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| 2. |
- Renault, Valérie, et al.
(författare)
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Human skeletal muscle satellite cells : aging, oxidative stress and the mitotic clock
- 2002
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Ingår i: Experimental Gerontology. - : Elsevier. - 0531-5565 .- 1873-6815. ; 37:10-11, s. 1229-1236, Article Number: PII S0531-5565(02)00129-8
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Tidskriftsartikel (refereegranskat)abstract
- Normal satellite cell cultures, isolated from human skeletal muscle, have a limited proliferative capacity and inevitably reach replicative senescence. In this study, we have focused on the consequences of a single oxidative stress by hydrogen peroxide (H(2)O(2)) on both proliferative capacity and myogenic characteristics. Treatment with 1mM H(2)O(2) for 30 min causes a small decrease in the viability and lifespan while the number of cells which are able to proliferate, decreases dramatically. This premature arrest of the cells in a non-proliferative state was not due to spontaneous differentiation since there was no increase in the number of myogenin positive cells. This stress did not affect the myogenicity of the cells or their ability to differentiate and fuse to form multinucleated myotubes. In addition, the mitotic clock does not seem to be modified by oxidative stress treatment since the rate of telomere shortening was similar in H(2)O(2)-treated and control cells. This could be the consequence of the high level of oxygen consumption with an even higher level of ROS being produced in skeletal muscle than in other tissues which would be counteracted by an increase in the antioxidant defense system.
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| 3. |
- Ross, Owen A., et al.
(författare)
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Mitochondrial DNA damage in lymphocytes : a role in immunosenescence?
- 2002
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Ingår i: Experimental Gerontology. - : Elsevier. - 0531-5565 .- 1873-6815. ; 37:2-3, s. 329-340
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Tidskriftsartikel (refereegranskat)abstract
- An age-related increase of DNA damage/mutation has been previously reported in human lymphocytes. The high copy number and mutation rate make the mtDNA genome an ideal candidate for assessing damage and to act as a potential biomarker of ageing. In the present study, two assays were developed to evaluate the level of mtDNA4977 and the accumulation of point mutations with age. A competitive polymerase chain reaction (PCR) methodology incorporating three primers was used to detect and quantify the levels of mtDNA4977 and a novel heteroduplex reference strand conformational analysis (RSCA) technique was used to analyse the accumulation of point mutations. The assays were applied to an in vitro model of T cell ageing and ex vivo DNA samples from an elderly cohort of subjects and a younger control group. The mtDNA4977 was detected in all the DNA samples examined but only a very low concentration was observed and no age-related increase or accumulation was observed. No accumulation of point mutations was identified using RSCA within the T cell clones as they were aged or the ex vivo lymphocytes from the elderly cohort. A higher level of variation was observed within the ex vivo DNA samples, verifying the high resolution of RSCA and its ability to identify different mtDNA species, although no correlation with age was observed. The low level of mtDNA damage observed with respect to the ex vivo lymphocyte DNA samples within this study may be due in part to the high turnover of blood cells/mtDNA, which may inhibit the accumulation of genetically abnormal mtDNA that may play a role in immunosenescence. A similar explanation may also apply to the in vitro model of T cell ageing if the vast majority of the cells are replicating rather than entering senescence.
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| 4. |
- Terman, Alexei, 1957-, et al.
(författare)
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Mitochondrial recycling and aging of cardiac myocytes : The role of autophagocytosis
- 2003
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Ingår i: Experimental Gerontology. - 0531-5565 .- 1873-6815. ; 38:8, s. 863-876
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms of mitochondrial alterations in aged post-mitotic cells, including formation of so-called 'giant' mitochondria, are poorly understood. To test whether these large mitochondria might appear due to imperfect autophagic mitochondrial turnover, we inhibited autophagocytosis in cultured neonatal rat cardiac myocytes with 3-methyladenine. This resulted in abnormal accumulation of mitochondria within myocytes, loss of contractility, and reduced survival time in culture. Unlike normal aging, which is associated with slow accumulation of predominantly large defective mitochondria, pharmacological inhibition of autophagy caused only moderate accumulation of large (senescent-like) mitochondria but dramatically enhanced the numbers of small mitochondria, probably reflecting their normally more rapid turnover. Furthermore, the 3-methyladenine-induced accumulation of large mitochondria was irreversible, while small mitochondria gradually decreased in number after withdrawal of the drug. We, therefore, tentatively conclude that large mitochondria selectively accumulate in aging post-mitotic cells because they are poorly autophagocytosed. Mitochondrial enlargement may result from impaired fission, a possibility supported by depressed DNA synthesis in large mitochondria. Nevertheless, enlarged mitochondria retained immunoreactivity for cytochrome c oxidase subunit 1, implying that mitochondrial genes remain active in defective mitochondria. Our findings suggest that imperfect autophagic recycling of these critical organelles may underlie the progressive mitochondrial damage, which characterizes aging post-mitotic cells.
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| 6. |
- Alafuzoff, Irina, et al.
(författare)
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The need to unify neuropathological assessments of vascular alterations in the ageing brain : Multicentre survey by the BrainNet Europe consortium
- 2012
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Ingår i: Experimental Gerontology. - : Elsevier BV. - 0531-5565 .- 1873-6815. ; 47:11, s. 825-833
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Tidskriftsartikel (refereegranskat)abstract
- Here, we summarise the results after carrying out a large survey regarding the assessment of vascular alterations, both vessel changes and vascular lesions in an inter-laboratory setting. In total, 32 neuropathologists from 22 centres, most being members of BrainNet Europe (BNE), participated by filling out a questionnaire with emphasis on assessment of common vascular alterations seen in the brains of aged subjects. A certain level of harmonisation has been reached among BNE members regarding sectioning of the brain, harvesting of brain tissue for histology and staining used when compared to the survey carried out in 2006 by Pantoni and colleagues. The most significant variability was seen regarding the assessment of severity and of clinical significance of vascular alterations. Two strategies have recently been recommended regarding the assessment of vascular alterations in aged and demented subjects. The National Institute on Aging - Alzheimer's Association (NIA-AA) recommends the assessment of hippocampal sclerosis, vascular brain injury and microvascular lesions in 12 regions. Although this strategy will be easy to follow, the recommendations do not inform how the load of observed alterations should be assessed and when the observed lesions are of significance. Deramecourt and his colleagues recommend an assessment and semiquantitative grading of various pathologies in 4 brain regions. This strategy yielded a total score of 0 to 20 as an estimate of pathology load. It is, however, not clear which score is considered to be of clinical significance. Furthermore, in several BNE trials the semiquantitative assessment has yielded poor agreement rates; an observation that might negatively influence the strategy proposed by Deramecourt and his colleagues. In line with NIA-AA, a dichotomised approach of easily recognisable lesions in a standardised set of brain regions harvested for neuropathological assessment and applying reproducible sampling and staining strategies is recommended by BNE. However, a simple strategy regarding assessment of load of alteration is urgently needed to yield reproducible, and at the same time, comparable results between centres.
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| 7. |
- 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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| 8. |
- Benedict, Christian, et al.
(författare)
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Intranasal insulin as a therapeutic option in the treatment of cognitive impairments
- 2011
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Ingår i: Experimental Gerontology. - : Elsevier BV. - 0531-5565 .- 1873-6815. ; 46:2-3, s. 112-115
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Tidskriftsartikel (refereegranskat)abstract
- The brain is a major target of circulating insulin. Enhancing central nervous insulin action has been shown to improve memory functions in animals as well as in humans, benefitting in particular hippocampus-dependent (declarative) memory. As Alzheimer's disease (AD) is associated with reduced central nervous insulin signaling and attenuated permeation of blood-borne insulin across the blood-brain-barrier, the cognitive decline in AD patients may at least in part be derived from impaired brain insulin signaling. Thus, therapeutic strategies to overcome central nervous system insulin deficiency and resistance might be an attractive option in the treatment of cognitive impairments like AD. Insulin can be effectively delivered directly to the brain via the intranasal route that enables the hormone to bypass the blood-brain barrier and modulate central nervous functions. This review summarizes a series of studies demonstrating beneficial effects of intranasal insulin on memory functions both in healthy humans and in patients with cognitive impairments such as AD. These experiments in humans consistently indicate that enhancing brain insulin signaling by intranasal administration of the hormone improves hippocampus-dependent memory in the absence of adverse side effects. Considering that insulin also acts as a neuroprotective signal, up-regulating brain insulin levels by intranasal insulin administration appears to be a promising approach in the treatment and prevention of central nervous system insulin deficiency and resistance as found in AD.
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| 9. |
- Boussard, Annika, et al.
(författare)
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The link between relative brain size and cognitive ageing in female guppies (Poecilia reticulata) artificially selected for variation in brain size
- 2021
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Ingår i: Experimental Gerontology. - : Elsevier BV. - 0531-5565 .- 1873-6815. ; 146
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive ageing is the general process when certain mental skills gradually deteriorate with age. Across species, there is a pattern of a slower brain structure degradation rate in large-brained species. Hence, having a larger brain might buffer the impact of cognitive ageing and positively affect survival at older age. However, few studies have investigated the link between relative brain size and cognitive ageing at the intraspecific level. In particular, experimental data on how brain size affects brain function also into higher age is largely missing. We used 288 female guppies (Poecilia reticulata), artificially selected for large and small relative brain size, to investigate variation in colour discrimination and behavioural flexibility, at 4-6, 12 and 24 months of age. These ages are particularly interesting since they cover the life span from sexual maturation until maximal life length under natural conditions. We found no evidence for a slower cognitive ageing rate in large-brained females in neither initial colour discrimination nor reversal learning. Behavioural flexibility was predicted by large relative brain size in the youngest group, but the effect of brain size disappeared with increasing age. This result suggests that cognitive ageing rate is faster in large-brained female guppies, potentially due to the faster ageing and shorter lifespan in the large-brained selection lines. It also means that cognition levels align across different brain sizes with older age. We conclude that there are cognitive consequences of ageing that vary with relative brain size in advanced learning abilities, whereas fundamental aspects of learning can be maintained throughout the ecologically relevant life span.
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