Multidimensional MRI Reveals Cellular-Scale Microstructural Phenotypes in Human Brain Aging

Brain aging is accompanied by profound cellular and microstructural changes that precede overt tissue loss, yet in vivo MRI studies largely emphasize macroscopic measures or isolated diffusion and relaxation metrics, providing limited insight into how cellular-scale tissue architecture is altered across the adult lifespan. Here, we apply multidimensional diffusion-relaxation MRI (MD-MRI) to map voxel-wise microstructural phenotypes in cognitively unimpaired adults spanning early adulthood to late life (23-77 years). Rather than relying on predefined compartment models, MD-MRI resolves continuous voxel-wise distributions in a joint diffusion-relaxation space, enabling an integrated, model-free description of how cellular shape, size, restriction, and chemical environment vary with age. Using this approach, we reveal age-related multilateral shifts within a complex microstructural landscape, marked by increasing heterogeneity and disorder across brain tissue. With age, cellular-scale features showed a systematic transition from small to larger length-scale structures accompanied by reduced microscopic restriction, indicating a loss of fine cellular barriers and expansion of extracellular space. In parallel, we show tissue-dependent alterations in fast-relaxing properties aligned with known gray- and white-matter aging processes, including iron accumulation and myelin loss. Together, these findings indicate that normative brain aging involves progressive reorganization of structure and composition at the cellular level, rather than uniform shifts in bulk tissue properties. By decoupling cellular-scale shape, size, restriction, and chemical environment in vivo, MD-MRI identifies increasing cellular heterogeneity and breakdown of microscopic restriction as central features of human brain aging and provides a biologically interpretable framework for linking microstructural reorganization to age-related functional decline.