KeAi Talks: Mitochondrial Communications Serial Webinar 7
20 七月 2022, 10:00 - 11:35
Time: Wednesday 20 July, 10:00 - 11:35 (Beijing time)
Agenda:
10:00 – 10:05
Mitochondrial Communications introduction
Huan Guo, publisher of journal MITOCO
10:05 – 11:05
DNA damage and mitochondrial dysfunction in neurodegeneration and ageing
Vilhelm A. Bohr, MD, PhD
Senior Investigator, Section on DNA repair, National Institute on Aging, NIH, USA
Afl Prof, University of Copenhagen, Denmark
11:05 – 11:35
Mitochondrial homeostasis in healthy ageing and the use of AI in related drug development
Evandro F. Fang, PhD
Associate Professor, Molecular Gerontology, University of Oslo (UiO), Norway
Host:
Professor Zhenglong Gu, PhD
Assistant Director, Institute of Precision Medicine, Fudan University, China
Contact:
Ms. Huan Guo, huanguo@keaipublishing.com
Meeting ID: 824 9404 2656
Password: 5566
Zoom link: https://keaipublishing.zoom.us/j/82494042656?pwd=Y0dML3JPSFVYR0VRck9kOEtkYWo2dz09#success
Abstract:
Globally, there were 962 million elderly people (aged 60+ years) in 2017, a number that will rise to 2.1 billion by 2050, bringing formidable healthcare and socio-economic challenges1, 2. Ageing is arguably the highest risk factor for numerous human diseases, so understanding the molecular mechanisms of human ageing is key to developing interventional and therapeutic strategies that will promote healthy longevity.
The accumulation of damaged mitochondria, correlating with higher cellular ROS, is a hallmark of ageing and age-related neurodegeneration, including Alzheimer’s disease (AD). However, the molecular mechanisms of impaired mitochondrial homeostasis and their relationship to AD are still elusive. Mitophagy is the cellular self-clearing process of damaged and superfluous mitochondria, and therefore plays a fundamental role in maintaining neuronal function and survival1, 3, 4. We hypothesise that age-susceptible defective mitophagy causes the accumulation of damaged mitochondria, which, in combination with the two AD-defining pathologies, Aβ plaques and tau tangles, further exacerbate AD progression. Restoration of mitophagy through upregulation of cellular NAD+, a primary molecule in human health and life, along with genetic approaches, forestalls pathology and cognitive decline in C. elegans and three mouse models of AD and improves mitochondrial function in the AD iPSC neurons5, 6. We are now involved in more than five clinical trials on the use of NAD+ precursors to treat AD and premature ageing diseases, among others7. Additionally, we are using artificial intelligence (AI) to propel drug screening and drug design targeting AD and ageing pathways8.
Key references:
- Fang, E.F.et al.A research agenda for ageing in China in the 21st century (2nd edition): Focusing on basic and translational research, long-term care, policy and social networks. Ageing Res Rev 64, 101174 (2020).
- Fang, E.F.et al.A research agenda for aging in China in the 21st century. Ageing Res Rev 24, 197-205 (2015).
- Aman, Y.et al.Autophagy in healthy ageing and disease. Nat Aging 1, 634-650 (2021).
- Fang, E.F.et al.Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157, 882-896 (2014).
- Fang, E.F.et al.Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci 22, 401-412 (2019).
- Lautrup, S., Sinclair, D.A., Mattson, M.P. & Fang, E.F. NAD(+) in Brain Aging and Neurodegenerative Disorders. Cell Metab30, 630-655 (2019).
- Reiten, O.K., Wilvang, M.A., Mitchell, S.J., Hu, Z. & Fang, E.F. Preclinical and clinical evidence of NAD(+) precursors in health, disease, and ageing. Mech Ageing Dev, 111567 (2021).
- Xie, C.et al.Amelioration of Alzheimer’s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow. Nat Biomed Eng (In press).
Speaker backgrounds:
Speaker 1
Vilhelm A. Bohr, MD, PhD
Senior Investigator, Section on DNA repair, National Institute on Aging, NIH, USA Afl Prof University of Copenhagen, Denmark
Dr. Bohr’s early professional training took place at the University of Copenhagen, Denmark, where he earned an MD in 1978, and PhD and DSc degrees in 1987. After training in neurology and infectious diseases at the University Hospital in Copenhagen, he undertook postdoctoral studies in Biochemistry at the university. In 1992, he was appointed Chief of the Laboratory of Molecular Genetics at the National Institute on Aging (NIA) in the US.
Throughout his career, Dr. Bohr has advanced understanding of DNA repair pathways and mechanisms and the cellular response to oxidative DNA damage and oxidative stress. He has been especially interested in the repair and function of the mitochondrial genome. Early in his career, he developed a widely-used method for studying DNA repair in the transcribed portion of the genome and found that transcriptionally-active genes are preferentially repaired through a process now known as transcription-coupled nucleotide excision repair (TC-NER). The discovery of TC-NER provided strong evidence of the tight interaction between the cellular machineries for DNA repair and transcription in mammalian cells.
His recent studies have resulted in seminal findings about the relationships between DNA damage, DNA repair capacity and aging-associated neurodegeneration, and he has proposed important models describing crosstalk between the nuclear and mitochondrial genomes, as well as the importance of energy homeostasis/imbalance and mitochondrial dysfunction in aging-related neurodegenerative disease. He and his colleagues found that NAD levels are lower in diseases with deficient DNA repair leading to mitochondrial dysfunction. Intervention with NAD supplementation has shown excellent benefits in mice and other model systems of neurodegeneration and DNA repair deficits including Alzheimer’s disease.
Speaker 2
Evandro F. Fang, PhD
Associate Professor, Molecular Gerontology, University of Oslo (UiO), Norway
Dr. Fang is an Associate Professor of Molecular Gerontology at the University of Oslo (UiO), Norway. His group studies the molecular mechanisms of human ageing and age-predisposed neurodegeneration. More specifically, the Fang laboratory focuses on the molecular mechanisms that help cells clear their damaged and aged mitochondria, a process termed “mitophagy”, as well as the roles of the NAD+-mitophagy/autophagy axis in healthy ageing and Alzheimer’s disease (AD) inhibition. NAD+ is a fundamental molecule in life and health and decreases in ageing and AD. Dr Fang is fascinated with and actively engaged in moving his laboratory findings to translational applications and is involved in more than five NAD+-based clinical trials, with the overarching goal of establishing novel and safe biological approaches to promote longer and healthier human lives.
After finishing his PhD at the Chinese University of Hong Kong, he had a six-year postdoc training with Prof. Vilhelm Bohr on molecular gerontology at the National Institute on Ageing in the US. He opened his lab in Oslo in the fall of 2017.
He has published over 100 papers in international peer-reviewed journals including Cell, Cell Metabolism, Nature Reviews MCB, Nature Neuroscience, Nature Ageing, and Nature Biomedical Engineering. He has received several awards, including the Butler-Williams Scholar on Aging 2016 from NIA (USA) and the Scientific Award to Young Scientist in the Natural Sciences for 2020 from The Royal Norwegian Society of Sciences and Letters (Norway). He is the founding (co)coordinator of the Norwegian Centre on Healthy Ageing network (NO-Age), the Norwegian National anti-Alzheimer’s disease Network (NO-AD) and the Hong Kong-Nordic Research Network.