmed the feasibility of a multicentre AD biomarker programme for future clinical trials.
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| 6. |
- Rossi, Derrick J., et al.
(författare)
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Hematopoietic stem cell aging: Mechanism and consequence
- 2007
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Ingår i: Experimental Gerontology. - : Elsevier BV. - 1873-6815 .- 0531-5565. ; 42:5, s. 385-390
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Tidskriftsartikel (refereegranskat)abstract
- Advancing age is frequented by the onset of a variety of hematological conditions characterized by diminished homeostatic control of blood cell production. The fact that upstream hematopoietic stem and progenitor cells are obligate mediators of homeostatic control of all blood lineages, has implicated the involvement of these cells in the pathophysiology of these conditions. Indeed, evidence from our group and others has suggested that two of the most clinically significant age-associated hematological conditions, namely, the diminution of the adaptive immune system and the elevated incidence of myeloproliferative diseases, have their origin in cell autonomous changes in the functional capacity of hematopoietic stem cells.
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| 7. |
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| 8. |
- Strindhall, J., et al.
(författare)
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No Immune Risk Profile among individuals who reach 100 years of age : Findings from the Swedish NONA immune longitudinal study
- 2007
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Ingår i: Experimental Gerontology. - : Elsevier BV. - 0531-5565 .- 1873-6815. ; 42:8, s. 753-761
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Tidskriftsartikel (refereegranskat)abstract
- In the present NONA immune longitudinal study, we investigate the previously identified Immune Risk Profile (IRP), defined by an inverted CD4/CD8 ratio and associated with persistent cytomegalovirus infection and increased numbers of CD8+CD28- cells, relative 6-year survival and age in NONA individuals. These subjects have now reached age 92, 96, and for the first time in this study, 100 years at follow-up. A 55 year old middle-aged group was used for comparison. Immunological monitoring included the analysis of numbers of lymphocytes and neutrophils, the T-cell subsets CD3+CD4+, CD3+CD8+, CD8+CD28+, CD8+CD28-, and the CD4/CD8 ratio. Longitudinal data were analysed by multivariate analyses of variance (MANOVA) from four measurement occasions at 2-year inter-intervals. One-way ANOVA was used for cross-sectional comparisons at baseline and the 6-year follow-up. The results confirmed the importance of the IRP as a major predictor of mortality in this population of very old. Moreover, the results suggested that survival to the age of 100 years is associated with selection of individuals with an "inverted" IRP that was stable across time, i.e., maintenance of a high CD4/CD8 ratio and low numbers of CD8+CD28- cells. The results underlines the importance of a longitudinal study design in dissecting immune parameters predictive of survival and show for the first time that centenarian status is associated with avoidance of the IRP over at least the previous 6 years and probably throughout life. © 2007 Elsevier Inc. All rights reserved.
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| 9. |
- Mitnitski, Arnold, et al.
(författare)
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A cross-national study of transitions in deficit counts in two birth cohorts: implications for modeling ageing.
- 2007
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Ingår i: Experimental gerontology. - : Elsevier BV. - 0531-5565. ; 42:3, s. 241-6
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Tidskriftsartikel (refereegranskat)abstract
- Generally, health does not improve with age, and many physical and physiological functions are known to decline. These changes do not occur uniformly, however; for many reasons, some people experience significant improvement in their health over non-trivial time intervals. Earlier, we showed that 5-year transitions in health status in elderly people (age 65+ years) can be modeled as a stochastic process, using a modified Poisson distribution with four readily interpretable parameters. The original description was based on follow-up of a single cross-sectional study, thus mixing age and cohort effects. Here, we again used a multistate Markov chain to model 5-year deficit accumulation in relation to frailty in both a Swedish birth cohort (aged 70 years at inception) and, from the original cross-sectional study, a Canadian birth cohort, aged 69-71. In both datasets, we found again that a modified Poisson describes the transition in health status with high precision. The parameters of the model though different, are close to each other, even though the cohorts are from different countries, were assembled 20 years apart, and counted different deficits. The model suggests that all health transitions, including health improvement, worsening, and death, can be summarized in a unified stochastic model with a few interpretable parameters.
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