Circulating PAR-Binding Proteins as Candidate Mediators of Age-Dependent Cognitive Decline

Aging is associated with systemic changes in circulating plasma proteins that influence tissue function. Heterochronic parabiosis and plasma transfer experiments in mice have established that exposure to young or old blood is sufficient to modulate neurogenesis, synaptic plasticity, and cognition, indicating that age-regulated plasma proteins contribute causally to brain aging phenotypes. In parallel, the most recent proteome-wide studies of poly(ADP-ribose) (PAR) signaling have identified hundreds of candidate proteins that interact with PAR through non-covalent PAR binding motifs, including proteins involved in DNA repair, stress responses, inflammation, and metabolism, which are known as key ageing-associated factors. Multiple plasma proteomic studies in humans have defined sets of proteins whose abundance differs between young and older adults, and cross-referencing these datasets suggests that a subset of age-regulated plasma proteins may have experimental and/or predicted PAR-binding capacity. This review integrates evidence from heterochronic parabiosis, PAR-binding proteome (PARome) studies and age-stratified plasma proteomics to examine whether PAR-binding plasma proteins can form a mechanistically relevant subset of circulating age-dependent factors. Here we review how altered levels of these proteins with age may interface with intracellular PAR signaling networks to influence brain plasticity, inflammatory tone, and metabolic resilience, providing a potential explanation for the beneficial effects of young plasma and the detrimental effects of old plasma observed in parabiosis.