Normal brain aging is considered “successful” when it is associated with low functional decline at different levels of complexity. These include molecular, cellular, and neuronal network, as well as more integrated levels such as metabolic, sensory, motor, and behavioral levels. However, a new hypothesis has recently pointed to the importance of compensatory mechanisms for “successful” brain aging. These compensatory mechanisms are aimed to “correct” age-related dysfunctions in a homeostatic manner. According to this new hypothesis, neurodegeneration results predominantly from the gradual, age-related loss of compensatory mechanisms that correct for age-accumulated dysfunctions. This concept may appear fundamentally at odds with previous hypotheses postulating that neurodegeneration results mainly from an accumulation of dysfunctions at all levels of complexity.

This special issue aims to gather evidence that these two hypotheses are closely related. Neurodegenerative diseases become overt likely when the level of age-associated dysfunctions over-passes the capacity of the homeostatic compensatory mechanisms. Guiding future research with such a conceptual frame should bring useful clues to understanding the enormous potential of the mammalian brain and how to exploit it to achieve successful cognitive aging.

Potential topics include, but are not limited to:

• Age-related dysfunctions at the molecular (mitochondrial energy production, DNA repair mechanisms, and Ca²⁺ buffering capacity…) and cellular (neuronal dendritic branching and spine remodeling, glutamate uptake capacity of astrocytes, and threshold of microglia activation…) levels
• Identification of putative compensatory mechanisms such as more efficient detoxification of reactive oxygen radicals, steroidogenesis, and DNA repair mechanisms etc…
• Understanding age-dependent control of neuronal excitability and reorganization of neuronal microcircuits and networks
• Differences in the activation of brain regions during cognitive tasks between young and old neurologically normal subjects
• Synergistic contribution of physical activity and cognitive stimulation to foster neuroplasticity during aging
• Role of age-related alterations in homeostatic reflex set-points in the human brain with a focus on nutritional drive in the elderly
• Brain vascular disorders: causes, consequences, or associated lesions inage-related neurodegenerative diseases