Fibroageing: An ageing pathological feature driven by dysregulated extracellular matrix-cell mechanobiology

Ageing is a multifactorial biological process leading to a progressive decline of physiological functions. The process of ageing includes numerous changes in the cells and the interactions between cell-cell and cell-microenvironment remaining as a critical risk factor for the development of chronic degenerative diseases. Systemic inflammation, known as inflammageing, increases as a consequence of ageing contributing to age-related morbidities. But also, persistent and uncontrolled activation of fibrotic pathways, with excessive accumulation of extracellular matrix (ECM) and organ dysfunction is markedly more frequent in the elderly. In this context, we introduce here the concept of Fibroageing, that is, the propensity to develop tissue fibrosis associated with ageing, and propose that ECM is a key player underlying this process. During ageing, molecules of the ECM become damaged through many modifications including glycation, crosslinking, and accumulation, leading to matrix stiffness which intensifies ageing-associated alterations. We provide a framework with some mechanistic hypotheses proposing that stiff ECM, in addition to the well-known activation of fibrotic positive feedback loops, affect several of the hallmarks of ageing, such as cell senescence and mitochondrial dysfunction, and in this context, is a key mechanism and a driver thread of Fibroageing.     

8精氨酸加压素_(4-9)肽对衰老脑突触体氨基酸掺入的影响

本文采用分离实触体体外摄取的方法研究8精氨酸加压素_(4-9)(AVP_(4-9))肽片段对青年(3月龄)和衰老(27月龄)大鼠脑的突触体氨基酸掺入和蛋白质合成的影响。结果显示,衰老时海马、额叶和颞叶皮质突触体的~3H—亮氨酸摄取明显减少(P<0.01),AVP_(4-9)肽能够促进上述脑区的突触体的亮氨酸摄取能力,以海马的突触体对AVP_(4-9)肽的反应最强,AVP_(4-9)肽对老年鼠各脑区的促进作用较青年鼠减弱,提示AVP_(4-9)肽对老年性神经精神疾病记忆损害的潜在治疗作用可能与其提高突触体的活性及增加蛋白质合成能力有关。     

Long-run effects of gestation during the Dutch Hunger Winter famine on labor market and hospitalization outcomes

The Dutch Hunger Winter (1944/45) is the most-studied famine in the literature on long-run effects of malnutrition in utero. Its temporal and spatial demarcations are clear, it was severe, it was not anticipated, and nutritional conditions in society were favorable and stable before and after the famine. This is the first study to analyze effects of in utero exposure on labor market outcomes and hospitalization late in life, and the first to use register data covering the full Dutch population to examine long-run effects of this famine. We provide results of famine exposure by sub-interval of gestation. We find a significantly negative effect of exposure during the first trimester of gestation on employment outcomes 53 or more years after birth. Hospitalization rates in the years before retirement are higher after middle or late gestational exposure.     

Inclusion body myositis: The interplay between ageing,muscle degeneration and autoimmunity

Inclusion body myositis (IBM) is a slowly progressive muscle disease affecting ageing individuals. IBM presents with a distinctive pattern of weakness involving the quadriceps and finger flexor muscles, although other muscles including pharyngeal muscles become affected over time. Pathological hallmarks of IBM include autoimmune features, including endomysial infiltration by highly differentiated T cells, as well as degenerative features marked by intramyofibre protein aggregates organised into inclusion bodies. Despite some progress in understanding the cellular pathways involved in IBM, it remains untreatable, and the progression of the disease leads to progressive weakness, disability, wheelchair dependency and loss of independence. Therefore, there is an urgent need to improve our understanding of the underlying mechanisms and pathways involved in this disease to identify new treatment targets. Here, we discuss the current understanding of aetiopathogenesis, the interrelationship between autoimmunity and degeneration, and how ageing is a major influencer of both these features.     

Self-rated health among older adults: a cross-national comparison

Self-rated health (SRH) may have different implications in various social and cultural settings. However, few studies are available concerning SRH among older persons across countries. The aim of this study was to analyse whether there are cross-national differences in the association between status characteristics, several diseases common among older persons, activities of daily living (ADL), and SRH. The study base was the Comparison of Longitudinal European Studies on Aging (CLESA), which includes data from six population-based studies on aging conducted in Finland, Israel, Italy, The Netherlands, Spain and Sweden. The study population comprised 5,629 persons, with participants from all countries except Italy. Logistic regression analyses were used to assess the relationship between status characteristics, health conditions, ADL and SRH. To examine whether the association among status characteristics, health conditions, ADL and outcome differed across the CLESA countries, interaction terms defined as variable*country were considered separately for each variable. Regression analyses revealed that sex, education, lifetime occupation, heart disease and respiratory disease were differently distributed across countries. Among homogeneous factors, marital status (OR=1.21), hypertension (OR=1.41), stroke (OR=1.67), diabetes (OR=2.15), cancer (OR=1.47), musculoskeletal diseases (OR=2.44), and ADL (OR=2.72) turned out to be significantly associated with fair or poor SRH. The results indicate that there are differences in self-ratings of health across countries. These differences cannot be explained entirely by status characteristics, self-reported diseases or functional ability. However, an important finding was that in all countries most of the indicators of medical and functional health were homogeneously associated with SRH.     

Physical disability among older Italians with diabetes. The ILSA Study

Aims/hypothesis We studied the role of diabetic complications and comorbidity in the association between diabetes and disability in the elderly.Methods Data were from a nationally representative sample of 5632 older Italians, aged 65 years and older, and who participated in the Italian Longitudinal Study on Aging. Clinical diagnoses of diabetes and other major chronic conditions were made by a physician, while disability was assessed by self-reported information on activities of daily living and physical performance tests.Results After adjusting for age, education and BMI, disability on the basis of activities of daily living was associated with diabetes in women, but not in men (odds ratio [OR] 1.65, CI: 1.22–2.23 and OR 1.21, CI: 0.84–1.75 respectively). In contrast, the association between severe and/or total disability on the basis of physical performance tests and diabetes was strong in both sexes (OR 2.81, CI: 1.44–5.41 and OR 2.16, CI: 1.25–3.73 respectively). Adjusting for traditional complications and comorbidity reduced the excess odds of disability by 38% in women and by 16% in men.Conclusions/interpretation Disability in older Italians with diabetes is frequent and only partially attributable to traditional diabetic complications and comorbidity.The ILSA Working Group: S. Maggi, N. Minicuci, A. Di Carlo, M. Baldereschi, Italian National Research Council (CNR); L. Candelise, E. Scarpini, University of Milan; P. Carbonin, Catholic University of the Sacred Heart, Rome; G. Farchi, E. Scafato, S. Brescianini, National Institutes of Health, Rome; F. Grigoletto, E. Perissinotto, G. Enzi, University of Padua; C. Loeb, Italian National Research Council, Genoa; C. Gandolfo, University of Genoa; N. Canal, M. Franceschi, San Raffaele Institute, Milan; A. Ghetti, R. Vergassola, Health Area 10, Florence; D. Inzitari, University of Florence; S. Bonaiuto, F. Fini, A. Vesprini, G. Cruciani, Italian National Institute of Research and Care on Aging, Fermo; A. Capurso, P. Livrea, V. Lepore, University of Bari; L. Motta, D. Maugeri, G. Carnazzo, P. Bentivegna, University of Catania; F. Rengo, University of Naples; all Italy     

Network remodeling of intramural coronary resistance arteries in the aged rat: A statistical analysis of geometry

AimsTo identify the geometrical alterations in the age-remodeled rat coronary artery network and to develop a useful technique to analyze network properties in the rat heart.Methods and resultsWe analyzed the networks of the left anterior descendent coronary arteries on in situ perfused hearts of young (3 months) and old (18 months) male rats. All segments and branching over >80 μm diameter were analyzed using 50 μm long cylindrical ring units of the networks. Arterial widening and paucity, increased tortuosity were typical features in the old network. In addition, axis angles deviated more from the mother branches in the old, whereas the diameters of daughter branches fit the Murray law in both groups. The detected changes in the old network resulted in a longer blood flow route for the same direct distance.ConclusionWe developed a useful method to investigate arterial network property changes in the rat heart. Ageing resulted in longer, more tortuous flow route in the LAD network that might be hemodynamically disadvantageous.     

Growth Factors in Intervertebral Disc Homeostasis

Intervertebral disc degeneration is a complex age-related pathology associated with back pain. Research on the growth factors that regulate disc homeostasis is of critical importance for understanding the basis of the disease. Here we summarize the data on the expression and function of various growth factors in the disc from in vivo and in vitro studies, as well as on their alterations during degeneration and ageing. Such studies are becoming more crucial in the prospect of clinical application of growth factors for the treatment of disc degeneration.     

Towards measurement of the Healthy Ageing Phenotype in lifestyle-based intervention studies

Introduction

Given the biological complexity of the ageing process, there is no single, simple and reliable measure of how healthily someone is ageing. Intervention studies need a panel of measures which capture key features of healthy ageing. To help guide our research in this area, we have adopted the concept of the “Healthy Ageing Phenotype” (HAP) and this study aimed to (i) identify the most important features of the HAP and (ii) identify/develop tools for measurement of those features.

Methods

After a comprehensive assessment of the literature we selected the following domains: physiological and metabolic health, physical capability, cognitive function, social wellbeing, and psychological wellbeing which we hoped would provide a reasonably holistic characterisation of the HAP. We reviewed the literature and identified systematic reviews and/or meta-analysis of cohort studies, and clinical guidelines on outcome measures of these domains relevant to the HAP. Selection criteria for these measures included: frequent use in longitudinal studies of ageing; expected to change with age; evidence for strong association with/prediction of ageing-related phenotypes such as morbidity, mortality and lifespan; whenever possible, focus on studies measuring these outcomes in populations rather than on individuals selected on the basis of a particular disease; (bio)markers that respond to (lifestyle-based) intervention. Proposed markers were exposed to critique in a Workshop held in Newcastle, UK in October 2012.

Results

We have selected a tentative panel of (bio)markers of physiological and metabolic health, physical capability, cognitive function, social wellbeing, and psychological wellbeing which we propose may be useful in characterising the HAP and which may have utility as outcome measures in intervention studies. In addition, we have identified a number of tools which could be applied in community-based intervention studies designed to enhance healthy ageing.

Conclusions

We have proposed, tentatively, a panel of outcome measures which could be deployed in community-based, lifestyle intervention studies. The evidence base for selection of measurement domains is less well developed in some areas e.g. social wellbeing (where the definition of the concept itself remains elusive) and this has implications for the identification of appropriate tools. Although we have developed this panel as potential outcomes for intervention studies, we recognise that broader agreement on the concept of the HAP and on tools for its measurement could have wider utility and e.g. could facilitate comparisons of healthy ageing across diverse study designs and populations.