GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE338nnn/GSE338219/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE338219GEOGSEfalsePyrroloquinoline Quinone Improves Cognitive-Related Behavioral Performance Associated with Enhanced Mitochondrial Bioenergetics in Naturally Aged MiceWe investigated whether pyrroloquinoline quinone (PQQ) could improve cognitive performance in twenty-month-old naturally aged mice and explored the potential mechanisms involved. Results showed that PQQ supplementation improved spatial working memory and recognition memory without inducing anxiety-like behavior, and was associated with better preservation of hippocampal neuronal integrity. In HT-22 hippocampal neuronal cells, PQQ reduced reactive oxygen species (ROS) accumulation, restored mitochondrial membrane potential, and enhanced mitochondrial respiratory capacity. Hippocampal transcriptomic analysis and upstream regulator prediction identified SIRT1 as a major regulator associated with the PQQ-induced transcriptional response, while uncoupling protein 2 (UCP2) emerged as a candidate downstream mitochondrial effector. Consistently, PQQ increased hippocampal SIRT1 protein expression and downregulated UCP2 at both mRNA and protein levels. Pharmacological inhibition of SIRT1 attenuated the PQQ-induced increase in ATP production and partially weakened the regulatory effect of PQQ on UCP2, supporting the involvement of SIRT1 in PQQ-associated mitochondrial bioenergetic regulation. Collectively, these findings indicate that PQQ improves cognitive-related behavioral performance in naturally aged mice and is associated with mitochondrial bioenergetic regulation, and suggest that modulation of a SIRT1–UCP2-associated pathway may contribute to its neuroprotective effects.2026/07/14GSE338219GSM9869387GSM9869386GSM9869385GSM9869396GSM9869395GSM9869394GSM9869393GSM9869392GSM9869391GSM9869390GSM9869389GSM986938824247338219Mus musculus[42650185]