Brain-wide reductions in cell size and volume emerge early during adulthood in Drosophila melanogaster.

Aging is accompanied by complex cellular changes in the brain, yet alterations in cell size and brain volume during early adulthood remain poorly characterized. We used flow cytometry to examine cell size in the aging Drosophila melanogaster brain across genotypes, sexes, and brain regions, comparing the optic lobes (OL) and central brain (CB). We found substantial heterogeneity in brain cell sizes accompanied by a significant decrease in average cell sizes with age across genotypes, sexes, and regions. This reduction emerged early in adulthood and occurred in both the OL and CB, although the OL contained smaller cells than the CB. In parallel, we detected significant age-dependent accumulation of polyploid cells, defined as cells with a greater than 2C DNA content. Although polyploid cells were larger than diploid cells, they also exhibited an age-associated decline in average size. Adult-specific neuronal overexpression of Myc blunted the age-associated reduction in average cell size, indicating that this phenotype is modifiable by a known cell growth regulator. To determine whether cellular changes were accompanied by tissue-level alterations, we used micro-computed tomography to assess brain volume during early adulthood. In w1118 flies, brain volume decreased with age regardless of sex, consistent with the decrease we observe in average brain cell size. Together, these findings identify early brain-wide changes in cell size and volume during early adulthood in Drosophila melanogaster as prominent features of early brain aging and provide a foundation for investigating age-dependent cellular remodeling and its underlying mechanisms and functional consequences.