Current studies have indicated the association of chronic sterile inflammation (inflammation in the absence of pathogens) with the pathogenesis of age-related and metabolic diseases. The inflammation is under the control of transcription factor NF-B through an antagonistic crosstalk between SIRT1, PARP-1, and -2 signaling pathways. The transcriptional activity of NF-B is increased in various tissues with aging and metabolic abnormalities and is related with various aging and metabolic diseases such as Alzheimer’s disease, diabetes, and osteoporosis. Furthermore, NF-B activation with chronic inflammation is connected with many known life span and metabolic regulators including DNA damage, obesity, SIRT, and PARP. Thus, the crossroads between PARP and SIRT signaling pathways represent efficient therapeutic targets for extending health span without metabolic diseases.