IRE1

Aging and related diseases are associated with alterations in oxidative status and low-grade inflammation, as well as a decreased endoplasmic reticulum (ER) unfolded protein response (UPR). UPR is a functional mechanism by which cells attempt to protect themselves against ER stress. Researchers analyzed these proteins in peripheral blood mononuclear cells of elderly subjects and used computer simulation to predict the key proteins associated with these biomolecules underlying physiological adaptations to exercise. They collected blood samples about five to six days before and after the training period and analyzed various oxidative stress biomarkers in peripheral blood mononuclear cells. The study takes research one step further in helping to elucidate the benefits of exercise in this population. Aging involves a balance between oxidants and antioxidants, low-grade inflammation and a protein response that occurs at the cellular level, which is responsible for many health disorders. Exercise has been shown to regulate the inflammatory response, balance oxidants such as free radicals that build up in the cells and damage DNA; and ameliorate the process by which cells protect themselves against these stressors. Furthermore, resistance training in older adults is recommended to help maintain muscle, flexibility and balance. Aging and related diseases are associated with alterations in oxidative status and low-grade inflammation, as well as a decreased endoplasmic reticulum (ER) unfolded protein response (UPR). UPR is a functional mechanism by which cells attempt to protect themselves against ER stress, resulting from the accumulation of the unfolded/misfolded proteins. One group of proteins associated with the aging process is the mitochondrial heat shock protein 60 (HSP60), which has been demonstrated to play a protective role in the ability for cells to remain active and healthy. Currently, there is limited research investigating the effects of resistance training in older adults on the expression of HSP60 and Klotho, a gene involved in the aging process in mammals. A new study by researchers at Florida Atlantic University, in collaboration with the University of León in Spain, examined whether an eight-week resistance training program would modulate the oxidative status, the UPR activation and key inflammatory pathways as well as their relationships with HSP60 and Klotho proteins. For the study, researchers analyzed these proteins in peripheral blood mononuclear cells of elderly subjects. In addition, they utilized computer simulation to predict the key proteins associated with these biomolecules underlying physiological adaptations to exercise. They collected blood samples approximately five to six days before and after the training period and just before training intervention in young subjects who were included for basal assessments. Researchers also analyzed various oxidative stress biomarkers in peripheral blood mononuclear cells. Results of the study, published in the journal Antioxidants, demonstrated that the levels of the inflammatory proteins (pIRAK1, TLR4, and TRAF6), as well as different markers of the redox balance (catalase, GSH, LP, NRF2, PC, ROS, SOD1, and SOD2) remained unchanged with training. Importantly, untrained elderly subjects showed a significant reduction in pIRE1/IRE1 ratio when compared to trained elderly subjects. Such a finding was further confirmed by a gene ontology analysis, showing that endoplasmic reticulum stress is a key mechanism modulated by IRE1. Additionally, analysis did not show the training effect on the expression of HSP60 and Klotho or their relationships with other outcome variables. Although elderly male and female subjects were included in the training program, researchers did not find any sex effects in the study. These findings might partially support the modulatory effect of resistance training on the endoplasmic reticulum in the elderly. "Regular physical activity is suggested to be an effective intervention in improving age-related diseases such as osteoporosis, sarcopenia or muscle loss and dynapenia or loss of muscle strength, cardiovascular diseases, and type 2 diabetes," said Chun-Jung "Phil" Huang, Ph.D., co-author and a professor in the Department of Exercise Science and Health Promotion within FAU's Charles E. Schmidt College of Science. "Although the beneficial effects of regular physical exercise to alleviate inflammation and oxidative stress are well-established, the processes of these physiological adaptations with regard to protein folding or UPR remains to be explored. That is why we used a systems biology approach for our study." The resistance training protocol for the study consisted of 16 sessions over eight weeks (two sessions per week), with a minimum of 48 hours between sessions. The participants started with a 10-minute warm-up on a cycle ergometer. Subsequently, eight different resistance exercises (leg press, ankle extension, bench press, leg extension, bicep curl, pec deck, high pulley traction, and dumbbell lateral lift) were performed using the exercise device. For each exercise, participants performed three sets of 12-8-12 repetitions. There was a two-to-three-minute rest between each repetition and a three-minute rest between each exercise. "We know how very important physical activity is for older adults and our study takes research one step further in helping to elucidate the benefits of exercise in this population," said Huang. Study co-authors are senior author Brisamar Estébanez, Ph.D.; Marta Rivera-Viloria; and José A. de Paz, M.D., all with the University of León; José E. Vargas, Ph.D., Universidad Federal do Paraná, Curtiba; and Nishant P. Visavadiay, Ph.D.; and Andy V. Kahmoui, Ph.D., both with FAU's Department of Exercise Science and Health Promotion.

Scientists have found that a stress response in cells, when 'switched on' at a post-reproductive age, could be the key to slow down ageing and promote longevity. Scientists at Nanyang Technological University, Singapore (NTU Singapore) have found that a stress response in cells, when 'switched on' at a post-reproductive age, could be the key to slow down ageing and promote longevity. In lab experiments on a type of roundworm that shares similarities with humans, the NTU Singapore team found that switching on this stress response in aged worms by feeding them a high-glucose diet extended their lifespan as compared to worms fed a normal diet. This is the first time a link between this stress response and ageing has been uncovered, said the NTU team of their findings published on 19 October in Nature Communications. While further studies are needed to gain a deeper understanding of this link, the scientists said their findings open the door to the development of therapies that could delay the onset or even tackle age-related disorders such as cancer, dementia, and stroke. Cell biologist and study lead Associate Professor Guillaume Thibault from the NTU School of Biological Sciences said: "Ageing is a critical risk factor for a variety of human pathologies, from metabolic diseases such as diabetes to cancer and neurodegenerative diseases. From a public health perspective, determining the cellular pathways that underpin the ageing process could take us one step closer to developing novel therapeutic strategies to treat age-related disorders. "While our study found that a high-glucose diet could be useful to slow down ageing and promote longevity in aged worms, we are not recommending that the aged population should now turn to a high-sugar diet. What this study does show is that triggering certain stress responses in cells may translate to longevity, and that activating this stress response with a drug might be critical to decelerate cellular ageing." Aside from showing that the effect of manipulating this stress response in aged worms, the NTU scientists also showed that the same response, when 'switched off' in young worms fed a high-glucose diet, helped them to live longer than worms on a normal diet. Commenting as an independent expert, Professor Rong Li, Director of the Mechanobiology Institute at the National University of Singapore said: "Metabolic diseases have serious consequences in the elderly if left untreated. This work is impactful because the scientists identified a cellular pathway, called the unfolded protein response, which affects lifespan in animals fed a high glucose diet. They found that inhibiting this pathway dramatically extended the lifespan of these animals. They therefore propose that targeting this pathway may extend lifespan in humans with metabolic disorder." This study is aligned with the research pillar of the University's NTU2025 five-year strategic plan, which focuses on health and society as one area with potential for significant intellectual and societal impact. How the cell's stress response is activated Cells produce a stress response when stressors (such as an excess of glucose) cause a build-up of problematic 'unfolded' proteins in the cell. The stress response, called the unfolded protein response, works to clear up these problematic proteins to restore balance in the cell. Ageing could also lead to an accumulation of unfolded proteins due a natural decline in the ability of the cell's machinery to produce healthy proteins, triggering the same stress response. The molecular machinery in the cell tackles this build-up through its 'stress sensors', which initiate a series of molecular mechanisms to rescue the cell from this stress. If the overload of unfolded proteins is not resolved, the prolonged unfolded protein response induces cell death instead. Unfolded protein response in aged worms led to healthier ageing To investigate how the unfolded protein response affects longevity in animals, the scientists induced this response in adult roundworms (Caenorhabditis elegans) using glucose. While C. elegans is significantly anatomically simpler than a human, it relies on many of the same genes that humans do to control the division of cells and to programme faulty cells to die. The scientists fed some of the worms a high-glucose diet at two different life stages: young i.e.at the start of their adulthood (Day 1), and at a post-reproductive age (Day 5), when the worms are aged and no longer fertile. A control group of worms were fed a normal diet throughout. The scientists found that the aged worms given a high-glucose diet lived for 24 days -- almost twice the lifespan of the young worms given the same diet (13 days). Worms on a normal diet lived for 20 days. Aside from living longer, the aged worms on a high-glucose diet were more agile and had more energy storage cells as compared to worms given a normal diet, suggesting healthier ageing. Prolonged stress response in young worms led to cell death A day after feeding the worms a high-glucose diet, the NTU scientists monitored the activity of the three stress sensors that are each responsible for a cellular pathway in the unfolded protein response. They found that that one of the stress sensors, IRE1, was significantly more active in young worms compared to aged worms. When the scientists removed the gene coding for IRE1 in worms to 'switch off' the cellular pathway the stress sensor initiates, they found that young worms fed a high-glucose diet from Day 1 lived for 25 days -- twice as long as when the IRE1 gene was intact. This suggests that the increased activity of stress sensor IRE1 seen in young worms fed a high-glucose diet from Day 1 -- what the scientists say is a prolonged unfolded protein response -- was responsible for shortening their lifespan. Assoc Prof Thibault said: "We believe that the high-glucose diet fed to the aged worms stimulated their otherwise sluggish unfolded protein response and switched on certain cellular pathways, tackling not just the stress caused by excess glucose but also other ageing-related stress, restoring cellular stability. "In contrast, young worms subjected to a high-glucose diet provoked unresolved stress in the cells due to an overactivated IRE1. This prolonged activation led the cells to initiate cell death instead." The findings suggest that a drug that reduces the activity of IRE1 while increasing the activity of the other two stress sensors could potentially be developed to decelerate cellular ageing and consequently extend lifespans, he added. More studies and findings will need to be conducted in the roundwormsto further dissect the complex mechanism behind the lifespan extension induced by a high-glucose diet, as well as how this mechanism interacts with other processes in cells. Other authors of the study are research fellow Dr Cenk Celik and research assistant Aishah Tul-Firdaus Abdul Khalid from NTU; former NTU researchers Caroline Beaudoin-Chabot, Wang Lei, Subhash Thalappilly, Xu Shiyi; and NTU graduates Koh Jhee Hong, Venus Lim Wen Xuan, and Low Ann Don. Lifespan of C. elegans (stress response is switched on) Worms on a high-glucose diet from Day 1: 13 days Worms on a high-glucose diet from Day 5: 24 days Worms on a normal diet: 20 days Lifespan of C. elegans with IRE1 gene removed (stress response is switched off) Worms on a high-glucose diet from Day 1: 25 days Worms on a high-glucose diet from Day 5: 19 days Worms on a normal diet: 16 days This work was supported by the Singapore Ministry of Education Academic Research Fund Tier 2 (2018-T2-1-002) and Tier 1 (2019-T1-002-011); and the Ministry of Health, Singapore, National Medical Research Council Open Fund Individual Research Grant (MOH-000566).

The Lead Discovery Center (LDC) has teamed up with McGill University in Canada, Institut National de la Santé Et de la Recherche Médicale (INSERM) in France and Semmelweis University in Hungary to discover new approaches for the treatment of alpha-1 antitrypsin deficiency (ATD), a rare genetic disorder that lead to severe lung and liver diseases. January 8, 2019. Dortmund, Germany – The Lead Discovery Center (LDC) has teamed up with McGill University in Canada, Institut National de la Santé Et de la Recherche Médicale (INSERM) in France and Semmelweis University in Hungary to discover new approaches for the treatment of alpha-1 antitrypsin deficiency (ATD), a rare genetic disorder that lead to severe lung and liver diseases. The partners receive a total of €1.1 million in funding under the transnational E-Rare-3 programme on rare diseases. ATD is caused by mutations of alpha1-antitrypsin (A1AT), an enzyme that is primarily produced in the liver and normally transported to the lung where it helps maintain organ health and function. Genetic alterations lead to misfolded proteins which can no longer be secreted. In the lung, the absence of functional A1AT can lead to critical disorders such as chronic obstructive pulmonary disease (COPD). In the liver, the accumulation of mutant A1AT can cause liver fibrosis, cirrhosis and subsequently hepatic failure. To date, there is no effective pharmacological treatment for ATD. This project builds on ground-breaking results of project partner Eric Chevet and his team at INSERM that provide a novel, highly promising target for ATD treatment. They have shown that the activation of a certain enzyme, IRE1, triggers the release of fully functional ZA1AT from the liver. ZA1AT is the most frequent mutant form of A1AT. The project partners will work together to identify and develop small molecules that can rescue active ZA1AT via IRE1-modulation. The objective is to establish a lead compound series with favourable drug-like properties and proof-of-concept in in-vivo models within three years. The partnership builds on highly productive existing collaborations between the players and leverages their complementary strengths and capabilities. The teams of McGill University and INSERM contribute leading expertise in the underlying biology of protein misfolding diseases in general, and A1AT and IRE1 function in particular, while the teams of Semmelweis University and LDC bring in world-class medicinal chemistry know-how and infrastructure (incl. pharmacology), together with a proven track record in drug discovery from target level through to proof-of-concept. The project also gains support from leading clinicians and patient organizations committed to finding a cure for ATD and to improving the lives of people affected worldwide. “This is a unique and truly powerful constellation,” says Bert Klebl, managing director of the LDC. “With our combined expertise and commitment, we are perfectly positioned to advance this project and make a difference to the lives of patients suffering from this rare and widely under-recognized disease.” >> Contact PR Lead Discovery Center +49 (0)231-97 42 70 00 pr@lead-discovery.de About the LDC The Lead Discovery Center (LDC) was established in 2008 as a novel approach to capitalize on the potential of excellent basic research for the discovery of new therapies for diseases with high medical need. The LDC takes on promising early-stage projects from academia and transforms them into innovative pharmaceutical leads that reach initial proof-of-concept in animals. In close collaboration with high-pro from academia and industry, the LDC is building a strong and growing portfolio of small molecule leads with exceptional medical and commercial potential. The LDC sustains a preferred partnership with the Max Planck Society and has formed alliances with AstraZeneca, Apeiron, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Grünenthal, Johnson & Johnson Innovation, Merck KGaA, Qurient and Sotio as well as various investors and leading translational drug discovery centres around the globe. >> More information at