Background: We attempt to identify specific differentially methylated and expressed genes in people with LONGEVITY family history, it will contribute to discover significant features about human LONGEVITY. Methods: A prevalence study was conducted during October 2017 to January 2019 in Bama County of Guangxi, China and individuals were recruited and grouped into LONGEVITY family (n=60) and non-LONGEVITY family (n=60) to identify differentially methylated genes (DMGs). The expression profile dataset GSE16717 was downloaded from the GEO database in which individuals were divided into 3 groups, namely LONGEVITY (n=50), LONGEVITY offspring (n=50) and control (n=50) for identifying differentially expressed genes (DEGs). It was considered significantly different when P or adjusted P 0. 05. Results: In total, 117 LONGEVITY-related hypermethylated genes enriched in interleukin secretion/production regula-tion, chemokine signaling pathway and natural killer cell-mediated cytotoxicity. Another 296 significant key LONGEVITY-related DEGs primarily involved in protein binding, nucleus, cytoplasm, T cell receptor signaling pathway and Meta-bolic pathway, H19 and PFKFB4 were found to be both methylated and downregulated in people with LONGEVITY fam-ily history. Conclusion: Human LONGEVITY-specific genes involve in many immunity regulations and cellular immunity pathways, H19 and PFKFB4 show hypermethylated and suppressed status in people with LONGEVITY family history and might serve as LONGEVITY candidate genes.