BtBs seminario - The 5“A”s: ageing, autophagy, Alzheimer’s, Artificial intelligence, and an “A” molecule” in brain protection and healthy longevity

Evandro Fei Fang, University of Oslo and Akershus University Hospital, Norway

Increased lifespan enables people to live longer, but not necessarily healthier lives1-3. Ageing is arguably the highest risk factor for numerous human diseases, including Alzheimer’s disease (AD); understanding the molecular mechanisms of human aging holds the promise of developing interventional and therapeutic strategies for many diseases simultaneously, promoting healthy longevity. Accumulation of damaged mitochondria is a hallmark of aging and age-related AD. Mitophagy is the cellular self-clearing process that removes damaged and superfluous mitochondria, playing a fundamental role in maintaining neuronal homeostasis and survival1, 4, 5. We hypothesise that age-susceptible defective mitophagy causes accumulation of damaged mitochondria, first in the high energy-demanding and ‘fragile’ entorhinal cortex Layer II region, leading to inflammation, senescence, and finally cellular dysfunction and/or death; this age-related risk combines with genetic and environmental risks causing AD and its progression6. Mitophagy/autophagy restoration, through pharmaceutical (e.g., NAD+, passion fruit components, and urolithin A) and genetic approaches, forestalls pathology and cognitive decline in AD animal models and improves function of AD iPSC-derived neurons7-9. Additionally, AI is now being used to propel drug screening and design specifically targeting AD and ageing10. The Evandro Fang lab is now leading/involved in several clinical trials looking into the use of NAD+ precursors to treat AD and premature ageing diseases, among others.

Key References
1. 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).
2. Fang, E.F. et al. A research agenda for aging in China in the 21st century. Ageing Res Rev 24, 197-205 (2015).
3. Fu, L. et al. Global, regional, and national burden of HIV and other sexually transmitted infections in older adults aged 60-89 years from 1990 to 2019: results from the Global Burden of Disease Study 2019. Lancet Healthy Longev 5, e17-e30 (2024).
4. Aman, Y. et al. Autophagy in healthy ageing and disease. Nat Aging 1, 634-650 (2021).
5. Fang, E.F. et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157, 882-896 (2014).
6. Kobro-Flatmoen, A. et al. Re-emphasizing early Alzheimer's disease pathology starting in select entorhinal neurons, with a special focus on mitophagy. Ageing Res Rev 67, 101307 (2021).
7. 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).
8. Lautrup, S., Sinclair, D.A., Mattson, M.P. & Fang, E.F. NAD(+) in Brain Aging and Neurodegenerative Disorders. Cell Metab 30, 630-655 (2019).
9. Cao, S.Q., Aman, Y., Fang, E.F. & Tencomnao, T. P. edulis Extract Protects Against Amyloid-beta Toxicity in Alzheimer's Disease Models Through Maintenance of Mitochondrial Homeostasis via the FOXO3/DAF-16 Pathway. Mol Neurobiol (2022).
10. 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 6, 76-93 (2022).

co-organizzatori: TeCSBi - BtBs - UNIMIB

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