Two-photon in vivo imaging reveals cell type-specific mitophagy dynamic changes in mouse somatosensory cortex during aging

Mitochondrial homeostasis is maintained through mitochondrial autophagy, a process commonly known as mitophagy. Recent research has begun to highlight the region- and cell type-specific nature of mitophagy during brain aging; however, these dynamics have largely remained unexplored in living brains. To address this gap, we conducted two-photon mt-Keima imaging in somatosensory cortical neurons and astrocytes in behaving mice across two age groups. Our observations revealed a reduction in mitophagy levels in both cell types during aging, and we consistently found a higher level of mitophagy in astrocytes compared to neurons across both age groups, indicating a cell type-specific mitophagy dynamics that is independently of the aging process. NAD+ augmentation improved mitophagy level in both neurons and astrocytes in old-aged mice at the dose and method of administration tested. Collectively, our data underscore the critical importance of both neuronal and astrocytic metabolic roles in brain aging. The findings also suggest that NAD+ repletion has clinical value in potentially improving these cell type-specific mitophagy dynamics during aging.