New studies underscore the importance of middle age in maintaining brain health, particularly due to significant shifts in the way brain cells handle damaged mitochondria. Failures in this critical recycling process have been associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s. However, investigating this process in the aging mammalian brain has proven difficult until recently.
Mitochondria, which are often described as the power generators of our cells, are vital for keeping cells healthy. When they become damaged, they are eliminated through a recycling mechanism known as mitophagy, a process essential for the longevity and functionality of cells, especially in the brain. Disruptions in mitophagy have been closely linked to neurodegenerative diseases like Alzheimer’s and Parkinson’s, emphasizing the need for drug development and new therapeutic strategies.
Recent research conducted by the McWilliams lab at the University of Helsinki, led by doctoral student Anna Rappe, MSc, reveals a dynamic and unexpected pattern of mitophagy across various types of brain cells as they age. For instance, in a specific area of the mouse brain that controls movement, levels of mitophagy increased with age. In contrast, memory-related brain cells exhibited an initial rise in mitophagy that sharply decreased in old age. These results highlight midlife as a crucial turning point for maintaining brain health, providing fresh insights into the molecular processes that support brain function in mammals.
Another significant discovery from the study indicates that some lysosomes, which are responsible for degrading cellular waste, lose their acidity as the brain ages. This notable finding aligns with changes seen in Alzheimer’s disease models, suggesting that normal aging processes may worsen the development of neurodegenerative diseases. These results challenge earlier beliefs that mitophagy consistently declines with age, demonstrating that in longer-living mammals, this recycling process is much more intricate and variable.
Prior research, typically involving short-lived organisms like yeast and worms, suggested a general decline in mitophagy over an organism’s lifespan, proposing it as a key sign of aging. However, studying mitophagy in the mammalian brain has been difficult due to the complexity of neural tissue and traditional research limitations. Only recently have advanced techniques emerged that allow for tracking mitophagy in various tissues and organs in mammals. The McWilliams Lab utilized state-of-the-art methods in mouse genetics, optobiology, neuroscience, and sophisticated imaging to monitor mitophagy in different brain cell types over time. Their findings underscore the necessity for new perspectives in the study of brain aging in long-lived species, particularly emphasizing midlife as a vital period for sustaining brain function.
Significance for understanding brain aging in health and disease
Associate Professor Thomas McWilliams, who oversaw the research, elaborated on the implications of these findings:
“It is well established that mitophagy decreases in shorter-lived species. While there are shared genes and mechanisms among species, longer-lived mammals have tissues that have evolved to address different challenges. Our research shows that mitophagy is quite dynamic in the aging mouse brain and suggests that midlife is a significant phase for maintaining mammalian brain health.”
He noted that while advancements have been made in understanding neurodegenerative diseases, the high failure rate of existing therapies underlines the need for innovative strategies.
“There remains a lot to learn, but we are thrilled about these new insights that enhance our understanding of brain aging. Along with our clinical partners, we are dedicated to moving this research closer to practical human applications. We anticipate that our findings will provide companies and researchers with a valuable guide to speed up the development of new treatments for brain diseases.”
Additional details
The study has been published in The EMBO Journal and has gained international recognition, with Anna Rappe receiving accolades at multiple conferences, including the 2024 Nordic Autophagy Society Conference (the EMBO Journal Best Poster Prize in Iceland), the 2024 Anatomici Fenniae Symposium (Joint best prize in Helsinki, Finland), and previously at the 2022 FENS Forum (Paris, FR) – Europe’s largest neuroscience conference, where this work began during her MSc in the McWilliams lab (best poster prize). Earlier this year, McWilliams received a grant of 1.12 million EUR from the Jane and Aatos Erkko Foundation to further investigate human-specific autophagy mechanisms.
The research was led by Associate Professor Thomas McWilliams and his team at the University of Helsinki, with significant collaborative efforts from Dr. Helena Vihinen and Dr. Eija Jokitalo at the HiLIFE Electron Microscopy Unit, and Dr. Antti Hassinen from the FIMM HCA Unit.
