Virtual Workshop on Biochemistry of Ageing
March 30, 2021
About this Event
The Portuguese Biochemical Society (SPB) presents a virtual Workshop on Biochemistry of Ageing, bringing together researchers to present and discuss latest advances in fundamental and translational research on ageing.
The workshop will include two sessions, each consisting of four 20-minute talks.
Date: March 30,
Session I 2:00 p.m. – 3:20 p.m.
Session II 3:40 a.m. – 5:00 p.m.
Dora Brites (Univ. Lisboa), Chair
Bárbara Rocha (Univ. Coimbra)
Cecília Santos (Univ. Beira Interior, Covilhã)
Paula Ludovico (Univ. Minho)
Vítor Costa (Univ. Porto)
Dora Brites (University of Lisbon)
Chairs: Vítor Costa (University of Porto), Bárbara Rocha (University of Coimbra)
Teresa Pereira, iBB & IST, University of Lisbon
Bruno Bernardo de Jesus, iBiMED, University of Aveiro
Joana Palha, ICVS, University of Minho
Lino Ferreira, FMUC, University of Coimbra
Chairs: Cecília Santos (University of Beira Interior), Paula Ludovico (University of Minho)
Hugo Barreto, Instituto Gulbenkian de Ciência (IGC)
Bruno Miguel Lopes-Bastos, IRCAN, University of Nice
Ana Teresa Viegas, CNC-UC, CIBB & IIIUC, University of Coimbra
Elsa Logarinho, I3S, University of Porto
Dora Brites (University of Lisbon)
Bruno Lopes-Bastos research is focused on the role of the tumor environment on different aspects of tumor progression. During his bachelor’s degree in Biology (Universidade de Coimbra) and Research master’s in Biomedical Research (Imperial College, UK), he acquired knowledge in both cancer and molecular biology. In 2013 he started a PhD in cancer research at the University of Cardiff (UK), where he has studied the role of the endothelium microenvironment on cancer dormancy and how cancer cells might exit dormancy by modulating the endothelium (Lopes-Bastos et al. Anticancer Research 2016; Lopes-Bastos et al. Oncotarget 2017). After his Ph.D, he joined Miguel Ferreira’s team at the Instituto Gulbenkian de Ciência to study the role of telomere shortening in promoting cancer in a non-cell autonomous manner. In 2019, he was awarded a Fondation recherche médicale (FRM) postdoctoral fellowship to continue his research with Miguel Ferreira at the Institute for Research on Cancer and Aging, Nice (Lex et al. PNAS 2020).
Joana Palha is full professor of Biochemistry at the School of Medicina, University of Minho (Braga, Portugal), and researcher at the Life and Health Sciences Research Institute (ICVS). PhD in Biomedical Sciences in 1995 (University of Porto, Portugal, research project at Columbia University, New York, USA), MSc in Public Health in 2016 (Karolinska Institute, Stockholm, Sweden), BSc in Biochemistry in 1992 (University of Porto, Portugal). Published over 100 articles in peer-reviewed journals. Started her career in 1992 on thyroid hormones, studying one of the first knock-out mouse models. She led pioneer studies that revealed an endocrine function of the blood brain barriers, particularly the choroid plexus, in brain homeostasis. She has been coordinating translational and clinical research, with focus on the endocrine axis. Her studies in humans have recently contributed to the change in the national policy on iodine supplementation to the Portuguese population, with specific guidelines for women in reproductive age and pregnant women.
Hugo Barreto did his Bachelor in Biology at the Faculdade de Ciências da Universidade de Lisboa. He then did his Master in Applied Microbiology at the Faculdade de Ciências da Universidade de Lisboa and his Master Thesis in Faculdade de Farmácia da Universidade de Lisboa, where he studied the genetic regulation of the Type VII secretion system of the bacterium Bacillus subtilis. He is currently doing a PhD in the Evolutionary Biology group headed by Isabel Gordo at Instituto Gulbenkian de Ciência, where he is studying the evolution of a gut commensal bacterium, Escherichia coli, in the gut of aging mice.
Lino Silva Ferreira holds a Ph.D. in Biotechnology from the University of Coimbra (Portugal). He did postdoctoral work at INEB (Portugal) and MIT (USA) in the group of Robert Langer in the areas of stem cells and nanotechnologies. He established his research group in 2008 at the University of Coimbra. Since then is the director of the Biomaterials and Stem Cell-Based Therapeutics research group, CNC coordinator of the MIT-Portugal Program and the founder of the biotech company Matera. He is also the associate editor of Biomaterials Science Journal (RSC). In 2012, he was awarded with a prestigious European Research Council starting grant and in 2016 a prestigious ERA Chair position at the University of Coimbra. His group has interest in the development of tissue models from stem cells and in the use of nanomedicine platforms to modulate the activity of endogenous (stem) cells.
Teresa Pereira da Silva is a Research Associate at the Stem Cell Engineering Research Group (SCERG) of the Institute of Bioengineering and Biosciences (iBB) at Instituto Superior Técnico (Lisbon, Portugal), working in collaboration with Instituto de Medicina Molecular João Lobo Antunes (iMM). She has completed her master’s degree in Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Coimbra, in 2014. During her master studies, she has worked at the Centre for Neuroscience and Cell Biology (CNC, Coimbra, Portugal). In 2018, she received her PhD degree in Bioengineering at Instituto Superior Técnico, in which she established the production of cerebellar organoids from human pluripotent stem cells as well as functional cerebellar neurons under defined conditions. Currently, the main focus of her research work is to apply these new models to study neurodegenerative diseases, such as ataxias, which are caused by dysfunction of the cerebellum, in order to identify specific pathways involved in disease development and manipulate them for developing new therapeutic strategies.
Since 2015 E. Logarinho (EL) leads the Aging & Aneuploidy group, dedicated to high-profile research on the mechanisms of cell cycle deregulation and genomic instability contributing to aging and age-related diseases. Her research disclosed chromosomal instability (CIN) as a hallmark of human aneuploid amniocytes [Elife 2015;Sci Rep 2016] and aged dermal fibroblasts [Nat Commun 2018;Embo Rep 2020]. Presently, her group applies interdisciplinary approaches to address how regulated instruction of proliferative fitness and genomic stability decelerates senescence in mouse models of Down syndrome, progeria and aging. Within i3S Cancer Program, EL is tackling the question on how aging is the major risk factor for tumorigenesis, with focus on CIN and senescence. EL is currently vice-coordinator of the Cancer Program and member of the Restrictive Scientific Council. EL co-authored 35 publications with 1114 citations (h-index 20), 25% on top journals. EL has secured >2.5M€ competitive funding.
Bruno de Jesus research has been focused on molecular mechanisms driving aging as well as age related diseases. He has recently joined the newly founded iBiMED at the University of Aveiro to contribute building an internationally visible research program. During his PhD with Jean-Marc Egly at the University of Strasbourg, he has discovered that several DNA repair proteins could act simultaneously in distinct repair pathways, providing an explanation for the biochemical defects found within patients. With Maria Blasco at CNIO, Madrid, he studied the contribution of telomeres and telomerase to tissue homeostasis and regeneration. With M. Carmo-Fonseca at IMM-JLA, Lisbon he investigated how age-related barriers could be manipulated to facilitate the reprogramming of adult somatic cells. In 2018 he joined University of Aveiro, as an Assistant Professor at the Department of Medical Sciences / iBiMED, where he is presently developing as principal investigator a research program on aging, cancer and stem cells.
Ana Teresa Barros-Viegas has a BSc and a MSc degree in Biomedical Sciences (University of Algarve) and a PhD in Health Sciences (University of Coimbra). In collaboration with the University of Liverpool, her PhD thesis aimed to develop a new gene therapy for Alzheimer’s disease. Ana has participated in several national and international conferences. She is co-author of 7 peer-reviewed articles and received 17 individual national and international awards. Ana is committed to Responsible Research and Innovation, which led her to work also in science communication. Currently, Ana is a PhD researcher at CNC-UC and is dedicated to the development of SleepApneaID - an innovative diagnostic tool for Sleep Apnea. Ana is responsible for the science communication activities and is also focused on the business development and market access plan of the project. Furthermore, Ana holds a specialisation in Medical Affairs & Medical Marketing, and she is also a candidate of Master of Business Administration at The Lisbon MBA (Católica-Lisbon SBE, Nova SBE in collaboration with MIT Sloan School of Management).
Telomere shortening creates a pro-tumorigenic environment
Institute for Research on Cancer and Aging, Nice (IRCAN)
Cancer is an age-related disease, and its incidence increases exponentially with advancing age. Due to the absence of telomerase expression in most somatic tissues, telomeres shorten as we grow older. Telomeres are DNA-protein complexes at the end of eukaryotic chromosomes that confer genome stability. Due to the “end-replication problem” telomeres get shorter with each cell division, trigging senescence or apoptosis once they reach the Hayflick limit. Therefore, telomere shortening is considered a tumour suppressor. On the other hand, telomere shortening leads to genomic instability – a hallmark of cancer. Interestingly, cancer increases when telomeres are shorter. However, it is unclear how telomere shortening contributes to cancer. Most studies focus on the role of telomere shortening in the cancer cells themselves, here, we studied the influence of an environment created by tissues with short telomeres, therefore a prematurely aged environment, on pre- cancer cells. We generated chimeric zebrafish in which telomerase WT pre-melanoma cells grow in either telomerase WT or telomerase mutant (tert-/-) zebrafish. We observed that the tert-/- microenvironment caused a 25% increase in tumour incidence by week 30. We also observed the same phenomenon when we transplanted melanoma cells into the tert-/- second generation (G2), which present very short telomeres and high levels of senescence and inflammation at larval stage. Interestingly, the tert-/- effect was averted with nonsteroid anti-inflammatory drugs.
Collectively, our data suggests that an environment with short telomeres promotes tumorigenesis in a non-cell autonomous manner. Therefore, telomere shortening, and senescence may have a second consequence of inducing chronic inflammation, which seems to be responsible to increase tumorigenesis in our model. Hence, we propose here that telomere shortening observed during aging gives rise to an inflammatory environment which leads to increase tumorigenesis with age.
The choroid-plexus brain barrier: in and out of the brain in aging
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; and ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
The brain barriers (endothelial blood-brain and blood-spinal cord barriers, and epithelial blood-cerebrospinal fluid barrier) separate the central nervous system from the blood. While viewed, for long, as mere obstacles for drug delivery into the brain, evidence has mounted to show that they are rather active participants in the cross talk between the brain and the other organs. Recent studies have highlighted their bidirectional role, as signaling into and out of the brain. This presentation will address the choroid plexus as an active participant in the communication between the periphery and the brain, in physiological conditions (including aging), in response to peripheral stimuli such as inflammation and as an endocrine mediator in the context normal aging and in diseases of the central nervous, such as Alzheimer’s disease.
The Landscape of Adaptive Evolution of a Gut Commensal Bacteria in Aging Mice
Instituto Gulbenkian de Ciência (IGC)
Aging is a complex process, with many associated time-dependent phenotypes. The gut microbiota have long been postulated as an important factor in shaping healthy aging. During aging, changes in the microbiota composition occur, with taxa that are rare in adults becoming dominant in the elderly. Increased inflammation associated with aging is also known to modulate and be modulated by the microbiota. Ecological interactions are known to affect the evolution of bacteria both in vitro and in vivo, but the extent to which these and the host age-dependent inflammatory environment can alter the pattern of evolutionary change of a gut commensal lineage is still unknown. Here, we provide the first genomic analysis of such evolution in cohorts of old mice, under controlled host genetics and lifestyle conditions. We find that Escherichia coli evolution when colonizing the gut of old mice significantly differs from its evolution in young mice. Evolution toward metabolic adaptation is slower in old than young mice, and mutational targets concerning stress-related functions were found specifically in the inflamed gut of old mice. Taking the genetic basis of E. coli short-term evolution as a reflection of the environment it experiences, the sequencing data indicate that aging imposes a more stressful environment to this important colonizer of the mammalian gut.
Progeria as a model of physiological vascular ageing?
Faculty of Medicine, University of Coimbra
Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease in children that leads to early death. Smooth muscle cells (SMCs) are the most affected cells in HGPS patients, although the reason for such vulnerability remains poorly understood. In this work, we developed a chip formed from HGPS-SMCs that were generated from induced pluripotent stem cells (iPSCs) to study their vulnerability to flow shear stress. HGPS-iPSC SMCs cultured under arterial flow conditions detached from the chip after a few days of culture; this process was mediated by the up-regulation of metalloprotease 13 (MMP13). Importantly, double mutant LmnaG609G/G609GMmp13-/- mice or LmnaG609G/G609GMmp13+/+ mice treated with a MMP inhibitor showed lower SMC loss in the aortic arch than controls. MMP13 up-regulation appears to be mediated by the up-regulation of heparan sulfate, a glycocalyx component. Our results offer a new platform for developing treatments for HGPS patients that may complement previous pre-clinical and clinical treatments.
Scalable generation of cerebellar organoids from human pluripotent stem cells
iBB – Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Portugal
Human induced pluripotent stem cells (iPSCs) have great potential for disease modeling and provide a valuable source for regenerative approaches. However, generating iPSC-derived models to study brain diseases remains a challenge. Recently, we described the generation of cerebellar neuroepithelium formed from human iPSCs, recapitulating the early developmental events of the cerebellum. Additionally, an efficient maturation of replated cerebellar progenitors into distinct types of functional cerebellar neurons was also achieved under defined and feeder-free conditions. However, defining protocols that allow the production of large numbers of organoids and a high yield of mature neurons in 3D culture systems is still difficult. We present a new approach for the reproducible and scalable generation of organoids that adopt cerebellar identity and further mature into cerebellar neurons under chemically defined and feeder-free 3D dynamic conditions. Our suspension culture was maintained for as long as 3 months, allowing the possibility of large-scale production of cerebellar organoids, and their applicability in high-throughput processes.
Inhibition of age-associated genomic instability: emerging strategy to delay cellular senescence and aging
Aging and Aneuploidy Lab, Instituto de Investigação e Inovação em Saúde, Universidade do Porto
One of the major goals of aging research is to develop strategies to delay and even reverse aging. Emerging findings indicate that genomic variations, including mosaic chromosomal alterations, are a relevant and under-recognized mechanism underlying human aging and age-related diseases. Our group has been focused on genetic and pharmacological interventions protecting against genomic instability and addressing their impact in the extension of the healthspan of ageing mice. Our most recent findings will be presented.
Aging barriers in cellular reprogramming
Dep of Medical Sciences and Institute of Biomedicine – iBiMED, University of Aveiro
Stem cells and iPSC are the major players in regenerative medicine. Here, we will explore the current knowledge on the potential roles of stem cells in tissue replacement and on how aging impacts on stem cells dynamics and in the capacity to reprogram adult cells to pluripotency. Anti-aging strategies, in particular approaches exploring age-related pathways, greatly impact on the plasticity of mature cells and are envisioned as the future of tissue-regenerative medicine. We have previously studied the age-associated decline in reprogramming efficiency of fibroblasts derived from transgenic mice carrying doxycycline-inducible Oct4, Sox2, Klf4, and c-Myc. We found that fibroblasts from old mice express higher levels of Zeb2, a transcription factor that activates epithelial-to-mesenchymal transition (EMT). As reprogramming requires suppression of pro-EMT signals, we hypothesized that Zeb2 overexpression contributes to the inefficient reprogramming of old fibroblasts. Downregulation of Zeb2 protein, and subsequent induction with doxycycline, resulted in efficient reprogramming into pluripotent cells with capacity to spontaneously form differentiated tumors comprising the three germ layers. Futhermore, knocking-down Zeb2 maintained ES cells challenged with commitment signals in the ground state of self-renewal and pluripotency. In conclusion, our study identified Zeb2 as a novel target for rejuvenation strategies.
The potential of microRNA modulation in Alzheimer’s disease
CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal;
Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal Alzheimer’s disease (AD) is the most common dementia disorder worldwide characterized by the abnormal accumulation of senile plaques and neurofibrillary tangles, accompanied by neuronal loss and neuroinflammation, leading to a progressive cognitive impairment. However, the exact molecular mechanisms underlying AD remain unclear. Several studies have proposed a key role for miRNA during the pathogenesis of this disorder. Since miRNA expression changes during senescence, the identification of miRNA profiles as “molecular signatures” may contribute to the development of new therapies for aging-related diseases, such as Alzheimer’s disease (AD). This study aimed to modulate the levels of selected miRNAs predicted to target proteins involved in AD. Using bioinformatic tools, we selected miRNAs with high affinity to APP and BACE1 mRNAs and their binding sites were validated through the luciferase assay. MiR-31 was selected for in vivo studies since its in vitro overexpression decreased the expression of both mRNAs. MiR-31 modulation was achieved in the brain of the 3xTg-AD model, following stereotactic injection of lentivirus containing the miR-31 precursor sequence. Behavioral tests showed a significant improvement in the cognitive function of the animals treated with miR-31, with respect to control groups. Moreover, animals injected with miR-31 presented a strong reduction in the number of Aβ plaques in the subiculum and hippocampus, as well as a significant reduction in human APP and mouse BACE1 mRNA and protein levels, compared to control groups. Our study demonstrates that miRNA modulation is a promising strategy to decrease APP and BACE1 expression, leading to a reduction of Aβ deposition and to the amelioration of cognitive function in 3xTg-AD animals. Given the high conservation of miRNAs across species, new significant insights into senescence may arise from this study, supporting new diagnostic and therapeutic avenues for neurodegenerative disorders.