Extracellular vesicles, ageing, and therapeutic interventions

A more comprehensive understanding of the human ageing process is required to help mitigate the increasing burden of age-related morbidities in a rapidly growing global demographic of elderly individuals. One exciting novel strategy that has emerged to intervene involves the use of extracellular vesicles to engender tissue regeneration. Specifically, this employs their molecular payloads to confer changes in the epigenetic landscape of ageing cells and ameliorate the loss of functional capacity. Understanding the biology of extracellular vesicles and the specific roles they play during normative ageing will allow for the development of novel cell-free therapeutic interventions. Hence, the purpose of this review is to summarise the current understanding of the mechanisms that drive ageing, critically explore how extracellular vesicles affect ageing processes and discuss their therapeutic potential to mitigate the effects of age-associated morbidities and improve the human health span

Microvesicles as vehicles for tissue regeneration: Changing of the guards

Purpose of Review: Microvesicles (MVs) have been recognised as mediators of stem cell function, enabling and guiding their regenerative effects. Recent Findings: MVs constitute one unique size class of extracellular vesicles (EVs) directly shed from the cell plasma membrane. They facilitate cell-to-cell communication via intercellular transfer of proteins, mRNA and microRNA (miRNA). MVs derived from stem cells, or stem cell regulatory cell types, have proven roles in tissue regeneration and repair processes. Their role in the maintenance of healthy tissue function throughout the life course and thus in age related health span remains to be elucidated. Summary: Understanding the biogenesis and mechanisms of action of MVs may enable the development of cell-free therapeutics capable of assisting in tissue maintenance and repair for a variety of age-related degenerative diseases. This review critically evaluates recent work published in this area and highlights important new findings demonstrating the use of MVs in tissue regeneration

Circulating markers of ageing and allostatic load: a slow train coming

Dealing with the growing burden of age-related morbidities is one of the greatest challenges facing modern society. How we age across the lifecourse and how psychosocial and lifestyle factors interplay with the biology of ageing remains to be fully elucidated. Sensitive and specific biomarkers with which to interrogate the biology of the ageing process are sparse. Recent evidence suggests that non-coding RNAs are key determinants of such processes and that these can be used as potential circulatory bio-markers of ageing. They may also provide a mechanism which mediates the spread of allostatic load across the body over time, ultimately reflecting the immunological health and physiological status of tissues and organs. The interplay between exosomal microRNAs and ageing processes is still relatively unexplored, although circulating microRNAs have been linked to the regulation of a range of physiological and pathological processes and offer insight into mechanistic determinants of healthspan

Fabry disease: a new model of premature aging?

No abstract available

Association between exposure to second-hand smoke and telomere length: cross-sectional study of 1303 non-smokers

Background: Both active smoking and second-hand smoke (SHS) are important risk factors for many age-related diseases. Active smoking is associated with shortened telomere length. However, whether SHS accelerates telomere attrition with age is uncertain. The aim of this study was to examine the association between SHS exposure and shortening by age of leukocyte telomere length among adult non-smokers. Methods: We undertook a cross-sectional study of the association between self-reported levels of SHS exposure and telomere length shortening per annum on a subgroup of participants from the Scottish Family Health Study. Inclusion was restricted to non-smokers aged ≥ 18 years, who had provided self-reported overall usual SHS exposure (total hours per week) and blood samples for telomere analysis. Linear regression models were used to compare the ratio of telomere repeat copy number to single copy gene number (T/S)by age according to SHS exposure. Results: Of the 1303 eligible participants, 779 (59.8%) reported no SHS exposure, 495 (38.0%) low exposure (1–19 h per week) and 29 (2.2%) high exposure (≥20 h per week). In the univariate linear regression analyses, relative T/S ratio declined with increasing age in all exposure groups. Telomere length decreased more rapidly with increasing age among those with high exposure to SHS [adjusted coefficient −0.019, 95% confidence interval (CI) −0.031- −0.007) when compared with both those with no exposure to SHS (adjusted coefficient −0.006, 95% CI −0.008- −0.004) (high vs no SHS: P = 0.010) and those with low exposure to SHS (adjusted coefficient −0.005, 95% CI −0.007- −0.003) (high vs low SHS: P = 0.005). Conclusions: Our findings suggest that high SHS exposure may accelerate normal biological ageing, and support efforts to protect the public from SHS exposure. Further studies on relevant mechanisms should be conducted

Current epigenetic aspects the clinical kidney researcher should embrace

Chronic kidney disease (CKD), affecting 10-12% of the world's adult population, is associated with a considerably elevated risk of serious comorbidities, in particular, premature vascular disease and death. Although a wide spectrum of causative factors has been identified and/or suggested, there is still a large gap of knowledge regarding the underlying mechanisms and the complexity of the CKD phenotype. Epigenetic factors, which calibrate the genetic code, are emerging as important players in the CKD-associated pathophysiology. In this article, we review some of the current knowledge on epigenetic modifications and aspects on their role in the perturbed uraemic milieu, as well as the prospect of applying epigenotype-based diagnostics and preventive and therapeutic tools of clinical relevance to CKD patients. The practical realization of such a paradigm will require that researchers apply a holistic approach, including the full spectrum of the epigenetic landscape as well as the variability between and within tissues in the uraemic milieu

More miles on the clock: Neighbourhood stressors are associated with telomere length in a longitudinal study

Background There is a substantial gap in health and longevity between more affluent and more deprived areas, and more knowledge of the determinants of this health divide is required. Experience of the local residential environment is important for health although few studies have examined this in relation to biological markers of age such as telomere length. We sought to examine if residents’ perceptions of neighbourhood stressors over time were associated with telomere length in a community study. Methodology/Principal findings In a prospective cohort study of 2186 adults in the West of Scotland, we measured neighbourhood stressors at three time points over a 12-year period and telomere length at the end of the study. Using linear regression models, we found that a higher accumulation of neighbourhood stressors over time was associated with shorter telomere length, even after taking cohort, social class, health behaviours (smoking status, diet, physical activity), BMI and depression into account among females only (Beta = 0.007; 95%CI [0.001, 0.012]; P < 0.014). Conclusions/Significance Neighborhood environments are potentially modifiable, and future efforts directed towards improving deleterious local environments may be useful to lessen telomere attrition

The role of the microbiota in sedentary life style disorders and ageing: Lessons from the animal kingdom

A paradox of so-called developed countries is that, as the major historical causes of human mortality are eliminated or mitigated by medical progress, life-style related diseases have become major killers. Furthermore, as life-span is extended by the combined effects of modern medicine, health-span is struggling to keep apace because of the burden of non-communicable diseases linked to diet and sedentary life-style. The gut microbiome is now recognized as a plastic environmental risk factor for many of these diseases, the microbiome being defined as the complex community of co-evolved commensal microbes that breaks down components of a complex diet, modulates innate immunity, and produces signalling molecules and metabolites that can impact on diverse regulatory systems in mammals. Aspects of the so-called â Westernâ life-style linked to disease risk such as energy dense diet and antibiotic treatment are known to affect the composition and function of the microbiome. Here we review the detailed mechanisms whereby the gut microbiome may modulate risk of diseases linked to sedentary life-style, and ageing related health loss. We focus on the comparative value of natural animal models such as hibernation for studying metabolic regulation, and the challenge of extrapolating from animal models to processes that occur in human ageing

The role of thiamine dependent enzymes in obesity and obesity related chronic disease states: a systematic review

The WHO 2016 report indicates that worldwide obesity is rising, with over 600 million people in the obese range (BMI&gt;30). The recommended daily calorie intake for adults is 2000 kcal and 2500 kcal for women and men respectively. The average American consumes 3770 kcal/day and the average person in the UK consumes 3400 kcal/day. With such increased caloric intake, there is an increased load on metabolic pathways, in particular glucose metabolism. Such metabolism requires micronutrients as enzyme co-factors. The recommended daily allowance (RDA) for thiamine is 1.3 mg/day and 0.5 mg thiamine is required to process 1000 kilocalories (kcal). Therefore, despite the appearance of being overfed, there is now increasing evidence that the obese population may nutritionally depleted of essential micronutrients. Thiamine deficiency has been reported to be in the region of 16-47% among patients undergoing bariatric surgery for obesity. Thiamine, in turn, requires magnesium to be in its active form thiamine diphosphate, (TDP). TDP also requires magnesium to achieve activation of TDP dependent enzymes, including transketolase (TK), pyruvate dehydrogenase (PDH) and alpha-keto glutaric acid dehydrogenase (AKGDH), during metabolism of glucose. Thiamine and magnesium therefore play a critical role in glucose metabolism and their deficiency may result in the accumulation of anaerobic metabolites including lactate due to a mismatch between caloric burden and function of thiamine dependent enzymes. It may therefore be postulated that thiamine and magnesium deficiency are under-recognized in obesity and may be important in the progress of obesity and obesity related chronic disease states. The aim of the present systematic review was to examine the role of thiamine dependent enzymes in obesity and obesity related chronic disease states

The role of the microbiota in sedentary life style disorders and ageing: lessons from the animal kingdom

A paradox of so‐called developed countries is that, as the major historical causes of human mortality are eliminated or mitigated by medical progress, life‐style related diseases have become major killers. Furthermore, as life‐span is extended by the combined effects of modern medicine, health‐span is struggling to keep apace because of the burden of non‐communicable diseases linked to diet and sedentary life‐style. The gut microbiome is now recognized as a plastic environmental risk factor for many of these diseases, the microbiome being defined as the complex community of co‐evolved commensal microbes that breaks down components of a complex diet, modulates innate immunity, and produces signalling molecules and metabolites that can impact on diverse regulatory systems in mammals. Aspects of the so‐called “Western” life‐style linked to disease risk such as energy dense diet and antibiotic treatment are known to affect the composition and function of the microbiome. Here we review the detailed mechanisms whereby the gut microbiome may modulate risk of diseases linked to sedentary life‐style, and ageing related health loss. We focus on the comparative value of natural animal models such as hibernation for studying metabolic regulation, and the challenge of extrapolating from animal models to processes that occur in human ageing