Periodic Reporting for period 2 - ARDRE (Ageing, Regeneration, and Drug Research)
Période du rapport: 2021-08-01 au 2025-07-31
Aging is linked to a functional decline in organismic function throughout most living organisms, including both animals and plants. Age-related decline in tissue function is counter-acted by regeneration processes restoring tissue functions in aged organisms. However, regenerative capacity is limited in higher organisms including humans, and the reasons for these limitations are not well understood. The project aims at better understanding molecular mechanisms underlying aging and regeneration, which will allow to develop new drugs and drug-like compounds to improve regeneration and help to reduce the pathological burden of age-associated diseases. As life expectancy and the proportion of elderly people increase, effective measures to promote healthy ageing are urgently needed. The scientific aims of ARDRE are to explore molecular mechanisms leading to severe disabilities associated with old age, and identify small molecules with the potential to prevent their development. Innovative new insights are expected through the exploration of evolutionarily conserved molecular mechanisms of ageing and regeneration across kingdoms, comprising life forms as distant as plants and fungi, nematodes and tunicates to fish and mice, and finally humans. The ultimate goal is to develop regenerative strategies for reversing age-related damage to various tissues and organ systems.
Conclusions of the action ARDRE: Work in ARDRE has provided significant new knowledge in the areas of aging research, regeneration research and drug research. Due to the combination of all three areas in an integrated project we have been able to combine new insight into processes of aging and regeneration with state-of-the-art technology for drug development. The combined results of ARDRE research create a great opportunity for the development of new products and procedures in the fields of aging and regeneration, to cope with global trends in the fields of aging, obesity, and neurodegenerative diseases.
Conclusions of the action ARDRE: Work in ARDRE has provided significant new knowledge in the areas of aging research, regeneration research and drug research. Due to the combination of all three areas in an integrated project we have been able to combine new insight into processes of aging and regeneration with state-of-the-art technology for drug development. The combined results of ARDRE research create a great opportunity for the development of new products and procedures in the fields of aging and regeneration, to cope with global trends in the fields of aging, obesity, and neurodegenerative diseases.
The recruitment of suitable early-stage researchers (ESRs) for all 12 PhD positions was successfully completed. The rigorous recruitment procedure ensured that only excellent candidates were chosen. We established a number of supervision arrangements to provide our PhD students with the best possible support, allowing them to benefit from the interdisciplinary nature of the program. ARDRE PIs organized various conferences, including the yearly Joint AGE_REG & ARDRE Summer Schools and Winter Schools, the 2nd FEBS Workshop Ageing and Regeneration, and annual Life Science PhD Meetings in Innsbruck. We also organized ARDRE Mini retreats, to bring together the ARDRE ESRs in an informal setting, in absence of their supervisors.
Overview of ARDRE results, their exploitation and dissemination: Highlights in the area of aging research comprise novel insight in the role of cellular senescence in skin aging and new insight into how senescent cells can be targeted for rejuvenation in the skin and other tissues. In addition, we obtained new insight into the role of adipocytes in weight loss in humans and the role of adipocytes in the context of caloric restriction. Highlights in the area of regeneration research have addressed the interplay between development and regeneration using as model organisms the two invertebrate species Hydra oligactis and Ciona intestinalis, which allows to recapitulate the evolution of critical aspects of regenerative capacity in animal evolution. ARDRE ESRs also used pluripotent stem cells to model human age-associated neurological diseases, such as Parkinson’s disease and Hutchinson Guilford progeria. In the area of drug research, ARDRE ESRs focused on the role of calcium channels in human neurodevelopmental diseases, including in silico phenotype prediction based on the structure of small molecules. Additional work in this branch yielded new insight in the use of drugs targeting mTOR and PI3K for novel aspects of tumor therapy. Finally, the isolation and characterization of novel natural compounds for treating human diseases was a key part of ARDRE. Concerning dissemination, the action ARDRE generated an impressive list of publications (n = 53 so far), among them publications in top journals, including Nature, Nature Communications, Cell, Aging Cell, PNAS, and The FEBS Journal, respectively. So far, 9 ESRs have defended their PhD theses; for the remaining 3 ESRs, we expect the defensio to happen in the near future. In 2 ARDRE subprojects that were combined with a secondment of the respective ESR to a pharmaceutical company, exploitation of project results has already started. In several cases, ARDRE PIs were contacted by private companies who are interested in collaboration for exploiting key project results. For the remaining projects, exploitation of project results is currently being prepared and we anticipate considerable exploitation activities in the near future.
Overview of ARDRE results, their exploitation and dissemination: Highlights in the area of aging research comprise novel insight in the role of cellular senescence in skin aging and new insight into how senescent cells can be targeted for rejuvenation in the skin and other tissues. In addition, we obtained new insight into the role of adipocytes in weight loss in humans and the role of adipocytes in the context of caloric restriction. Highlights in the area of regeneration research have addressed the interplay between development and regeneration using as model organisms the two invertebrate species Hydra oligactis and Ciona intestinalis, which allows to recapitulate the evolution of critical aspects of regenerative capacity in animal evolution. ARDRE ESRs also used pluripotent stem cells to model human age-associated neurological diseases, such as Parkinson’s disease and Hutchinson Guilford progeria. In the area of drug research, ARDRE ESRs focused on the role of calcium channels in human neurodevelopmental diseases, including in silico phenotype prediction based on the structure of small molecules. Additional work in this branch yielded new insight in the use of drugs targeting mTOR and PI3K for novel aspects of tumor therapy. Finally, the isolation and characterization of novel natural compounds for treating human diseases was a key part of ARDRE. Concerning dissemination, the action ARDRE generated an impressive list of publications (n = 53 so far), among them publications in top journals, including Nature, Nature Communications, Cell, Aging Cell, PNAS, and The FEBS Journal, respectively. So far, 9 ESRs have defended their PhD theses; for the remaining 3 ESRs, we expect the defensio to happen in the near future. In 2 ARDRE subprojects that were combined with a secondment of the respective ESR to a pharmaceutical company, exploitation of project results has already started. In several cases, ARDRE PIs were contacted by private companies who are interested in collaboration for exploiting key project results. For the remaining projects, exploitation of project results is currently being prepared and we anticipate considerable exploitation activities in the near future.
Several observations in the published literature suggest that aging processes are tightly linked with the capability of multicellular organisms to cope with age-related damage by regenerative processes. However, mechanistic links between aging and regeneration are still scarce. Accordingly, a systematic analysis of these molecular links bears the promise to increase our understanding of both aging and regeneration, with the ultimate aim to promote healthy aging. By carrying out their work in the ARDRE host labs, ARDRE ESRs succeeded in providing new insight into molecular mechanisms of aging, regeneration, and their interplay. Additional progress beyond the state of the art has been provided by the interaction between ESRs working in basic science and ESRs working in drug research, with the aim to develop together new pharmacological treatments for age-associated conditions and to promote regeneration.
Socio-economic impact and wider societal implications of ARDRE: The investigation of mechanisms involved in skin aging along with the development of novel compounds which target senescent cells (senolytica) has a huge potential i) for a better understanding of the aging process and ii) to increase the quality of life for the elderly and limit the societal burden of age-associated diseases. Similarly, work performed on mechanisms underlying caloric restriction and weight loss will provide improved treatment options for obesity, a key societal problem with rising global importance. The work on regeneration performed in ARDRE will allow to harness mechanisms of tissue regeneration, so far available exclusively in lower organisms, for human biology and potential clinical applications. The work performed on modeling aging and aging-associated neurodegenerative diseases in iPSC-derived human organoid models bears the promise to inspire new therapies for these diseases and other age-associated limitations. Work performed in drug research by ARDRE ESRs, along with the identification of novel natural compounds, will allow the identification of new compounds for modulating the activity of calcium channels in various diseases, as well as mTOR- and PI3K-dependent signaling in tumors.
Socio-economic impact and wider societal implications of ARDRE: The investigation of mechanisms involved in skin aging along with the development of novel compounds which target senescent cells (senolytica) has a huge potential i) for a better understanding of the aging process and ii) to increase the quality of life for the elderly and limit the societal burden of age-associated diseases. Similarly, work performed on mechanisms underlying caloric restriction and weight loss will provide improved treatment options for obesity, a key societal problem with rising global importance. The work on regeneration performed in ARDRE will allow to harness mechanisms of tissue regeneration, so far available exclusively in lower organisms, for human biology and potential clinical applications. The work performed on modeling aging and aging-associated neurodegenerative diseases in iPSC-derived human organoid models bears the promise to inspire new therapies for these diseases and other age-associated limitations. Work performed in drug research by ARDRE ESRs, along with the identification of novel natural compounds, will allow the identification of new compounds for modulating the activity of calcium channels in various diseases, as well as mTOR- and PI3K-dependent signaling in tumors.