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Paul G. Shiels
Wolfson Wohl Translational Research Centre Institute of Cancer Sciences University of Glasgow Bearsden Glasgow UK

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Research article
Published: 14 August 2021 in Molecular Nutrition & Food Research
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Introduction Resistant starch type-2 (RS2) can mitigate inflammation and oxidative stress in hemodialysis (HD) patients. However, there is still a lack of knowledge on the impact of the RS2 on the gut microbiota community in these patients. Thus, this study aims to evaluate the effects of enriched RS2 cookies on the gut microbiome in HD patients. Methods and Results This comprises a randomized, double-blind, placebo-controlled trial of age-, sex-, and BMI-matched patients and controls. The RS2 group receives enriched RS2 cookies (16 g d-1 of Hi-Maize 260, Ingredion) for 4 weeks, while the placebo group received cookies made with manioc flour. Fecal microbiota composition is evaluated by the 16S ribosomal RNA gene. Analysis of the microbiota reveals that Pielou's evenness is significantly decreased after RS2 supplementation. Notably, it is observed that RS2 intervention upregulates significantly 8 Amplicon Sequencing Variants (ASV's), including Roseburia and Ruminococcus gauvreauii, which are short-chain fatty acids (SCFA) producers. Furthermore, it is associated with the downregulation of 11 ASVs, such as the pro-inflammatory Dialister. Conclusions RS2 intervention for 4 weeks in HD patients effectively alters SCFA producers in the gut microbiota, suggesting that it could be a good nutritional strategy for patients with chronic kidney disease (CKD) on HD.

ACS Style

Julie Ann Kemp; Bruna Regis de Paiva; Henrique Fragoso dos Santos; Hugo Emiliano de Jesus; Hannah Craven; Umer Z. Ijaz; Natalia Alvarenga Borges; Paul G. Shiels; Denise Mafra. The Impact of Enriched Resistant Starch Type‐2 Cookies on the Gut Microbiome in Hemodialysis Patients: A Randomized Controlled Trial. Molecular Nutrition & Food Research 2021, 2100374 .

AMA Style

Julie Ann Kemp, Bruna Regis de Paiva, Henrique Fragoso dos Santos, Hugo Emiliano de Jesus, Hannah Craven, Umer Z. Ijaz, Natalia Alvarenga Borges, Paul G. Shiels, Denise Mafra. The Impact of Enriched Resistant Starch Type‐2 Cookies on the Gut Microbiome in Hemodialysis Patients: A Randomized Controlled Trial. Molecular Nutrition & Food Research. 2021; ():2100374.

Chicago/Turabian Style

Julie Ann Kemp; Bruna Regis de Paiva; Henrique Fragoso dos Santos; Hugo Emiliano de Jesus; Hannah Craven; Umer Z. Ijaz; Natalia Alvarenga Borges; Paul G. Shiels; Denise Mafra. 2021. "The Impact of Enriched Resistant Starch Type‐2 Cookies on the Gut Microbiome in Hemodialysis Patients: A Randomized Controlled Trial." Molecular Nutrition & Food Research , no. : 2100374.

Review article
Published: 28 July 2021 in Biochemical Journal
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The sum total of life course exposures creates an exposome that has a significant impact on age-related health. Understanding the interplay between exposome factors and the (epi) genome, offers pertinent insights into the ageing process and its relationship with the accumulation of allostatic load. We propose to exploit this to develop a biomimetic approach that will provide insight into how evolution through natural selection in other species has solved many age related human health issues. In particular, we will emphasise the need to reconnect a more mechanistic approach to medical science with a broader natural sciences approach, using biomimetics to mitigate the global burden of age related ill health. In particular, we will discuss how such an approach indicates leverage of the activities of the Nrf 2 gene to enhance health span via reintroduction of the classical ‘Food as Medicine’ concept, including modulation of the microbiome and the creation of more salutogenic and biophilic environments. Additionally, we will discuss how this approach integrates with novel and developing senotherapies.

ACS Style

Paul G. Shiels; Johanna Painer; Barbara Natterson-Horowitz; Richard J. Johnson; Jaime J. Miranda; Peter Stenvinkel. Manipulating the exposome to enable better ageing. Biochemical Journal 2021, 478, 2889 -2898.

AMA Style

Paul G. Shiels, Johanna Painer, Barbara Natterson-Horowitz, Richard J. Johnson, Jaime J. Miranda, Peter Stenvinkel. Manipulating the exposome to enable better ageing. Biochemical Journal. 2021; 478 (14):2889-2898.

Chicago/Turabian Style

Paul G. Shiels; Johanna Painer; Barbara Natterson-Horowitz; Richard J. Johnson; Jaime J. Miranda; Peter Stenvinkel. 2021. "Manipulating the exposome to enable better ageing." Biochemical Journal 478, no. 14: 2889-2898.

Journal article
Published: 16 June 2021 in Scientific Reports
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Imbalanced nutrition is associated with accelerated ageing, possibly mediated by microbiota. An analysis of the circulatory microbiota obtained from the leukocytes of participants in the MRC Twenty-07 general population cohort was performed. We now report that in this cohort, the most biologically aged exhibit a significantly higher abundance of circulatory pathogenic bacteria, including Neisseria, Rothia and Porphyromonas, while those less biologically aged possess more circulatory salutogenic (defined as being supportive of human health and wellbeing) bacteria, including Lactobacillus, Lachnospiraceae UCG-004 and Kocuria. The presence of these salutogenic bactreria is consistent with a capacity to metabolise and produce Nrf2 agonists. We also demonstrate that associated one carbon metabolism, notably betaine levels, did not vary with chronological age, but displayed a difference with socioeconomic position (SEP). Those at lower SEP possessed significantly lower betaine levels indicative of a poorer diet and poorer health span and consistent with reduced global DNA methylation levels in this group. Our data suggest a clear route to improving age related health and resilience based on dietary modulation of the microbiota.

ACS Style

Hannah Craven; Dagmara McGuinness; Sarah Buchanan; Norman Galbraith; David H. McGuinness; Brian Jones; Emilie Combet; Denise Mafra; Peter Bergman; Anne Ellaway; Peter Stenvinkel; Umer Z. Ijaz; Paul G. Shiels. Socioeconomic position links circulatory microbiota differences with biological age. Scientific Reports 2021, 11, 1 -10.

AMA Style

Hannah Craven, Dagmara McGuinness, Sarah Buchanan, Norman Galbraith, David H. McGuinness, Brian Jones, Emilie Combet, Denise Mafra, Peter Bergman, Anne Ellaway, Peter Stenvinkel, Umer Z. Ijaz, Paul G. Shiels. Socioeconomic position links circulatory microbiota differences with biological age. Scientific Reports. 2021; 11 (1):1-10.

Chicago/Turabian Style

Hannah Craven; Dagmara McGuinness; Sarah Buchanan; Norman Galbraith; David H. McGuinness; Brian Jones; Emilie Combet; Denise Mafra; Peter Bergman; Anne Ellaway; Peter Stenvinkel; Umer Z. Ijaz; Paul G. Shiels. 2021. "Socioeconomic position links circulatory microbiota differences with biological age." Scientific Reports 11, no. 1: 1-10.

Review article
Published: 26 May 2021 in Clinical Science
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The worldwide landscape of an ageing population and age-related disease brings with it huge socio-economic and public healthcare concerns across nations. Correspondingly, monumental human and financial resources have been invested in biomedical research, with a mission to decode the mechanisms of ageing and how these contribute to age-related disease. Multiple hallmarks of ageing have been identified that are common across taxa, highlighting their fundamental importance. These include dysregulated mitochondrial metabolism and telomeres biology, epigenetic modifications, cell–matrix interactions, proteostasis, dysregulated nutrient sensing, stem cell exhaustion, inflammageing and immuno-senescence. While our understanding of the molecular basis of ageing is improving, it remains a complex and multifactorial process that remains to be fully understood. A key aspect of the shortfall in our understanding of the ageing process lies in translating data from standard animal models to humans. Consequently, we suggest that a ‘biomimetic’ and comparative approach, integrating knowledge from species in the wild, as opposed to inbred genetically homogenous laboratory animals, can provide powerful insights into human ageing processes. Here we discuss some particularities and comparative patterns among several species from the animal kingdom, endowed with longevity or short lifespans and unique metabolic profiles that could be potentially exploited to the understanding of ageing and age-related diseases. Based upon lessons from nature, we also highlight several avenues for renewed focus in the pathophysiology of ageing and age-related disease (i.e. diet-microbiome-health axis, oxidative protein damage, adaptive homoeostasis and planetary health). We propose that a biomimetic alliance with collaborative research from different disciplines can improve our understanding of ageing and age-related diseases with long-term sustainable utility.

ACS Style

Lu Dai; Leon Schurgers; Paul G. Shiels; Peter Stenvinkel. A biomimetic natural sciences approach to understanding the mechanisms of ageing in burden of lifestyle diseases. Clinical Science 2021, 135, 1251 -1272.

AMA Style

Lu Dai, Leon Schurgers, Paul G. Shiels, Peter Stenvinkel. A biomimetic natural sciences approach to understanding the mechanisms of ageing in burden of lifestyle diseases. Clinical Science. 2021; 135 (10):1251-1272.

Chicago/Turabian Style

Lu Dai; Leon Schurgers; Paul G. Shiels; Peter Stenvinkel. 2021. "A biomimetic natural sciences approach to understanding the mechanisms of ageing in burden of lifestyle diseases." Clinical Science 135, no. 10: 1251-1272.

Journal article
Published: 18 May 2021 in Antioxidants & Redox Signaling
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Significance: Chronic kidney disease (CKD) can be regarded as a burden of lifestyle disease that shares common underpinning features and risk factors with the ageing process; a complex constituted by several adverse components, including chronic inflammation, oxidative stress, early vascular ageing and cellular senescence. Recent Advances: A systemic approach to tackle CKD, based on mitigating the associated inflammatory, cell stress and damage processes, has the potential to attenuate the effects of CKD, but also pre-empts the development and progression of associated morbidities. In effect, this will enhance health span and compress the period of morbidity. Pharmacological, nutritional and potentially lifestyle-based interventions are promising therapeutic avenues to achieve such a goal. Critical Issues: In the present review, currents concepts of inflammation and oxidative damage as key pathomechanisms in CKD are addressed. In particular, potential beneficial but also adverse effects of different systemic interventions in patients with CKD are discussed. Future Directions: Senotherapeutics, the NRF2–KEAP1 signaling pathway, the endocrine klotho axis, inhibitors of the sodium–glucose cotransporter 2 (SGLT2), and live bio-therapeutics have the potential to reduce the burden of CKD and improve quality of life, as well as morbidity and mortality, in this fragile high-risk patient group.

ACS Style

Thomas Ebert; Ognian Neytchev; Anna Witasp; Karolina Kublickiene; Peter Stenvinkel; Paul G. Shiels. Inflammation and oxidative stress in CKD and dialysis patients. Antioxidants & Redox Signaling 2021, 1 .

AMA Style

Thomas Ebert, Ognian Neytchev, Anna Witasp, Karolina Kublickiene, Peter Stenvinkel, Paul G. Shiels. Inflammation and oxidative stress in CKD and dialysis patients. Antioxidants & Redox Signaling. 2021; ():1.

Chicago/Turabian Style

Thomas Ebert; Ognian Neytchev; Anna Witasp; Karolina Kublickiene; Peter Stenvinkel; Paul G. Shiels. 2021. "Inflammation and oxidative stress in CKD and dialysis patients." Antioxidants & Redox Signaling , no. : 1.

Narrative review
Published: 09 March 2021 in Clinical Nutrition
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Summary Garlic, a member of the Allium family, widely used in cooking for many centuries, displays well described antioxidant and anti-inflammatory properties, as a result of its constituent organosulfur compounds, such as alliin, allicin, ajoene S-allyl-cysteine, diallyl sulfide and diallyl disulfide, among others. Although garlic has demonstrated beneficial effects in cardiovascular disease, diabetes, and cancer, its efficacy as a therapeutic intervention in chronic kidney disease remains to be proven. This review thus focuses on the potential benefits of garlic as a treatment option in chronic kidney disease and its ability to mitigate associated cardiovascular complications and gut dysbiosis.

ACS Style

Marcia Ribeiro; Livia Alvarenga; Ludmila F.M.F. Cardozo; Tuany R. Chermut; Joana Sequeira; Laís De Souza Gouveia Moreira; Karla Thaís Resende Teixeira; Paul G. Shiels; Peter Stenvinkel; Denise Mafra. From the distinctive smell to therapeutic effects: Garlic for cardiovascular, hepatic, gut, diabetes and chronic kidney disease. Clinical Nutrition 2021, 40, 4807 -4819.

AMA Style

Marcia Ribeiro, Livia Alvarenga, Ludmila F.M.F. Cardozo, Tuany R. Chermut, Joana Sequeira, Laís De Souza Gouveia Moreira, Karla Thaís Resende Teixeira, Paul G. Shiels, Peter Stenvinkel, Denise Mafra. From the distinctive smell to therapeutic effects: Garlic for cardiovascular, hepatic, gut, diabetes and chronic kidney disease. Clinical Nutrition. 2021; 40 (7):4807-4819.

Chicago/Turabian Style

Marcia Ribeiro; Livia Alvarenga; Ludmila F.M.F. Cardozo; Tuany R. Chermut; Joana Sequeira; Laís De Souza Gouveia Moreira; Karla Thaís Resende Teixeira; Paul G. Shiels; Peter Stenvinkel; Denise Mafra. 2021. "From the distinctive smell to therapeutic effects: Garlic for cardiovascular, hepatic, gut, diabetes and chronic kidney disease." Clinical Nutrition 40, no. 7: 4807-4819.

Journal article
Published: 18 November 2020 in Cell Reports Physical Science
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Metal-organic frameworks (MOFs) have been proposed as biocompatible candidates for the targeted intracellular delivery of chemotherapeutic payloads, but the site of drug loading and subsequent effect on intracellular release is often overlooked. Here, we analyze doxorubicin delivery to cancer cells by MIL-101(Cr) and UiO-66 in real time. Having experimentally and computationally verified that doxorubicin is pore loaded in MIL-101(Cr) and surface loaded on UiO-66, different time-dependent cytotoxicity profiles are observed by real-time cell analysis and confocal microscopy. The attenuated release of aggregated doxorubicin from the surface of [email protected] results in a 12 to 16 h induction of cytotoxicity, while rapid release of pore-dispersed doxorubicin from [email protected](Cr) leads to significantly higher intranuclear localization and rapid cell death. In verifying real-time cell analysis as a versatile tool to assess biocompatibility and drug delivery, we show that the localization of drugs in (or on) MOF nanoparticles controls delivery profiles and is key to understanding in vitro modes of action.

ACS Style

Panagiota Markopoulou; Nikolaos Panagiotou; Aurelia Li; Rocio Bueno-Perez; David Madden; Sarah Buchanan; David Fairen-Jimenez; Paul G. Shiels; Ross S. Forgan. Identifying Differing Intracellular Cargo Release Mechanisms by Monitoring In Vitro Drug Delivery from MOFs in Real Time. Cell Reports Physical Science 2020, 1, 100254 .

AMA Style

Panagiota Markopoulou, Nikolaos Panagiotou, Aurelia Li, Rocio Bueno-Perez, David Madden, Sarah Buchanan, David Fairen-Jimenez, Paul G. Shiels, Ross S. Forgan. Identifying Differing Intracellular Cargo Release Mechanisms by Monitoring In Vitro Drug Delivery from MOFs in Real Time. Cell Reports Physical Science. 2020; 1 (11):100254.

Chicago/Turabian Style

Panagiota Markopoulou; Nikolaos Panagiotou; Aurelia Li; Rocio Bueno-Perez; David Madden; Sarah Buchanan; David Fairen-Jimenez; Paul G. Shiels; Ross S. Forgan. 2020. "Identifying Differing Intracellular Cargo Release Mechanisms by Monitoring In Vitro Drug Delivery from MOFs in Real Time." Cell Reports Physical Science 1, no. 11: 100254.

Review
Published: 27 August 2020 in Frontiers in Endocrinology
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Klotho has been recognized as a gene involved in the aging process in mammals for over 30 years, where it regulates phosphate homeostasis and the activity of members of the fibroblast growth factor (FGF) family. The α-Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23), regulating phosphate homeostasis and vitamin D metabolism. Phosphate toxicity is a hallmark of mammalian aging and correlates with diminution of Klotho levels with increasing age. As such, modulation of Klotho activity is an attractive target for therapeutic intervention in the diseasome of aging; in particular for chronic kidney disease (CKD), where Klotho has been implicated directly in the pathophysiology. A range of senotherapeutic strategies have been developed to directly or indirectly influence Klotho expression, with varying degrees of success. These include administration of exogenous Klotho, synthetic and natural Klotho agonists and indirect approaches, via modulation of the foodome and the gut microbiota. All these approaches have significant potential to mitigate loss of physiological function and resilience accompanying old age and to improve outcomes within the diseasome of aging.

ACS Style

Sarah Buchanan; Emilie Combet; Peter Stenvinkel; Paul G. Shiels. Klotho, Aging, and the Failing Kidney. Frontiers in Endocrinology 2020, 11, 1 .

AMA Style

Sarah Buchanan, Emilie Combet, Peter Stenvinkel, Paul G. Shiels. Klotho, Aging, and the Failing Kidney. Frontiers in Endocrinology. 2020; 11 ():1.

Chicago/Turabian Style

Sarah Buchanan; Emilie Combet; Peter Stenvinkel; Paul G. Shiels. 2020. "Klotho, Aging, and the Failing Kidney." Frontiers in Endocrinology 11, no. : 1.

Perspective
Published: 24 June 2020 in Journal of Internal Medicine
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ACS Style

P. Stenvinkel; J. Painer; P.G. Shiels; A. Bansal; S. Fereidouni; B. Natterson‐Horowitz; R.J. Johnson; J.J. Miranda. SARS‐COV‐2 and biomimetics: What saves the planet will save our health. Journal of Internal Medicine 2020, 289, 244 -246.

AMA Style

P. Stenvinkel, J. Painer, P.G. Shiels, A. Bansal, S. Fereidouni, B. Natterson‐Horowitz, R.J. Johnson, J.J. Miranda. SARS‐COV‐2 and biomimetics: What saves the planet will save our health. Journal of Internal Medicine. 2020; 289 (2):244-246.

Chicago/Turabian Style

P. Stenvinkel; J. Painer; P.G. Shiels; A. Bansal; S. Fereidouni; B. Natterson‐Horowitz; R.J. Johnson; J.J. Miranda. 2020. "SARS‐COV‐2 and biomimetics: What saves the planet will save our health." Journal of Internal Medicine 289, no. 2: 244-246.

Review
Published: 04 April 2020 in Toxins
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Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)–kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23–klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them.

ACS Style

Thomas Ebert; Sven-Christian Pawelzik; Anna Witasp; Samsul Arefin; Sam Hobson; Karolina Kublickiene; Paul G. Shiels; Magnus Bäck; Peter Stenvinkel. Inflammation and Premature Ageing in Chronic Kidney Disease. Toxins 2020, 12, 227 .

AMA Style

Thomas Ebert, Sven-Christian Pawelzik, Anna Witasp, Samsul Arefin, Sam Hobson, Karolina Kublickiene, Paul G. Shiels, Magnus Bäck, Peter Stenvinkel. Inflammation and Premature Ageing in Chronic Kidney Disease. Toxins. 2020; 12 (4):227.

Chicago/Turabian Style

Thomas Ebert; Sven-Christian Pawelzik; Anna Witasp; Samsul Arefin; Sam Hobson; Karolina Kublickiene; Paul G. Shiels; Magnus Bäck; Peter Stenvinkel. 2020. "Inflammation and Premature Ageing in Chronic Kidney Disease." Toxins 12, no. 4: 227.

Review
Published: 09 December 2019 in Journal of Internal Medicine
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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.

ACS Style

P.W. O'toole; P.G. Shiels. The role of the microbiota in sedentary lifestyle disorders and ageing: lessons from the animal kingdom. Journal of Internal Medicine 2019, 287, 271 -282.

AMA Style

P.W. O'toole, P.G. Shiels. The role of the microbiota in sedentary lifestyle disorders and ageing: lessons from the animal kingdom. Journal of Internal Medicine. 2019; 287 (3):271-282.

Chicago/Turabian Style

P.W. O'toole; P.G. Shiels. 2019. "The role of the microbiota in sedentary lifestyle disorders and ageing: lessons from the animal kingdom." Journal of Internal Medicine 287, no. 3: 271-282.

Review
Published: 15 August 2019 in Biochemical Society Transactions
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Ageing is a process of decline in physiological function and capability over time. It is an anticipated major burden on societal health-care costs due to an increasingly aged global population. Accelerated biological ageing is a feature of age-related morbidities, which also appear to share common underpinning features, including low-grade persistent inflammation, phosphate toxicity, diminished Nrf2 activity, a depleted metabolic capability, depressed mitochondrial biogenesis and a low diversity gut microbiome. Social, psychological, lifestyle and nutritional risk factors can all influence the trajectory of age-related health, as part of an individual's exposome, which reflects the interplay between the genome and the environment. This is manifest as allostatic (over)load reflecting the burden of lifestyle/disease at both a physiological and molecular level. In particular, age-related genomic methylation levels and inflammatory status reflect exposome differences. These features may be mediated by changes in microbial diversity. This can drive the generation of pro-inflammatory factors, such as TMAO, implicated in the ‘diseasome’ of ageing. Additionally, it can be influenced by the ‘foodome’, via nutritional differences affecting the availability of methyl donors required for maintenance of the epigenome and by the provision of nutritionally derived Nrf2 agonists. Both these factors influence age-related physiological resilience and health. This offers novel insights into possible interventions to improve health span, including a rage of emerging senotherapies and simple modifications of the nutritional and environmental exposome. In essence, the emerging strategy is to treat ageing processes common to the diseasome of ageing itself and thus preempt the development or progression of a range of age-related morbidities.

ACS Style

Paul G. Shiels; Sarah Buchanan; Colin Selman; Peter Stenvinkel. Allostatic load and ageing: linking the microbiome and nutrition with age-related health. Biochemical Society Transactions 2019, 47, 1165 -1172.

AMA Style

Paul G. Shiels, Sarah Buchanan, Colin Selman, Peter Stenvinkel. Allostatic load and ageing: linking the microbiome and nutrition with age-related health. Biochemical Society Transactions. 2019; 47 (4):1165-1172.

Chicago/Turabian Style

Paul G. Shiels; Sarah Buchanan; Colin Selman; Peter Stenvinkel. 2019. "Allostatic load and ageing: linking the microbiome and nutrition with age-related health." Biochemical Society Transactions 47, no. 4: 1165-1172.

Review
Published: 01 February 2019 in Toxins
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Together with bone-mineral disorders, premature vascular ageing is a common feature of the uremic phenotype. A detailed understanding of mechanisms involved remains unclear and warrants further research. Available treatment options for end stage renal disease are principally dialysis and organ transplantation, as other treatment alternatives have proven insufficient. Chronic kidney disease (CKD) has been proposed as a model of early vascular and bone ageing, with accumulating evidence supporting the contribution of cellular senescence and the senescence-associated secretory phenotype (SASP) to cardiovascular pathology in CKD. Correspondingly, novel therapies based around the use of senolytic compounds and nuclear factor-erythroid-2-related factor 2 (Nrf2) agonists, have been suggested as attractive novel treatment options. In this review, we detail the contribution of the uremic environment to these processes underpinning ageing and how these relate to vascular health.

ACS Style

Sam Hobson; Samsul Arefin; Karolina Kublickiene; Paul G. Shiels; Peter Stenvinkel. Senescent Cells in Early Vascular Ageing and Bone Disease of Chronic Kidney Disease—A Novel Target for Treatment. Toxins 2019, 11, 82 .

AMA Style

Sam Hobson, Samsul Arefin, Karolina Kublickiene, Paul G. Shiels, Peter Stenvinkel. Senescent Cells in Early Vascular Ageing and Bone Disease of Chronic Kidney Disease—A Novel Target for Treatment. Toxins. 2019; 11 (2):82.

Chicago/Turabian Style

Sam Hobson; Samsul Arefin; Karolina Kublickiene; Paul G. Shiels; Peter Stenvinkel. 2019. "Senescent Cells in Early Vascular Ageing and Bone Disease of Chronic Kidney Disease—A Novel Target for Treatment." Toxins 11, no. 2: 82.

Journal article
Published: 28 August 2018 in International Journal of Environmental Research and Public Health
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There is growing interest in understanding which aspects of the local environment influence obesity. Using data from the longitudinal West of Scotland Twenty-07 study (n = 2040) we examined associations between residents’ self-reported neighbourhood problems, measured over a 13-year period, and nurse-measured body weight and size (body mass index, waist circumference, waist–hip ratio) and percentage body fat. We also explored whether particular measures such as abdominal obesity, postulated as a marker for stress, were more strongly related to neighbourhood conditions. Using life course models adjusted for sex, cohort, household social class, and health behaviours, we found that the accumulation of perceived neighbourhood problems was associated with percentage body fat. In cross-sectional analyses, the strongest relationships were found for contemporaneous measures of neighbourhood conditions and adiposity. When analyses were conducted separately by gender, perceived neighbourhood stressors were strongly associated with central obesity measures (waist circumference, waist–hip ratio) among both men and women. Our findings indicate that chronic neighbourhood stressors are associated with obesity. Neighbourhood environments are modifiable, and efforts should be directed towards improving deleterious local environments to reduce the prevalence of obesity.

ACS Style

Anne Ellaway; Ruth Dundas; Jonathan R. Olsen; Paul G. Shiels. Perceived Neighbourhood Problems over Time and Associations with Adiposity. International Journal of Environmental Research and Public Health 2018, 15, 1854 .

AMA Style

Anne Ellaway, Ruth Dundas, Jonathan R. Olsen, Paul G. Shiels. Perceived Neighbourhood Problems over Time and Associations with Adiposity. International Journal of Environmental Research and Public Health. 2018; 15 (9):1854.

Chicago/Turabian Style

Anne Ellaway; Ruth Dundas; Jonathan R. Olsen; Paul G. Shiels. 2018. "Perceived Neighbourhood Problems over Time and Associations with Adiposity." International Journal of Environmental Research and Public Health 15, no. 9: 1854.

Review
Published: 18 August 2018 in Cells
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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.

ACS Style

Nikolaos Panagiotou; Ognian Neytchev; Colin Selman; Paul G. Shiels. Extracellular Vesicles, Ageing, and Therapeutic Interventions. Cells 2018, 7, 110 .

AMA Style

Nikolaos Panagiotou, Ognian Neytchev, Colin Selman, Paul G. Shiels. Extracellular Vesicles, Ageing, and Therapeutic Interventions. Cells. 2018; 7 (8):110.

Chicago/Turabian Style

Nikolaos Panagiotou; Ognian Neytchev; Colin Selman; Paul G. Shiels. 2018. "Extracellular Vesicles, Ageing, and Therapeutic Interventions." Cells 7, no. 8: 110.

Original article
Published: 09 August 2018 in Aging Cell
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Chronic kidney disease and associated comorbidities (diabetes, cardiovascular diseases) manifest with an accelerated ageing phenotype, leading ultimately to organ failure and renal replacement therapy. This process can be modulated by epigenetic and environmental factors which promote loss of physiological function and resilience to stress earlier, linking biological age with adverse outcomes post‐transplantation including delayed graft function (DGF). The molecular features underpinning this have yet to be fully elucidated. We have determined a molecular signature for loss of resilience and impaired physiological function, via a synchronous genome, transcriptome and proteome snapshot, using human renal allografts as a source of healthy tissue as an in vivo model of ageing in humans. This comprises 42 specific transcripts, related through IFNγ signalling, which in allografts displaying clinically impaired physiological function (DGF) exhibited a greater magnitude of change in transcriptional amplitude and elevated expression of noncoding RNAs and pseudogenes, consistent with increased allostatic load. This was accompanied by increased DNA methylation within the promoter and intragenic regions of the DGF panel in preperfusion allografts with immediate graft function. Pathway analysis indicated that an inability to sufficiently resolve inflammatory responses was enabled by decreased resilience to stress and resulted in impaired physiological function in biologically older allografts. Cross‐comparison with publically available data sets for renal pathologies identified significant transcriptional commonality for over 20 DGF transcripts. Our data are clinically relevant and important, as they provide a clear molecular signature for the burden of “wear and tear” within the kidney and thus age‐related physiological capability and resilience.

ACS Style

Dagmara McGuinness; Suhaib Mohammed; Laura Monaghan; Paul A. Wilson; David Kingsmore; Oliver Shapter; Karen S. Stevenson; Shana M. Coley; Luke Devey; Robert B. Kirkpatrick; Paul G. Shiels. A molecular signature for delayed graft function. Aging Cell 2018, 17, e12825 .

AMA Style

Dagmara McGuinness, Suhaib Mohammed, Laura Monaghan, Paul A. Wilson, David Kingsmore, Oliver Shapter, Karen S. Stevenson, Shana M. Coley, Luke Devey, Robert B. Kirkpatrick, Paul G. Shiels. A molecular signature for delayed graft function. Aging Cell. 2018; 17 (5):e12825.

Chicago/Turabian Style

Dagmara McGuinness; Suhaib Mohammed; Laura Monaghan; Paul A. Wilson; David Kingsmore; Oliver Shapter; Karen S. Stevenson; Shana M. Coley; Luke Devey; Robert B. Kirkpatrick; Paul G. Shiels. 2018. "A molecular signature for delayed graft function." Aging Cell 17, no. 5: e12825.

Review
Published: 05 January 2018 in International Journal of Molecular Sciences
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Telomere biology, a key component of the hallmarks of ageing, offers insight into dysregulation of normative ageing processes that accompany age-related diseases such as cancer. Telomere homeostasis is tightly linked to cellular metabolism, and in particular with mitochondrial physiology, which is also diminished during cellular senescence and normative physiological ageing. Inherent in the biochemistry of these processes is the role of magnesium, one of the main cellular ions and an essential cofactor in all reactions that use ATP. Magnesium plays an important role in many of the processes involved in regulating telomere structure, integrity and function. This review explores the mechanisms that maintain telomere structure and function, their influence on circadian rhythms and their impact on health and age-related disease. The pervasive role of magnesium in telomere homeostasis is also highlighted.

ACS Style

Donogh Maguire; Ognian Neytchev; Dinesh Talwar; Donald McMillan; Paul G. Shiels. Telomere Homeostasis: Interplay with Magnesium. International Journal of Molecular Sciences 2018, 19, 157 .

AMA Style

Donogh Maguire, Ognian Neytchev, Dinesh Talwar, Donald McMillan, Paul G. Shiels. Telomere Homeostasis: Interplay with Magnesium. International Journal of Molecular Sciences. 2018; 19 (1):157.

Chicago/Turabian Style

Donogh Maguire; Ognian Neytchev; Dinesh Talwar; Donald McMillan; Paul G. Shiels. 2018. "Telomere Homeostasis: Interplay with Magnesium." International Journal of Molecular Sciences 19, no. 1: 157.

Journal article
Published: 11 October 2017 in International Journal Of Epidemiology
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BackgroundBoth 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.MethodsWe 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.ResultsOf 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).ConclusionsOur 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.

ACS Style

Liya Lu; Cathy Johnman; Liane McGlynn; Daniel F Mackay; Paul Shiels; Jill P Pell. Association between exposure to second-hand smoke and telomere length: cross-sectional study of 1303 non-smokers. International Journal Of Epidemiology 2017, 46, 1978 -1984.

AMA Style

Liya Lu, Cathy Johnman, Liane McGlynn, Daniel F Mackay, Paul Shiels, Jill P Pell. Association between exposure to second-hand smoke and telomere length: cross-sectional study of 1303 non-smokers. International Journal Of Epidemiology. 2017; 46 (6):1978-1984.

Chicago/Turabian Style

Liya Lu; Cathy Johnman; Liane McGlynn; Daniel F Mackay; Paul Shiels; Jill P Pell. 2017. "Association between exposure to second-hand smoke and telomere length: cross-sectional study of 1303 non-smokers." International Journal Of Epidemiology 46, no. 6: 1978-1984.

Review article
Published: 01 October 2017 in American Journal of Physiology-Renal Physiology
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Systemic inflammation in end-stage renal disease is an established risk factor for mortality and a catalyst for other complications, which are related to a premature aging phenotype, including muscle wasting, vascular calcification, and other forms of premature vascular disease, depression, osteoporosis, and frailty. Uremic inflammation is also mechanistically related to mechanisms involved in the aging process, such as telomere shortening, mitochondrial dysfunction, and altered nutrient sensing, which can have a direct effect on cellular and tissue function. In addition to uremia-specific causes, such as abnormalities in the phosphate-Klotho axis, there are remarkable similarities between the pathophysiology of uremic inflammation and so-called “inflammaging” in the general population. Potentially relevant, but still somewhat unexplored in this respect, are abnormal or misplaced protein structures, as well as abnormalities in tissue homeostasis, which evoke danger signals through damage-associated molecular patterns, as well as the senescence-associated secretory phenotype. Systemic inflammation, in combination with the loss of kidney function, can impair the resilience of the body to external and internal stressors by reduced functional and structural tissue reserves, and by impairing normal organ crosstalk, thus providing an explanation for the greatly increased risk of homeostatic breakdown in this population. In this review, the relationship between uremic inflammation and a premature aging phenotype, as well as potential causes and consequences, are discussed.

ACS Style

Jeroen P. Kooman; Marijke J. Dekker; Len A. Usvyat; Peter Kotanko; Frank M. van der Sande; Casper G. Schalkwijk; Paul G. Shiels; Peter Stenvinkel. Inflammation and premature aging in advanced chronic kidney disease. American Journal of Physiology-Renal Physiology 2017, 313, F938 -F950.

AMA Style

Jeroen P. Kooman, Marijke J. Dekker, Len A. Usvyat, Peter Kotanko, Frank M. van der Sande, Casper G. Schalkwijk, Paul G. Shiels, Peter Stenvinkel. Inflammation and premature aging in advanced chronic kidney disease. American Journal of Physiology-Renal Physiology. 2017; 313 (4):F938-F950.

Chicago/Turabian Style

Jeroen P. Kooman; Marijke J. Dekker; Len A. Usvyat; Peter Kotanko; Frank M. van der Sande; Casper G. Schalkwijk; Paul G. Shiels; Peter Stenvinkel. 2017. "Inflammation and premature aging in advanced chronic kidney disease." American Journal of Physiology-Renal Physiology 313, no. 4: F938-F950.

Journal article
Published: 01 July 2017 in The Journal of Rheumatology
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Objective.Systemic sclerosis (SSc) is a fibrotic immune-mediated disease of unknown etiology. Among its clinical manifestations, pulmonary involvement is the leading cause of mortality in patients with SSc. However, the genetic factors involved in lung complication are not well defined. We aimed to review the association of the MIF gene, which encodes a cytokine implicated in idiopathic pulmonary hypertension among other diseases, with the susceptibility and clinical expression of SSc, in addition to testing the association of this polymorphism with SSc-related pulmonary involvement.Methods.A total of 4392 patients with SSc and 16,591 unaffected controls from 6 cohorts of European origin were genotyped for the MIF promoter variant rs755622. An inverse variance method was used to metaanalyze the data.Results.A statistically significant increase of the MIF rs755622*C allele frequency compared with controls was observed in the subgroups of patients with diffuse cutaneous SSc (dcSSc) and with pulmonary arterial hypertension (PAH) independently (dcSSc: p = 3.20E–2, OR 1.13; PAH: p = 2.19E–02, OR 1.32). However, our data revealed a stronger effect size with the subset of patients with SSc showing both clinical manifestations (dcSSc with PAH: p = 6.91E–3, OR 2.05).Conclusion.We reviewed the association of the MIF rs755622*C allele with SSc and described a phenotype-specific association of this variant with the susceptibility to develop PAH in patients with dcSSc.

ACS Style

Lara Bossini-Castillo; Diana Campillo-Davó; Elena López-Isac; Francisco David Carmona; Carmen Pilar Simeón-Aznar; Patricia Carreira; José Luis Callejas-Rubio; Iván Castellví; Antonio Fernández-Nebro; Luis Rodríguez-Rodríguez; Manel Rubio-Rivas; Francisco J. García-Hernández; Ana Belén Madroñero; Lorenzo Beretta; Alessandro Santaniello; Claudio Lunardi; Paolo Airó; Anna-Maria Hoffmann-Vold; Alexander Kreuter; Gabriela Riemekasten; Torsten Witte; Nicolas Hunzelmann; Madelon C. Vonk; Alexandre E. Voskuyl; J. De Vries-Bouwstra; Paul Shiels; Ariane Herrick; Jane Worthington; Timothy R.D.J. Radstake; Javier Martin; the Spanish Scleroderma Group. An MIF Promoter Polymorphism Is Associated with Susceptibility to Pulmonary Arterial Hypertension in Diffuse Cutaneous Systemic Sclerosis. The Journal of Rheumatology 2017, 44, 1453 -1457.

AMA Style

Lara Bossini-Castillo, Diana Campillo-Davó, Elena López-Isac, Francisco David Carmona, Carmen Pilar Simeón-Aznar, Patricia Carreira, José Luis Callejas-Rubio, Iván Castellví, Antonio Fernández-Nebro, Luis Rodríguez-Rodríguez, Manel Rubio-Rivas, Francisco J. García-Hernández, Ana Belén Madroñero, Lorenzo Beretta, Alessandro Santaniello, Claudio Lunardi, Paolo Airó, Anna-Maria Hoffmann-Vold, Alexander Kreuter, Gabriela Riemekasten, Torsten Witte, Nicolas Hunzelmann, Madelon C. Vonk, Alexandre E. Voskuyl, J. De Vries-Bouwstra, Paul Shiels, Ariane Herrick, Jane Worthington, Timothy R.D.J. Radstake, Javier Martin, the Spanish Scleroderma Group. An MIF Promoter Polymorphism Is Associated with Susceptibility to Pulmonary Arterial Hypertension in Diffuse Cutaneous Systemic Sclerosis. The Journal of Rheumatology. 2017; 44 (10):1453-1457.

Chicago/Turabian Style

Lara Bossini-Castillo; Diana Campillo-Davó; Elena López-Isac; Francisco David Carmona; Carmen Pilar Simeón-Aznar; Patricia Carreira; José Luis Callejas-Rubio; Iván Castellví; Antonio Fernández-Nebro; Luis Rodríguez-Rodríguez; Manel Rubio-Rivas; Francisco J. García-Hernández; Ana Belén Madroñero; Lorenzo Beretta; Alessandro Santaniello; Claudio Lunardi; Paolo Airó; Anna-Maria Hoffmann-Vold; Alexander Kreuter; Gabriela Riemekasten; Torsten Witte; Nicolas Hunzelmann; Madelon C. Vonk; Alexandre E. Voskuyl; J. De Vries-Bouwstra; Paul Shiels; Ariane Herrick; Jane Worthington; Timothy R.D.J. Radstake; Javier Martin; the Spanish Scleroderma Group. 2017. "An MIF Promoter Polymorphism Is Associated with Susceptibility to Pulmonary Arterial Hypertension in Diffuse Cutaneous Systemic Sclerosis." The Journal of Rheumatology 44, no. 10: 1453-1457.