Mitochondria, often called the powerhouses of our cells, play an indispensable role in maintaining cellular vitality. When these mitochondria sustain damage, they are removed through a process known as mitophagy, which is vital for the health of long-lived cells, particularly those in the brain. There is a strong link between disrupted mitophagy and neurodegenerative diseases such as Alzheimer’s and Parkinson’s, highlighting its significance in the pursuit of therapeutic interventions and drug development.
Recently, groundbreaking research led by Anna Rappe, MSc, a doctoral researcher at the University of Helsinki’s McWilliams lab, has uncovered new and unexpected variations in mitophagy among different types of brain cells throughout the ageing process. Notably, in a specific region of the mouse brain associated with movement, mitophagy levels were found to increase with age. Conversely, in brain cells related to memory, there was an initial increase in mitophagy, which sharply declined as the mice reached old age. These observations pinpoint midlife as a critical juncture for promoting healthy brain ageing and provide fresh insights into the molecular mechanisms that support the functioning of the mammalian brain.
Another pivotal discovery from this study is the reduction in acidity of some lysosomes—structures that break down cellular debris—as the brain ages. This finding is particularly compelling as it mirrors changes observed in models of Alzheimer’s disease, suggesting that the ageing processes could intensify in the development of neurodegenerative diseases. These results defy the previously held belief that mitophagy uniformly declines with age across all species, demonstrating that this recycling process is far more dynamic and complex in longer-lived mammals.
Historically, studies employing short-lived models like yeast and worms have indicated a decline in mitophagy throughout an organism’s lifespan, marking it as a characteristic of ageing. However, exploring this phenomenon in the ageing mammalian brain has proven challenging due to the intricate nature of brain tissue and the limitations of traditional research methodologies. The advent of new tools capable of monitoring mitophagy in different tissues and organs in mammals has only recently become available. Utilising state-of-the-art techniques in mouse genetics, optobiology, neuroscience, and advanced imaging, the McWilliams Lab has been able to track mitophagy across various brain cell types over time. Their findings underscore the importance of adopting new perspectives when investigating brain ageing in species with longer lifespans, identifying midlife as a crucial phase for maintaining brain functionality.
Implications for Understanding Brain Ageing in Health and Disease Associate Professor Thomas McWilliams, who oversaw the research, emphasised the dynamic nature of mitophagy in the ageing brain of mice and the importance of midlife in maintaining brain health in mammals. He remarked, “There is no doubt that mitophagy diminishes in shorter-lived species. Although we share significant genes and mechanisms, the tissues of longer-lived mammals have evolved under unique pressures to tackle different challenges. Our research illustrates that mitophagy is highly dynamic in the ageing mouse brain, underscoring midlife as a pivotal time for brain health in mammals.”
Professor McWilliams further noted the significant strides made in understanding neurodegenerative diseases, although he acknowledged current treatments’ high failure rate, underscoring the necessity for novel approaches. Optimistically, He concluded, “Much work remains, but these new insights are reshaping our understanding of brain ageing. In collaboration with our clinical partners, we are dedicated to pushing this research forward towards applications that are more centered around human needs. We are hopeful that our findings will provide a valuable framework for companies and translational researchers, accelerating the development of new treatments for brain diseases.”
More information: Anna Rappe et al, Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging, EMBO Molecular Medicine. DOI: 10.1038/s44318-024-00241-y
Journal information: EMBO Molecular Medicine Provided by University of Helsinki
