One of the largest centenarian collections to-date was used to investigate the potential role of genetic variants in human longevity by analyzing the functional genes involved in various longevity pathways using three of the tested nsSNPs that revealed a P value of less than or equal to 0.01, located in three different genes: DUSP6, NALP1, and PERP, all of which are involved in the induction of apoptosis and other diverse pathways linked to longevity or the aging process [41-43]. The DUSP6 protein negatively regulates members of the mitogen-activated protein (MAP) kinase superfamily (MAPK/ERK, SAPK/JNK, p38), which are associated with cellular proliferation and differentiation [44-46]. Additionally, down-regulation of DUSP6 protein expression enhances carcinogenesis [47-49]. Its function as a tumor-suppressor gene [48,50] renders DUSP6 a potential modifier of human longevity. Down-regulation of PERP, besides its role as a key mediator of programmed cell death [42], has also been linked to different types of cancer [52-54]. NALP1 plays an important role in the immune system [55,56] and DNA sequence variants in the NALP1 region were shown to be associated with the risk of several epidemiologically associated autoimmune and autoinflammatory diseases [57]. Hence, DUSP6, NALP1, and PERP are very good candidates for influencing human health and, thus, longevity.

Genetic variants that are more frequent in the long-lived than in the control population (the T-allele of nsSNP rs2301582 [NALP1] and the G-allele of rs648802 [PERP]; Table 1) can be regarded as beneficial by enhancing tumor-suppressor activity (PERP) or strengthening the immune system (NALP1). In contrast, genetic variation that interferesdoi:10.1016/j.mrfmmm.2010.08.006.