Research on aging in model organisms has revealed different molecular mechanisms involved in the regulation of the lifespan. Studies on Saccharomyces cerevisiae have highlighted the role of the Sir2 family of genes, human Sirtuin homologs, as the longevity factors. In Caenorhabditis elegans, the daf-16 gene, a mammalian homolog of FoxO genes, was shown to function as a longevity gene. A wide array of studies has provided evidence for a role of the activation of innate immunity during aging process in mammals. This process has been called inflamm-aging. The master regulator of innate immunity is the NF-kappaB system. In this review, we focus on the several interactions of aging-associated signaling cascades regulated either by Sirtuins and FoxOs or NF-kappaB signaling pathways. We provide evidence that signaling via the longevity factors of FoxOs and SIRT1 can inhibit NF-kappaB signaling and simultaneously protect against inflamm-aging process.