Human longevity and diseases are likely influenced by multiple interacting genes within a few biologically conserved pathways. Using long-lived smokers as a phenotype ( n = 90)—a group whose survival may signify innate resilience—we conducted a genome-wide association study comparing them to smokers at ages 52–69 ( n = 730). These results were used to conduct a functional interaction network and pathway analysis, to identify single nucleotide polymorphisms that collectively related to smokers’ longevity. We identified a set of 215 single nucleotide polymorphisms (all of which had p <5×10 −3 in the genome-wide association study) that were located within genes making-up a functional interaction network. These single nucleotide polymorphisms were then used to create a weighted polygenic risk score that, using an independent validation sample of nonsmokers ( N = 6,447), was found to be significantly associated with a 22% increase in the likelihood of being aged 90–99 ( n = 253) and an over threefold increase in the likelihood of being a centenarian ( n = 4), compared with being at ages 52–79 ( n = 4,900). Additionally, the polygenic risk score was also associated with an 11% reduction in cancer prevalence over up to 18 years (odds ratio: 0.89, p = .011). Overall, using a unique phenotype and incorporating prior knowledge of biological networks, this study identified a set of single nucleotide polymorphisms that together appear to be important for human aging, stress resistance, cancer, and longevity.