<p>The incidence of brain diseases increases with aging, but the biological basis of brain aging is still poorly explored. Synaptic dysfunction occurs at the onset of brain diseases and synaptic neuromodulation systems, such as adenosine A_2A receptors (A_2AR), are necessary and sufficient to trigger brain dysfunction. Since A_2AR are upregulated upon aging, we compared wild-type and A_2AR global knockout mice to test if brain aging involves synaptic senescence linked to A_2AR overfunction, leading to synaptic and cognitive deterioration. Aging impacted different behavioral outputs, namely spatial learning and memory, coupled to aberrant synaptic plasticity in the hippocampus and prefrontal cortex. Moreover, aging led to an imbalance between excitation and inhibition markers and dysregulated key metabolic coordinators, including sirtuin-1, sirtuin-3, AMPK and p38MAPK. These cognitive impairments and synaptic and metabolic signaling alterations were not observed in aged mice with A_2AR genetic elimination. These findings suggest that A_2AR overfunction can be a key driver of age-associated memory deterioration and A_2AR blockade might promote healthy brain aging.</p> Graphical abstract <p>Aging affected memory and synaptic plasticity, disrupted the balance between excitation and inhibition markers and deregulated key metabolic regulators, namely SIRT1, SIRT3, AMPK and p38MAPK, in the hippocampus and prefrontal cortex of aged mice. A_2AR elimination prevented memory deterioration and most synaptic and metabolic-related alterations in both cortical regions were no longer present. Thus, A_2AR upregulation might be a driver of synaptic senescence-like metabolic and A_2AR blockade may help prevent synaptic dysfunction and, consequently, promote healthy aging.</p> <p></p>