Unlocking the Dynamics of Dopamine in Aging: Balancing Pre- and Post-Synaptic Mechanisms for Optimal Brain Function across the adult lifespan

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Many older adults experience impairment of cognitive functions, such as memory. While changes to the aging brain are often assumed to underlie cognitive decline, but it has turned out surprisingly hard to identify coupled brain-cognitive changes in aging. This challenge is magnified when searching for potentially modifiable brain alterations that could serve as targets for various kinds of interventions. A promising candidate mechanism is age-related alterations in neurotransmitters like dopamine (DA) and noradrenaline (NA), crucial for brain functions. Yet, existing models of aging related to DA and NA are inadequate, as past studies solely focused on either the DA or NA system and also emphasized a single facet of the multifaceted DA system (either pre- or post-synaptic). This represents a serious omission because various parts of the DA system are tightly regulated and the balance between pre- and post-synaptic markers, rather than each marker in isolation, might be more critical for efficient neuromodulatory function. Contrary to the prevailing notion of a global DA neurodegeneration, characterized by a hypodopaminergic condition, I hypothesis that aging is accompanied with loss of balance between pre- and post-synaptic DA systems. This imbalance holds profound implication for functional brain integrity and cognitive decline in aging. The overarching goal of this ground-breaking research program is to, for the first time, address the fundamental question of how the dynamic interplay between pre- and post-synaptic markers of the DA, along with its interaction with equally critical NA, evolves as individuals age and how these dynamics are linked to functional brain integrity and cognitive decline. Of particular interest is whether transiently restoring the balance between pre- and post-synaptic components of the DA system and NA through pharmacological intervention, opens a window to remodel the aging brain and improve cognitive function in some older individuals.