BACKGROUND: Wildland fires in the United States have increased in frequency and scale over the past 30 years exposing millions of people to hazardous air pollutants. Among others, aging individuals are particularly vulnerable to the effects of wildfire smoke. In this study, we assessed the neurobiological impacts of wood smoke (WS) on aged mice and the potential of anti-aging therapeutics to mitigate these impacts. METHODS: Female C57BL/6 J mice, aged 18 months, were divided into 10 groups and exposed to either filtered air (FA; 5 groups) or biomass derived WS (5 groups) for 4 h/day, every other day, for 14 days (7 exposures total) with an average particulate matter (PM) concentration of 448 µg/m per exposure. One FA control group and one WS exposed group were euthanized 24 h after the last exposure. The remaining 8 groups (4 FA and 4 WS exposed) were treated with either vehicle control, resveratrol and nicotinamide mononucleotide (RNMN), dasatinib and quercetin (DQ), or both RNMN and DQ (RNDQ) for 10 weeks. RESULTS: A significant reduction in NAD + within the prefrontal cortex was observed following the 14-day exposure to WS along with a reduction in serotonin. Serotonin reductions were observed up to 10 weeks post-exposure and co-occurred with neuroinflammation and behavioral alterations, including increased immobility in a forced swim test. RNMN conferred the greatest mitigating effect after WS exposure, while RNDQ treatment resulted in an upregulation of markers associated with aging in the brain. While the metabolic shift in the PFC following WS exposure was relatively modest, mice exposed to FA and vehicle control (10 weeks of natural aging) exhibited the greatest metabolic shift, including perturbed nicotinamide metabolism. CONCLUSION: Taken together, these findings highlight that subacute (14-day) exposure to WS results in persistent neurometabolomic and behavioral alterations in an aged mouse model and that intervention with RNMN may be a useful strategy to mitigate the adverse neurological outcomes observed. Further studies are needed to assess the specific impact of either resveratrol or NMN in isolation and to fully elucidate age-specific, as well as sex- and species-determinant, WS exposure response pathways.