Transformative advances in modeling brain aging and longevity: Success, challenges and future directions

Research on brain aging is crucial for understanding age-related neurodegenerative disorders and developing several therapeutic interventions. Numerous models ranging from two-dimensional (2D) cell-based, invertebrate, vertebrate, and sophisticated three-dimensional (3D) models have been used to understand the process of brain aging. Invertebrate models are ideal for researching conserved aging processes because of their simplicity, short lifespans, and genetic tractability. Moreover, vertebrate models, including zebrafish and rodents, exhibit more complex nervous systems and behaviors, enabling the exploration of age-related neurodegeneration and cognitive decline. 2D cell culture models derived from primary cells or immortalized cell lines are widely used for mechanistic studies at the cellular level but lack the physiological complexity of brain tissue. Recent advancements have shifted focus to 3D models, which better recapitulate the brain's microenvironment. Organoids derived from induced pluripotent stem cells mimic human brain architecture and enable the study of cell-cell interactions and aging in a human-specific context. Brain-on-a-chip systems integrate microfluidics and 3D cultures to model blood-brain barrier dynamics and neuronal networks. Additionally, scaffold-based 3D cultures and spheroids provide intermediate complexity, allowing researchers to study extracellular matrix interactions and age-related changes in neuronal function. These 3D models bridge the gap between traditional 2D cultures and animal-based in vivo studies, offering unprecedented insights into brain aging mechanisms. By combining these diverse models, researchers can unravel the multifaceted processes of brain aging and accelerate the development of targeted therapies for age-related neurodegenerative disorders.