Ageing Research at King's (ARK) Lecture:

Mitochondrial quality control and AI in healthy brain ageing and longevity

Evandro Fang, Co-Founder, Norwegian Centre on Healthy Ageing (NO-AGE), and Associate Professor of Molecular Gerontology at University of Oslo and Akershus University Hospital, Norway.

Event hosted by Dag Aarsland, ARK Co-Director, Head of Old Age Psychiatry and Richard Killick, Lecturer in Old Age Psychiatry

Brain ageing is closely associated with cognitive decline and neurodegenerative diseases. With the increase in life expectancy, a better understanding of brain ageing processes are fundamental for developing therapeutic interventions against the increasing incidence of neurodegenerative diseases and dementia in the population and to enhance health span. This ARK lecture builds on the 1st Norway-UK Ageing and Dementia Meeting, held at the University of Oslo in August 2023, to address the cell and molecular mechanisms of brain ageing and use of digital technologies to monitor cognitive function in the elderly.

Abstract

Increased lifespan enables people to live longer, but not necessarily healthier lives^{1, 2}. Ageing is arguably the highest risk factor for numerous human diseases, including Alzheimer’s disease (AD); thus 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. However, the molecular mechanisms of impaired mitochondrial homeostasis and their relationship to AD are still elusive. Mitochondrial autophagy (mitophagy) is the cellular self-clearing process that removes damaged and superfluous mitochondria, and therefore plays a fundamental role in maintaining neuronal homeostasis and survival^{1, 3, 4}. We hypothesise that age-susceptible defective mitophagy causes accumulation of damaged mitochondria, which in combination with the two AD-defining pathologies, Aβ plaques and tau tangles, further exacerbates AD onset and progression. Restoration of mitophagy, through pharmaceutical (e.g., NAD⁺, passion fruit components, and urolithin A) and genetic approaches, forestalls pathology and cognitive decline in mouse models of AD and improves neuronal function in AD iPSC-derived neurons^5-7. Additionally, artificial intelligence (AI) is now being used to propel drug screening, as well as being used for drug design specifically targeting AD and ageing pathways⁸. The Evandro Fang lab is now involved in several clinical trials looking into the use of NAD⁺ precursors to treat AD and premature ageing diseases, among others.