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

Area of Science:

• Neuroscience
• Aging Research
• Biomedical Engineering

Background:

• Understanding brain aging is vital for addressing neurodegenerative diseases.
• Various models, from simple invertebrates to complex vertebrates and cell cultures, have been employed.
• Traditional 2D cell cultures lack the complexity of in vivo brain tissue.

Purpose of the Study:

• To review and highlight the utility of diverse models in brain aging research.
• To emphasize the advantages of advanced three-dimensional (3D) models in recapitulating brain complexity.
• To discuss how these models facilitate the study of age-related neurodegeneration and therapeutic development.

Main Methods:

• Review of existing literature on brain aging models.
• Comparison of two-dimensional (2D) cell cultures, invertebrate, vertebrate, and three-dimensional (3D) models.
• Focus on advanced 3D models: organoids, brain-on-a-chip systems, scaffold-based cultures, and spheroids.

Main Results:

• Invertebrate models offer simplicity and genetic tractability for conserved aging processes.
• Vertebrate models provide insights into complex behaviors and neurodegeneration.
• 2D cultures are useful for cellular mechanisms but lack physiological complexity.
• 3D models, particularly organoids and brain-on-a-chip systems, better mimic brain microenvironment and human-specific aging.
• 3D models bridge the gap between 2D cultures and in vivo studies.

Conclusions:

• Advanced 3D models significantly enhance the study of brain aging mechanisms.
• These models offer unprecedented insights into cell-cell interactions, blood-brain barrier dynamics, and neuronal function in aging.
• Combining diverse models accelerates the development of targeted therapies for age-related neurodegenerative disorders.