| 1. |
- Dudhia, Jayesh, et al.
(författare)
-
Aging enhances a mechanically-induced reduction in tendon strength by an active process involving matrix metalloproteinase activity
- 2007
-
Ingår i: Aging Cell. - : Wiley. - 1474-9726 .- 1474-9718. ; 6:4, s. 547-556
-
Tidskriftsartikel (refereegranskat)abstract
- Age-associated and degenerative loss of functional integrity in soft tissues develops from effects of cumulative and subtle changes in their extracellular matrix (ECM). The highly ordered tendon ECM provides the tissue with its tensile strength during loading. As age and exercise collude in the high incidence of tendinopathies, we hypothesized that aged tendons fail due to cumulative damage resulting from a combination of diminished matrix repair and fragmentation of ECM proteins induced by prolonged cyclical loading, and that this is an active cell-mediated process. We developed an equine tendon explant model to examine the effect of age on the influence of prolonged cyclical loading at physiologically relevant strain rates (5% strain, 1 Hz for 24 h) on tissue mechanical properties, loss of ECM protein and matrix metalloproteinase (MMP) expression. We show significantly diminished mechanical strength of cyclically loaded tissue compared to controls (39.7 +/- 12%, P <= 0.05) this reduction was dependent on the presence of both viable cells and metalloproteinase activity. Furthermore, tendon from older specimens was more susceptible to weakening (11-30 years, 50% P <= 0.05) compared to immature and young mature tissue (1-3 years, 34%; 4-10 years, 35%, respectively). Cyclical load also induced release of degraded cartilage oligomeric matrix protein, an integral ECM protein, an effect that could be mimicked by culture with fibronectin fragments. These findings indicate prolonged cyclical loading of physiological magnitude decreases tendon tensile strength by an active process, and that MMPs may contribute to loss of functional competence, exaggerated by age, via load-induced proteolytic disruption of the ECM.
|
|
| 2. |
- Ganfornina, Maria D., et al.
(författare)
-
Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress
- 2008
-
Ingår i: Aging Cell. - : Wiley. - 1474-9726 .- 1474-9718. ; 7:4, s. 506-515
-
Tidskriftsartikel (refereegranskat)abstract
- Many nervous system pathologies are associated with increased levels of apolipoprotein D (ApoD), a lipocalin also expressed during normal development and aging. An ApoD homologous gene in Drosophila, Glial Lazarillo, regulates resistance to stress, and neurodegeneration in the aging brain. Here we study for the first time the protective potential of ApoD in a vertebrate model organism. Loss of mouse ApoD function increases the sensitivity to oxidative stress and the levels of brain lipid peroxidation, and impairs locomotor and learning abilities. Human ApoD overexpression in the mouse brain produces opposite effects, increasing survival and preventing the raise of brain lipid peroxides after oxidant treatment. These observations, together with its transcriptional up-regulation in the brain upon oxidative insult, identify ApoD as an acute response protein with a protective and therefore beneficial function mediated by the control of peroxidated lipids.
|
|
| 3. |
- Koopman, J J E, et al.
(författare)
-
Senescence rates in patients with end-stage renal disease: a critical appraisal of the Gompertz model.
- 2011
-
Ingår i: Aging Cell. - : Wiley. - 1474-9726 .- 1474-9718. ; Dec, s. 233-238
-
Tidskriftsartikel (refereegranskat)abstract
- The most frequently used model to describe the exponential increase in mortality rate over age is the Gompertz equation. Logarithmically transformed, the equation conforms to a straight line, of which the slope has been interpreted as the rate of senescence. Earlier, we proposed the derivative function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end-stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional kidney transplant have mortality rates comparable to the general population. Therefore, we calculated the age-specific mortality rates for European patients on dialysis (n=274,221; follow-up=594,767 person-years), for European patients with a functioning kidney transplant (n=61,286; follow-up=345,024 person-years), and for the general European population. We found higher mortality rates, but a smaller slope of logarithmical mortality curve for patients on dialysis compared to both patients with a functioning kidney transplant and the general population (p<0.001). A classical interpretation of the Gompertz model would imply that the rate of senescence in patients on dialysis is lower than in patients with a functioning transplant and lower than in the general population. In contrast, the derivative function of the Gompertz equation yielded highest senescence rates for patients on dialysis, whereas the rate was similar in patients with a functioning transplant and the general population. We conclude that the rate of senescence is better described by the derivative function of the Gompertz equation.
|
|
| 4. |
- Norddahl, Gudmundur, et al.
(författare)
-
Reduced repression of cytokine signaling ameliorates age-induced decline in hematopoietic stem cell function
- 2012
-
Ingår i: Aging Cell. - : Blackwell Publishing. - 1474-9718 .- 1474-9726. ; 11:6, s. 1128-1131
-
Tidskriftsartikel (refereegranskat)abstract
- Aging causes profound effects on the hematopoietic stem cell (HSC) pool, including an altered output of mature progeny and enhanced self-propagation of repopulating-defective HSCs. An important outstanding question is whether HSCs can be protected from aging. The signal adaptor protein LNK negatively regulates hematopoiesis at several cellular stages. It has remained unclear how the enhanced sensitivity to cytokine signaling caused by LNK deficiency affects hematopoiesis upon aging. Our findings demonstrate that aged LNK-/- HSCs displayed a robust overall reconstitution potential and gave rise to a hematopoietic system with a balanced lineage distribution. Although aged LNK-/- HSCs displayed a distinct molecular profile in which reduced proliferation was central, little or no difference in the proliferation of aged LNK-/- HSCs was observed after transplantation when compared to aged WT HSCs. This coincided with equal telomere maintenance in WT and LNK-/- HSCs. Collectively, our studies suggest that enhanced cytokine signaling can counteract functional age-related HSC decline.
|
|
| 5. |
- Cristea, Alexander, et al.
(författare)
-
Effects of aging and gender on the spatial organization of nuclei in single human skeletal muscle cells
- 2010
-
Ingår i: Aging Cell. - : Wiley. - 1474-9718 .- 1474-9726. ; 9:5, s. 685-697
-
Tidskriftsartikel (refereegranskat)abstract
- The skeletal muscle fibre is a syncitium where each myonucleus regulates the gene products in a finite volume of the cytoplasm, i.e., the myonuclear domain (MND). We analysed aging- and gender-related effects on myonuclei organization and the MND size in single muscle fibres from six young (21–31 years) and nine old men (72–96 years), and from six young (24–32 years) and nine old women (65–96 years), using a novel image analysis algorithm applied to confocal images. Muscle fibres were classified according to myosin heavy chain (MyHC) isoform expression. Our image analysis algorithm was effective in determining the spatial organization of myonuclei and the distribution of individual MNDs along the single fibre segments. Significant linear relations were observed between MND size and fibre size, irrespective age, gender and MyHC isoform expression. The spatial organization of individual myonuclei, calculated as the distribution of nearest neighbour distances in 3D, and MND size were affected in old age, but changes were dependent on MyHC isoform expression. In type I muscle fibres, average NN-values were lower and showed an increased variability in old age, reflecting an aggregation of myonuclei in old age. Average MND size did not change in old age, but there was an increased MND size variability. In type IIa fibres, average NN-values and MND sizes were lower in old age, reflecting the smaller size of these muscle fibres in old age. It is suggested that these changes have a significant impact on protein synthesis and degradation during the aging process.
|
|
| 6. |
- Gibson, Kate L, et al.
(författare)
-
B-cell diversity decreases in old age and is correlated with poor health status
- 2009
-
Ingår i: AGING CELL. - : Wiley. - 1474-9718 .- 1474-9726. ; 8:1, s. 18-25
-
Tidskriftsartikel (refereegranskat)abstract
- Older people suffer from a decline in immune system, which affects their ability to respond to infections and to raise efficient responses to vaccines. Effective and specific antibodies in responses from older individuals are decreased in favour of non-specific antibody production. We investigated the B-cell repertoire in DNA samples from peripheral blood of individuals aged 86-94 years, and a control group aged 19-54 years, using spectratype analysis of the IGHV complementarity determining region (CDR)3. We found that a proportion of older individuals had a dramatic collapse in their B-cell repertoire diversity. Sequencing of polymerase chain reaction products from a selection of samples indicated that this loss of diversity was characterized by clonal expansions of B cells in vivo. Statistical analysis of the spectratypes enabled objective comparisons and showed that loss of diversity correlated very strongly with the general health status of the individuals; a distorted spectratype can be used to predict frailty. Correlations with survival and vitamin B12 status were also seen. We conclude that B-cell diversity can decrease dramatically with age and may have important implications for the immune health of older people. B-cell immune frailty is also a marker of general frailty.
|
|
| 7. |
|
|
| 8. |
- Maklakov, Alexei A., et al.
(författare)
-
Sexual selection affects lifespan and aging in the seed beetle
- 2007
-
Ingår i: Aging Cell. - : Wiley. - 1474-9718 .- 1474-9726. ; 6:6, s. 739-744
-
Tidskriftsartikel (refereegranskat)abstract
- Sexual selection in general, and sexual conflict in particular, should affect the evolution of lifespan and aging. Using experimental evolution, we tested whether removal of sexual selection leads to the evolution of accelerated or decelerated senescence. We subjected replicated populations of the seed beetle Callosobruchus maculatus to either of two selection regimes for 35 generations. These regimes either allowed (polygamy) or removed the potential (monogamy) for sexual selection to operate. To test for the evolution of intrinsic differences between the two selection regimes, we assayed longevity in replicate cohorts of virgin females and males. Virgin females from populations evolving under sexual selection had reduced lifespan as predicted by the sexual conflict theory of aging. However, this reduction was due to increased baseline mortality rather than an increase in age-specific mortality rates with age. We discuss these findings in light of other data from this model system and suggest that system-specific idiosyncrasies may often modulate the general effects of male-female coevolution on the evolution of aging.
|
|
| 9. |
|
|
| 10. |
- Wiklund, Fredrik E, et al.
(författare)
-
Macrophage inhibitory cytokine-1 (MIC-1/GDF15) : a new marker of all-cause mortality
- 2010
-
Ingår i: Aging Cell. - : Wiley. - 1474-9718 .- 1474-9726. ; 9:6, s. 1057-1064
-
Tidskriftsartikel (refereegranskat)abstract
- Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is a member of the TGF-b superfamily, previously studied in cancer and inflammation. In addition to regulating body weight, MIC-1/GDF15 may be used to predict mortality and/or disease course in cancer, cardiovascular disease (CVD), chronic renal and heart failure, as well as pulmonary embolism. These data suggested that MIC-1/GDF15 may be a marker of all-cause mortality. To determine whether serum MIC-1/GDF15 estimation is a predictor of all-cause mortality, we examined a cohort of 876 male subjects aged 35-80 years, selected from the Swedish Population Registry, and followed them for overall mortality. Serum MIC-1/GDF15 levels were determined for all subjects from samples taken at study entry. A second (independent) cohort of 324 same-sex twins (69% female) from the Swedish Twin Registry was similarly examined. All the twins had telomere length measured and 183 had serum levels of interleukin 6 (IL-6) and C-reactive protein (CRP) available. Patients were followed for up to 14 years and had cause-specific and all-cause mortality determined. Serum MIC-1/GDF15 levels predicted mortality in the all-male cohort with an adjusted odds ratio (OR) of death of 3.38 (95%CI 1.38-8.26). This finding was validated in the twin cohort. Serum MIC-1/GDF15 remained an independent predictor of mortality when further adjusted for telomere length, IL-6 and CRP. Additionally, serum MIC-1/GDF15 levels were directly correlated with survival time independently of genetic background. Serum MIC-1/GDF15 is a novel predictor of all-cause mortality.
|
|
