Autophagy is a complex collection of processes that recycle structures in the cell. Structures are in some way identified as damaged or surplus, then engulfed in an autophagosome membrane. That autophagosome is transported to a lysosome, where it fuses with the lysosome. The cargo is then broken down into raw materials by the enzymes contained in the lysosome. Measuring autophagy is difficult. Any given approach can be interpreted in different ways. Is increased expression of one autophagy protein indicative of more efficient autophagy or indicative of a part of the process that is breaking, degrading overall efficiency? This gives rise to some debate over how autophagy changes with age, and whether the interventions thought to slow aging via improved autophagy are in fact doing so. Here, for example, researchers argue that autophagy of mitochondria, called mitophagy, doesn't in fact decline with age in brain cells.
Autophagy is a disease-relevant homeostatic quality control mechanism. While we understand how different forms of cellular stress induce specific autophagy pathways in cultured cells, our knowledge of how physiological autophagy pathways are regulated in healthy brain aging is extremely limited. Studies in short-lived model systems suggest that diminished mitophagy and autophagic capacity may sensitize certain brain cell types to degenerative processes as we age. However, the spatiotemporal modulation of mitophagy during healthy brain aging remains unclear.
Here, we establish the first dynamic landscape of mitochondrial turnover in the intact, aging mammalian brain at the single-cell level using high-resolution confocal imaging and cutting-edge reporter mice. Our findings reveal that decreased mitophagy is not a general hallmark of healthy aging in vivo but that different brain regions and neural subsets exhibit distinct mitophagy dynamics over time, usually remaining stable or even increasing throughout the mouse lifespan. By comparing different regions of the brain, including disease-associated neuronal and non-neuronal cell types, we revealed uncoupled and cell type-specific regulation of mitophagy and generalized autophagy throughout natural aging.
We found that mitophagy levels gradually increased throughout the aging process in several cell types, including cerebellar granule cells and microglia, seemingly independent of basal autophagy levels. In some cases, we observed more complex trajectories: we detected an age-dependent increase in mitophagy in the hippocampus CA1 and dentate gyrus subregions up until middle age, followed by a significant decline during old age, although not falling below those of young subjects. It will be crucial to determine whether these altered autophagy dynamics are causally linked to age-related cognitive changes observed in healthy aging. Clarifying the mechanisms driving age-dependent mitophagy dynamics in these hippocampal subregions may hold interventional relevance for memory-related pathologies such as dementia and Alzheimer's disease.
Link: https://doi.org/10.1038/s44318-024-00241-y
View the full article at FightAging
