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Transcriptional programming coordinates the proinflammatory programs needed for innate immune control of pathogens. PBMC from healthy aged participants had elevated baseline type 1 interferon gene signature compared to PBMC from younger adults, and levels could not be further induced by influenza vaccination [80]. Younger adult PBMC also showed increased oxidative phosphorylation and mitochondrial biogenesis programs that were absent in older adult PBMC, particularly in older adults that did not respond to vaccination. Circulating isolated monocyte subsets from elderly individuals showed altered transcriptional profiles in response to ex vivo TLR ligand stimulation including exaggerated superoxide and oxidative stress program signatures [81]. A large multicohort analysis showed that baseline gene expression predicts influenza vaccination response in young adults. Fifteen genes (upregulated: RAB24, GRB2, DPP3, ACTB, MVP, DPP7, ARPC4, PLEKHB2, ARRB1; down-regulated: PTPN22, PURA, SP4, CASP6, NUDCD2) were identified in young adults classified as “high responders” to influenza vaccination. These nine upregulated genes were not induced in older individuals, and no genes in older adults were differentially expressed in low and high responders, suggesting distinct responses lead to lower vaccine response in older individuals [82]. Hematopoietic stem cells (HSCs) from older individuals exhibit hypermethylation of the IRF8 locus [83], and thus epigenetic regulatory mechanisms may link the well-known myeloid skewing of HSCs with impaired IFN induction with age [26]. These age-related impairments may contribute to impaired vaccine response and the increased susceptibility of older persons to IAV infection.