HSPA14 belongs to the same functional group as HSPA1A and HSPA1L (70 kDa heat shock proteins (HSP70s)) previously reported as associated with human longevity. The level of the entire gene indicated a positive effect of the rare variants of HSPA14 on survival from middle-aged to old-aged. Hsp14 (also named hsp70L1) is a rather recently identified hsp70 protein and is known to be located in ribosomes, probably playing a role in the folding of newly translated proteins. Accordingly, the rare alleles of the HSPA14 SNPs reported here could be hypothesized to enhance such activity and avoid accumulation of newly translated proteins during aging. However, hsp14 also enhances cellular immunity in dendrites, e.g., stimulating secretion of for instance IL12 and TNF, and has therefore beenSuggested as an adjuvant for the treatment of cancer and infectious disease (Wu et al. 2005). An enhancement of such effects could intuitively be considered to pose a positive effect on longevity, although the connection between immune regulatory processes and longevity is, as explained below, probably not that straightforward.

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Bathum L, Christiansen L, Jeune B, Vaupel J, Mue M, Christensen K () Apolipoprotein e genotypes: When investigating survival during old age in the longitudinal study, we found rs2069827 (IL6) as the only SNP posing an effect - an effect which was confirmed in the Dutch replication cohort. The relation of immune regulatory genes to longevity is in general based on the idea of a balance between pro- and anti-inflammatory processes since aging is accompanied by both a decline in several immune functions (immunosenescence) and an increase in a chronic low-grade inflammation state (inflammaging). The genetic polymorphisms associated with longevity are presumed to increase the ability to cope with inflammaging (Jylhava and Hurme 2010). Therefore, one might expect the rare allele of rs2069827 (IL6) to hold a low pro-inflammatory activity. Such low activity could presumably be caused by low IL6 expression, yet in our qPCR study, we observed no difference in IL6 mRNA levels between rs2069827 genotype groups. Hence, the impact of this SNP does not appear to be mediated through changes in IL6 expression. Finally, rs2069827 may simply be a proxy for a causal variant not genotyped in the present study.

In conclusion, we here add data to the proposed roles of 16 frequently discussed candidate genes indicating that variation in APOE and CETP and possible HSPA14 is of importance in survival from middle age to old age whereas genetic variation in IL6 seems to affect survival during late life.