Funktionelle Untersuchungen der beiden Alien-Isoformen Alienα und CSN2

In dieser Arbeit konnten anhand eines Interaktionsassays Proteine der allgemeinen Transkriptionsinitiation und DNA-Reparatur, wie p33ING, als Interaktionspartner von Alien beschrieben werden. Des Weiteren wurde der Einfluss von Alien auf das Ubiquitin / Proteasom-System untersucht. Dabei konnte zum ersten Mal die Interaktion der Alien-Isoformen mit dem APC/C beschrieben werden. Infolge der Deregulation des APC/C durch die Überexpression von Alienα beziehungsweise CSN2 wurden die zellulären Proteinkonzentrationen verschiedener Zellzyklusregulatoren, wie Cyclin A, CDC6 und SnoN, verändert. Die Phosphorylierung von Alienα durch CDC2 führt dabei zur Inhibition der Interaktion mit dem APC/C in der Mitose. Auf der einen Seite konnte gezeigt werden, dass die Mimikrierung einer dauerhaften Phosphorylierung von Alienα die Bindung an den APC/C reprimiert. Dadurch wurden sowohl der APC/C Komplex als auch mehrere seiner Untereinheiten destabilisiert. Auf der anderen Seite führte die Deletion der Phosphorylierungsstelle zu einer dauerhaften Interaktion von Alienα und dem APC/C. Deshalb akkumulierten mitotische Cycline in der G1-Phase und der gesamte Zellzyklus wurde schneller durchlaufen. Darüber hinaus wurde eine Anhäufung von genetischen Schäden durch diese Deregulation des Zellzykluses gezeigt. Folglich kann eine Punktmutation in Alienα zum Umschalten zwischen einem langsamen, kontrollierten zu einem schnellen Zellzyklus mit vielen genetischen Schäden führen. Zusammenfassend wurde die Rolle von Alien sowohl als Transkriptionsfaktor, als auch bei der Regulation der Degradation von Proteinen bestätigt und um zusätzliche Wege erweitert. Damit konnte gezeigt werden, dass Alien in den Zellzyklus eingreift und für die genetische Stabilität und die Reduktion der Apoptose entscheidend ist. Aufgrund seiner Stellung als multifunktionaler Regulator zellulärer Prozesse könnte Alien somit für die Kontrolle der Tumorentstehung und Progression wichtig sein.In this work Alien was found to interact with several proteins of the general transcription initiation and DNA repair. Additionally, it could be shown that the two tumor suppressors p33ING1 and p33ING2 bind to Alienα and regulate its function. Furthermore the influence of Alien on the ubiqutin/proteasome system was examined. Hereby, the interaction of both Alien isoforms with the APC/C could be shown for the first time. By deregulating the APC/C through overexpression of Alienα as well as CSN2 the protein amount of several cell cycle regulators like Cyclin A, CDC6 and SnoN was altered. Due to the high homology of the two Alien isoforms a competition between Alienα and CSN2 for binding to the APC/C was detected. Phosphorylation of Alienα by CDC2 potentially inhibits the Alienα APC/C interaction during mitosis. On the one hand a mutation that mimics a constitutive phosphorylation of Alienα abolished its binding to the APC/C. Following, the APC/C complex as well as at least two of its subunits were destabilized. On the other hand deletion of the phosphorylation site leads to a permanent interaction of Alienα with the APC/C and higher concentrations of mitotic cyclins in the G1 phase. Thereby the whole cell cycle is accelerated and the accumulation of genetic instabilities is induced. So a single point mutation of Alienα switches between a slow, regulated cell cycle and a fast cell cycle possessing many genetic alterations. Deregulated Alien was shown to alter the cell cycle, increases genetic instability and reduces apoptosis. In conclusion Alien might be a key factor for prevention of tumor development and progression

Transient versus stable nature of fear of falling over 24 months in community-older persons with falls– data of the EU SCOPE project on Kidney function

BACKGROUND: Fear of falling (FoF) is an important risk factor for falls among older people. The objectives of our investigations were: a.) to present characteristics of older community-dwelling (CD) fallers with persistent or transient FoF (P-FoF or T-FoF) over 12 months, and b.) to investigate clinical predictors of P-FoF and T-FoF and c.) to explore differences between P-FoF and T-FoF. METHODS: Our series consisted of 389 older people reporting a fall or injurious fall at baseline and during 24 months follow-up participating in a multicenter prospective study. T-FoF was defined as participants reported “not at all” at baseline and “somewhat/fairly/very concerned” at follow-up, or “not at all” at follow-up, and “somewhat/fairly/very concerned” at baseline, and P-FoF was defined as participants answered “somewhat/fairly/very concerned” in both assessments at baseline and at follow-up. The association between risk factors and T-FoF or P-FoF was investigated by logistic regression analysis. RESULTS: The mean age of fallers in our sample was 79.0 years (SD 6.0), and 54.2% were females. Out of 389 older adults with a fall history at baseline, 83 participants (21.3%) did not report any FoF over time, P-FoF and T-FoF were observed in 42.7% and 35.9% of participants, respectively. After adjusting for potential confounders (e.g. age, gender), osteoporosis (OR = 2.04, 95%CI = 1.03–4.05) and impaired physical performance (OR = 2.38, 95%CI = 1.12–5.03) were significant predictors of T-FoF vs No-FoF. Osteoporosis (OR = 2.68, 95%CI = 1.31–5.48), depressive symptoms (OR = 3.54, 95%CI = 1.23–10.1) and living alone (OR = 2.44, 95%CI = 1.17–5.06) were significantly associated with P-FoF vs No-FoF. When comparing T-FoF and P-FoF, female gender (OR = 1.95, 95%CI = 1.16–3.27), BMI (OR = 1.08, 95%CI = 1.02–1.14), overall comorbidity (OR = 1.07, 95%CI = 1.02–1.13) and depression (OR = 2.55, 95%CI = 1.33–4.88) were significant predictors of P-FoF. CONCLUSIONS: T-FoF and P-FoF may be predicted by different sets of risk factors among older fallers. Thus, fallers should be screened for FoF especially when carrying specific risk factors, including female gender, osteoporosis, depression, living alone, impaired physical performance, BMI, comorbidity. These findings may be helpful in designing tailored intervention to blunt the risks related to consequence of FoF among older people experiencing falls. TRIAL REGISTRATION: The SCOPE study was registered prospectively at clinicaltrials.gov (NCT02691546; 25/02/2016). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12877-022-03357-0

Short physical performance battery is not associated with falls and injurious falls in older persons:longitudinal data of the SCOPE project

Introduction: Falls and fall-related injuries in older persons are a major public health problem. Our objective was to study the predictive value of the Short Physical Performance Battery (SPPB) in the cohort of the SCOPE project on falls, injurious falls, and possible difference of prediction between indoors and outdoors falls. Methods: For this sub-study of the SCOPE project participants reporting no falls at baseline, and survey data on falls at the 12-month and 24-month follow-up were included. Participant´s characteristics were assessed during the baseline interview and medical examinations. Falls as well as injurious falls and fall circumstances were obtained self-reported. SPPB and its association with fallers vs. no fallers at 12 and at 24 months were studied with logistic regression models. Results: The 1198 participants had a median age of 79 years (77–82), and a median SPPB of 10 (8–11), with a 52.5% of female. A total of 227 and 277 falls (12- and 24- month visits, respectively) were reported. In the crude model, the SPPB sum scores (p &lt; 0.001) as well as most single item scores were significant different between fallers and non-fallers over time. However, the association was attenuated in models adjusted for age, sex, marital status, number of medications, quality of life, handgrip strength, and muscle mass [e.g., 12 months; OR 0.94 (0.87–1.02)]. While SPPB fails to differentiate between injurious and non-injurious falls (p = 0.48), a lower SPPB score was associated with falls at home (p &lt; 0.01) after 24 months.Conclusion: SBPP was not able to significantly predict the risk of falling as well as experiencing an injurious fall. Trial registration: This study was registered prospectively on 25th February 2016 at clinicaltrials.gov (NCT02691546).</p

Diet-Induced and Age-Related Changes in the Quadriceps Muscle: MRI and MRS in a Rat Model of Sarcopenia

Background: Knowledge about the molecular pathomechanisms of sarcopenia is still sparse, especially with regard to nutritional risk factors and the subtype of sarcopenic obesity. Objective: The aim of this study was to characterize diet-induced and age-related changes on the quality and quantity of the quadriceps muscle in a rat model of sarcopenia by different magnetic resonance (MR) techniques. Methods: A total of 36 6-month-old male Sprague-Dawley rats were randomly subdivided into 2 groups and received either a high-fat diet (HFD) or a control diet (CD). At the age of 16 months, 15 HFD and 18 CD rats underwent MR at 1.5 T. T1-weighted images as well as T2 relaxation time maps were acquired perpendicular to the long axis of the quadriceps muscles. Maximum cross-sectional area (CSA) of the quadriceps muscle was measured on T1-weighted images, and T2 relaxation times of muscle were assessed in a region without visible intramuscular fat (T2lean muscle) and across the complete CSA (T2muscle). Furthermore, 1H-MR spectroscopy was performed to evaluate the relative lipid content of the quadriceps muscles. These measurements were repeated 5 months later in the surviving 8 HFD and 14 CD rats. Results: HFD rats revealed significantly decreased CSA and CSA per body weight (BW) as well as prolonged T2 relaxation times of muscle. A higher weight gain (upper tertile during the first 6 months of diet in CD rats) resulted in a significant change of T2muscle, but had no relevant impact on CSA. Advancing age up to 21 months led to significantly decreased BW, CSA and CSA/BW, significantly prolonged T2muscle and T2lean muscle and enlarged lipid content in the quadriceps muscle. Conclusions: In an experimental setting a chronically fat-enriched diet was shown to have a relevant and age-associated influence on both muscle quantity and quality. By translational means the employed MR techniques give rise to the possibility of an early detection and noninvasive quantification of sarcopenia in humans, which is highly relevant for the field of geriatrics

Quality of life and kidney function in older adults: prospective data of the SCOPE study

Abstract: A longitudinal alteration in health-related quality of life (HRQoL) over a two-year period and its association with early-stage chronic kidney disease (CKD) progression was investigated among 1748 older adults (>75 years). HRQoL was measured by the Euro-Quality of Life Visual Analog Scale (EQ-VAS) at baseline and at one and two years after recruitment. A full comprehensive geriatric assessment was performed, including sociodemographic and clinical characteristics, the Geriatric Depression Scale-Short Form (GDS-SF), Short Physical Performance Baery (SPPB), and estimated glomerular filtration rate (eGFR). The association between EQ-VAS decline and covariates was investigated by multivariable analyses. A total of 41% of the participants showed EQ-VAS decline, and 16.3% showed kidney function decline over the two-year follow-up period. Participants with EQ-VAS decline showed an increase in GDS-SF scores and a greater decline in SPPB scores. The logistic regression analyses showed no contribution of a decrease in kidney function on EQVAS decline in the early stages of CKD. However, older adults with a greater GDS-SF score were more likely to present EQ-VAS decline over time, whereas an increase in the SPPB scores was associated with less EQ-VAS decline. This finding should be considered in clinical practice and when HRQoL is used to evaluate health interventions among older adults

Mobility in Older Community-Dwelling Persons: A Narrative Review

Due to the demographic changes and the increasing awareness of the role of physical function, mobility in older age is becoming an important topic. Mobility limitations have been reported as increasingly prevalent in older persons affecting about 35% of persons aged 70 and the majority of persons over 85 years. Mobility limitations have been associated with increased fall risk, hospitalization, a decreased quality of life, and even mortality. As concepts of mobility are multifactorial and complex, in this narrative review, definitions, physical factors, and their age-related changes associated with mobility will be presented. Also, areas of cognitive decline and their impact on mobility, as well as neuromuscular factors related to mobility will be addressed. Another section will relate psychological factors such as Fall-related psychological concerns and sedentary behavior to mobility. Assessment of mobility as well as effective exercise interventions are only shortly addressed. In the last part, gaps and future work on mobility in older persons are discussed

A sustained high fat diet for two years decreases IgM and IL-1 beta in ageing Wistar rats

Background The immune system undergoes several alterations of innate and adaptive immunity during ageing. The main features of the aged immune system are a reduced diversity of T cell receptors and a reduced activity of innate immune cells with subsequent changes in adaptive immunity resulting in a less effective, less specific, and dys-regulated immune response and in an increased susceptibility towards infection, malignancy, and autoimmunity. The process is referred to as immunosenescence and is also modulated by environmental modifiers, such as dietary factors. High fat diet (HFD), via direct modulation of immune cell function by fatty acids and/or increased body fat mass, influences immune function. However, it is not clear whether HFD is beneficial or detrimental for the functioning of the ageing immune system. Methods Male Wistar rats fed with either a high fat diet (HFD 43 en% of fat) or control diet (SD, 25 en% of fat) over up to 24 month and were analyzed for plasma IL-1β, IL-6, TNF, IgM, IgG1, IgA, IgG2a, IgG2b, IgG2c, light chains lambda and kappa, testosterone, prolactin and percentage of splenic B cells and apoptosis rate, respectively. Results In general, all analyzed immunoglobuline isotypes increased with age, except for IgA. This increase was attenuated by HFD. In HFD and SD rats the percentage of B cells in the spleen and also their apoptotic rate was lower in aged as compared to young animals with no additional diet-induced effect. Testosterone and prolactin levels were lower in old animals, as expected. There was a statistical trend towards an increased prolactin/testosterone ratio in middle aged (6–12 monthsnth) HFD rats as compared to SD. IL-6 was neither affected by HFD nor age. On the other hand, HFD rats showed a decrease in IL-1β as compared to SD, which correlated with the above-mentioned suppressive effect on immunoglobulin isotypes, especially IgM. Conclusion In Wistar rats, HFD reveals an immunosuppressive effect in ageing animals by decreasing immunoglobulins, especially IgM, and IL-1β when compared to SD

Physiological stress in safer cycling in older age (SiFAr-stress): effect of a multicomponent exercise intervention—a study protocol for a randomized controlled trial

Background: SiFAr-Stress investigates the impact of cycling on stress levels in older adults. Uncertainty due to change to motorized bicycle or fear of falling can be perceived as stressors for cyclists. Stress activates different physiological signal cascades and stimulates the hypothalamic-pituitary-adrenal (HPA) axis, which leads to the release of the stress hormone cortisol and further effects such as the development of low-grade inflammation. Both can - in the long term - be associated with negative health outcomes. The aim of the study SiFAr-Stress is to analyze inflammatory processes as well as the activity of stress systems before and after a cycling intervention for older adults. Methods: In this study, community-dwelling older adults aged 65 years and older will be randomly assigned to either a cycling or a control intervention in a parallel-group design. Objective HPA axis-related measures (saliva cortisol and hair cortisol) will be assessed before, after, and 6-9 months after the cycling and control intervention (T0, T1, and T2). Furthermore, changes in cortisol reactivity in response to the cycling intervention will be investigated at the second and seventh training lessons. Furthermore, secondary outcomes (fear of falling, perceived stress, salivary alpha amylase, and C-reactive protein) will be assessed at T0, T1, and T2. Discussion: The study will be the first, in which stress- and health-related bio-physiological outcomes will be assessed in the context of a multicomponent exercise intervention, addressing cycling in older adults. It will enable us to better understand the underlying patho-physiological and psychological mechanisms and will help to improve interventions for this target group