HRAS1 and LASS1, along with APOE, are linked to human longevity and healthy aging. The study involved haplotype analysis in three candidate genes, which were tested for association with exceptional longevity. The results revealed that an HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. These findings were replicated in a second population. Additionally, the study developed a healthy aging profile using a deficit accumulation index that showed that this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional and causes enhanced expression of the gene, contributing to healthy aging and greater survival in the tenth decade of life. Therefore, rare gene variants are not necessary to explain complex traits such as aging; instead, rare congruence of common gene variants readily fulfills this role. The interaction between the three genes suggests new models for cellular and molecular mechanisms underlying exceptional survival and healthy aging that involve lipotoxicity. 

The study revealed that APOE e4 allele is a risk factor for early mortality, while the alleles e2 and e3 are enriched in exceptionally old individuals in some studies. Apolipoprotein E (APOE) is important in chylomicron and very low-density lipoprotein (VLDL) metabolism. Thus, it is one of the factors responsible for maintaining circulating lipid homeostasis. This balance can break down with age and is clearly disrupted in some individuals resulting in an increase in the risk for cardiovascular disease and other disorders. The rise in circulating cholesterol and triglycerides results in vascular damage and can be a cause of lipotoxicity, a potential trigger of insulin resistance and diabetes. This lipotoxicity may trigger responses that are mediated by HRAS1, a small G-protein involved in signal transduction. Furthermore, some of the pathways that are induced are modulated by ceramide, a product of the ceramide synthase LASS1. Ceramide synthase responds to growth and stress signals via Tor complex TORC2 and calcineurin, respectively. Lipotoxicity stimulates ceramide synthesis, and the resulting ceramide can signal apoptosis, resulting in the removal of damaged cells. It can also facilitate the transfer of cholesterol from cells to high-density lipoprotein (HDL). Therefore, the study postulates that the HRAS1 and LASS1 genes interact genetically with the APOE gene to reduce age-related increase in lipotoxic events, and that a combination of variants or haplotypes in these three genes is associated with exceptional survival. 

The study initiated a genetic analysis of exceptional longevity in the Georgia and Louisiana populations. The populations were admixed with the two major strata being of European and African origin. To address this problem, the study stratified each population by ethnic affiliation using an identical-by-descent (IBD) genetic system. The subjects in each population were placed into two major groups of African and European origin. Together, these two groups constituted 81% and 83% of subjects of 2059 years old and 72% and 77% of centenarians and nonagenarians in the Georgia and Louisiana samples, respectively. The ability to stratify was markedly enhanced by the Alu system used here, which can trace genealogy within the primate lineage. The mean correct prediction rates with the 100 above is associated with longevity, we genotyped the Georgia sample at the three relevant genomic regions. None of the HRAS1 or LASS1 variants showed an association with longevity.15 SNPs examined showed significance for departure from Hardy-Weinberg proportions in either the African or European-origin populations in Georgia. The same was found separately for the Louisiana population. We searched for combinations of haplotypes in the three genes (15 SNPs) in the Georgia population present at 0.01 or greater frequency, using expectation maximization. We then tested them for association with exceptional longevity (Table S4). Such associations were detected in the sub-population of European origin in Georgia, stratified with an assignment probability of 0.9 (Table 1), but not in the subpopulation of African origin. They involve the e3 containing APOE.

Table 1 shows the association of haplotypes with exceptional longevity and healthy aging. The European subpopulations (0.9 assignment probability) were examined. The haplotypes are ATTTC and CGCGCGT for APOE and HRAS1, respectively. Healthy and unhealthy were classified as described in Experimental procedures. OR, odds ratio; CI, 95% confidence interval.

Table 2 indicates haplotype frequencies in the general population. A structure assignment probability of 0.8 was used for this analysis to provide a conservative evaluation of any differences. The 20- to 59-year-old age groups were used here as representative of the general population. APOE (ATTTC) and HRAS1 (CGCGCGT) haplotypes are shown.

To determine whether these associations are present in the Louisiana population, we carried out the same analyses independently. The results obtained in the Georgia sample replicated in the Louisiana sample (Table 1). The same haplotype combinations were associated with exceptional longevity in the subpopulation of European origin in Louisiana, stratified with an assignment probability of 0.9, and no significant association was found in the African-origin subpopulation. The odds ratios were 2.93 and 2.97 for the APOE, HRAS1, and LASS1 (CCT) or (CGT) haplotype combinations, respectively. The lower odds ratio of the LASS1 (CCT)-containing haplotype combination in the Louisiana population is likely due to the greater demographic selection for centenarians than for nonagenarians in the Georgia and Louisiana samples, respectively, but this does not appear to apply to the LASS1 (CGT).