A famous Chinese poem says, "The most important thing is that the world can't be preserved, while the vermillion and the mirror are the same as the flower and the tree." Just as nothing in the world can be preserved indefinitely, aging is an unstoppable natural process. However, appropriate scientific methods can interfere with the aging process and lifespan to a certain extent.
The Ernst & Young Academy has thus organized an ‘EXPERT DIALOGUE’ by inviting a number of experts in related fields to have an in depth discussion around topics including ageing, autophagy, mitophagy, AI, and drug development for extension of healthy longevity and for related neurodegenerative diseases.
The invited experts include:
- Prof. Dr. David Rubinsztein (academician, UK), University of Cambridge
- Prof. Dr. Vilhelm Bohr (academician, Denmark and Norway), NIA and University of Copenhagen
- Associate Prof. Dr. Evandro Fei Fang, University of Oslo
- Zhangming Niu, Founder of MindRank AI
Q1: Can you briefly introduce the "autophagy mechanism" for us?
Expert consensus: In every cell in the human body, thousands of DNA and protein damage events occur every day. If this damage accumulates in cells in the brain, it will lead to the development and occurrence of various neurodegenerative diseases, including Alzheimer's disease (AD). Autophagy, also known as the "self-eating" of‘cellular garbage’ within a cell, is the process by which cells degrade damaged proteins, organelles, etc. Autophagy maintains the balance of cell structure, metabolism and function in the healthy body. Several studies have suggested that occurrence and development of various age-related diseases, such as AD and Parkinson’s disease, may be associated with autophagy defects. Autophagy is not a new topic in medicine. In 2016, Dr Yoshinori Ohsumi was awarded the Nobel prize for his work in describing the process of autophagy, and how it can slow the process of ageing. In January of this year, Nature featured a special Issue on Ageing wherein the latest developments around Autophagy in anti-aging research were presented. In that issue, Nature highlighted the ability to “turn up” autophagy as a novel and feasible therapy for ageing and age-related diseases, especially neurodegenerative diseases like AD and Parkinson’s. It also mentioned the large translational effort that has been ongoing to develop autophagy/mitophagy stimulators as drug candidates by some international pharmaceutical companies and AI drug discovery companies.
Q2: What is the current progress and status of anti-aging drug research and development worldwide, and what are the challenges/problems?
Expert consensus: Ageing research and the use of our scientific knowledge of ageing to develop anti-ageing molecules are hot topics. There are many scientific research institutions and companies working on the molecular mechanisms of ageing and the screening of anti-ageing drugs. One of the most critical challenges is the development of safe and bioavailable molecules as drug candidates for ageing and age-related diseases.
Rubinsztein says, “Such drugs will likely need to be taken in younger people to slow ageing. Thus, they will need to be safe and well-tolerated but also be generally beneficial.”
“There are tremendous opportunities at this time. The challenge is to find interventions with beneficial long-term effects and minimal side effects.” Bohr adds.
Expert consensus: To note, we would like to point out that the focus on ageing as a phenotype risks missing the point that most people don't die of ageing but die from ageing-associated diseases. This distinction is important. We need to understand the diseases, ageing, and the roles that ageing plays in disease. These are distinct but connected challenges.
Q3: How can we precisely target senescent cells and avoid potential adverse effects?
Expert consensus: Ten molecular mechanisms (hallmarks) of biological ageing have been proposed: DNA damage, telomere attrition, epigenetic alternations, mitochondrial dysfunction, deregulated nutrient-sensing, stem cell exhaustion, altered cellular communication, loss of proteostasis, cellular senescence, and compromised autophagy. The development of many anti-aging strategies are targeting on one or more of these biological hallmarks.
Senescence is a cellular a process by which a cell ages and permanently stops dividing but does not die. There is an age-related accumulation of senescent cells, and the accumulation of these cells may contribute to the development of metabolic and neurodegenerative diseases, including Alzheimer’s disease. In order to target the elimination of senescent cells specifically, scientists are developing strategies to either eradicate them (senolytic therapy) and/or reverse their transition from the senescent stage to a normal stage (senomorphic therapy).
While we are cautiously optimistic on targeting senescent cells as a potential strategy to minimize age-related side effects, many obstacles exist.
Rubinsztein explains, “There are several complexities that need to be considered with anti-senescence strategies. First, senescence has different biological effects in different tissues. Second, many of the strategies used to target senescence are non-specific and have pleiotropic effects. Third, senescence can have beneficial effects in certain contexts (e.g. cancers, wound healing). Fourth, it is difficult to disentangle cause and effect in some human scenarios involving senescence.”
Q4: Turning up autophagy is a hot-studied strategy in treating pathological ageing and age-related diseases, especially neurodegenerative diseases. What are the current status and future perspectives towards autophagy stimulation strategy on ageing and neurodegeneration?
Expert consensus: Autophagy is the cellular clearance process that cells use to eliminate damaged or unwanted sub-cellular components, and it is important for cellular homeostasis and healthy longevity. One such process, termed selective autophagy, targets the elimination of damaged mitochondria and so is commonly called ‘mitochondrial autophagy’ (or “mitophagy”). Both autophagy and mitophagy are reduced during ageing in the brain, as well as likely in other tissues. Thus, turning up autophagy has been experimentally validated in as a powerful strategy in treating age-related diseases especially neurodegenerative diseases in model organisms. Exactly 20 years ago, the Rubinsztein laboratory was the first one worldwide who demonstrated the neuroprotective benefits of autophagy. Over the past decades, as our understanding of the mechanisms of autophagy has expanded, new strategies targeting on different stages of autophagy (or its sub-type, like mitophagy) in fighting against ageing and treating age-related diseases have shown significant progress. Some of the examples were highlighted in the recent special issue of ageing in Nature (topic on autophagy).
Fang says, “My lab is working on the molecular mechanisms behind compromised mitophagy in ageing and Alzheimer’s disease. We have uncovered different mechanisms that may drive compromised mitophagy in ageing and Alzheimer’s disease, as well as identifying drugs that induce mitophagy, many of which show the capacity to extend lifespan and retain memory in animal models of ageing and Alzheimer’s disease.”
Bohr also adds, “The idea of stimulating mitophagy to treat diseases of neurodegeneration with mitophagy stimulating compounds is very promising and clinical trial are under way. NAD+ induces mitophagy, a major discovery we made when Evandro Fang was a postdoc in my laboratory (in NIH). NAD+ supplementation can in some cases clear senescent cells, so such intervention can also have senolytic effects and this is a promising approach because there are few or no side effects of NAD+ supplementation. With any drug treatment, adverse effects are not uncommon. Strategies that help us to identify robust, active molecules that are able to effect change in the cells, as well as the use of various lab-based approaches to exclude ‘toxic’ and ‘non-specific’ molecules, are important techniques to help us reduce unsuitable drug candidates when moving to clinical stage.”
Q5: Will anti-aging-related drug R&D breakthroughs be achieved due to the discovery of new targets or biological mechanisms?
Expert consensus: Yes, indeed. All the major anti-ageing strategies are ‘mechanism’ driven. For example, mechanistic studies of autophagy have propelled the development of new screening strategies to identify autophagy inducers.
Bohr says, “In part it is based on currently known targets or mechanisms. Recent work has shown that some pathways that have been known for a while, but are recently much better understood, can be targets for intervention. One such is the cGAS-Sting system that recognizes foreign DNA and which is activated in Alzheimer’s disease and Parkinson’s disease as well as in viral infections. Interventions are being developed that counter this signaling, an example of an intervention based on a current pathway.”
Q6: How do you view the prospects of AI with anti-aging drug research and development, and what changes can the introduction of AI bring to the existing problems of anti-aging drug development?
Expert consensus: In view of challenges such as time, cost, and complexity, it is natural to integrate artificial intelligence (AI) and mechanistic studies to improve the drug development process.
Bohr says, “I have limited knowledge of AI drug research but it has tremendous promise.”
Fang adds, “Recently, I led a multi-institutional study using AI coupled with “wet laboratory” validation to identify mitophagy inducers. From amongst a total of 3,200 compounds, we were able to identify 18 top-scoring compounds using AI, and 2 of them went on to be validated as potent mitophagy inducers in both cells and mice. The AI part of this study was in collaboration with Zhangming Niu at MindRank AI. Thus, we are truly aware of and believe in the importance of AI for broad applications in the anti-aging fields.”
Niu says, First of all, my main background is not biology. "Anti-aging drugs" are a large range, and many chronic diseases are related to aging. The content I describe below only involves the "anti-aging drugs" related to neurodegenerative diseases (such as ALS, Parkinson's disease and Alzheimer's disease).
"Professor Fang Fei mentioned that one of our research results was published in the journal Nature biomedical engineering. We have greatly reduced the cost and cycle of compound discovery through machine learning. For example, can we better understand the biological mechanism, biomarker, and target pathway of Alzheimer's, ALS, and other diseases through the knowledge map, and help scientists design better preclinical and clinical trials." Niu Zhangming says.
Q7: What are the constructive theoretical guidelines for the related industries from the current academic research on AI-driven anti-aging drug development?
Expert consensus: As we mentioned in Q3, the 10 hallmarks of ageing are one set of guidelines. The majority of the strategies, if not all, target only one or a few of these hallmarks.
Rubinsztein explains, “In future, AI-driven drug discovery will be able to rely increasingly on progress in being able to use AI and computational methods to infer protein structures, protein-protein interactions and protein-drug interactions.”
Niu: “Agree with what academician Rubinsztein mentioned. It is hoped that knowledge graph and AI image recognition technology related to single cell sequencing can boost the progress of the industry.”
Q8: As the process of anti-aging drug R&D in academia and industry continues to advance, can we look forward to a future in which human body quality and survival lifespan can be greatly improved and extended?
Expert consensus: Absolutely. Taking advantage of our great healthcare systems,improved techniques, healthy lifestyles, and the use of dietary supplements or drugs that could slow down ageing, the future will be bright with improved quality of life (extended healthspan) worldwide.
Rubinsztein says, “The key objective is to enhance quality of lifespan.”
Bohr adds, “I think there are perspectives for healthspan increase, not really for lifetime increase.”
After entering the exploration at the cellular level and even the molecular level, anti-aging research shows exciting diversity and possibilities. Whether drug design is carried out through targets or molecular mechanisms, or using artificial intelligence to drive more efficient research and development of anti-aging drugs, we can see that human beings continue to use science and technology to extend their own boundaries while seeking their own meaning. We pay tribute to the scientific research team dedicated to this work for the benefit of all mankind. We also hope to connect more like-minded people through our professional services and leave their mark in this great cause.
References and further reading
- Dolgin, E. The biological clean-ups that could combat age-related disease. Nature 601, S15-S17 (2022).
- Wei X, Li M, Zheng Z, et al. Senescence in chronic wounds and potential targeted therapies. Burns Trauma. 2022;10:tkab045. Published 2022 Feb 17. doi:10.1093/burnst/tkab045
- Park SJ, Frake RA, Karabiyik C, et al. Vinexin contributes to autophagic decline in brain ageing across species [published online ahead of print, 2021 Nov 30]. Cell Death Differ. 2021;10.1038/s41418-021-00903-y. doi:10.1038/s41418-021-00903-y
- Fleming A, Bourdenx M, Fujimaki M, et al. The different autophagy degradation pathways and neurodegeneration [published online ahead of print, 2022 Jan 31]. Neuron. 2022;S0896-6273(22)00056-3. doi:10.1016/j.neuron.2022.01.017
- Ravikumar B, Duden R, Rubinsztein DC. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet. 2002;11(9):1107-1117. doi:10.1093/hmg/11.9.1107
- Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem. 2003;278(27):25009-25013. doi:10.1074/jbc.M300227200
- Ravikumar B, Vacher C, Berger Z, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004;36(6):585-595. doi:10.1038/ng1362
- Aman Y, Schmauck-Medina T, Hansen M, et al. Autophagy in healthy aging and disease. Nat Aging. 2021;1(8):634-650. doi:10.1038/s43587-021-00098-4
- Xie C, Zhuang XX, Niu Z, et al. Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow. Nat Biomed Eng. 2022;6(1):76-93. doi:10.1038/s41551-021-00819-5