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. 2010 Oct;9(5):698-708.
doi: 10.1111/j.1474-9726.2010.00600.x. Epub 2010 Aug 4.

HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging

S Michal Jazwinski  1 , Sangkyu Kim, Jianliang Dai, Li Li, Xiuhua Bi, James C Jiang, Jonathan Arnold, Mark A Batzer, Jerilyn A Walker, David A Welsh, Christina M Lefante, Julia Volaufova, Leann Myers, L Joseph Su, Dorothy B Hausman, Michael V Miceli, Eric Ravussin, Leonard W Poon, Katie E Cherry, Michael A Welsch; Georgia Centenarian Study and the Louisiana Healthy Aging Study
Collaborators, Affiliations

HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging

S Michal Jazwinski et al. Aging Cell. 2010 Oct.

Abstract

The search for longevity-determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging. Subjects were recruited and stratified according to their genetically inferred ethnic affiliation to account for population structure. Haplotype analysis was performed in three candidate genes, and the haplotype combinations were tested for association with exceptional longevity. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. These results were replicated in a second population. A profile of healthy aging was developed using a deficit accumulation index, which showed that this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congruence of common gene variants readily fulfills this role. The interaction between the three genes described here suggests new models for cellular and molecular mechanisms underlying exceptional survival and healthy aging that involve lipotoxicity.

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Figures

Fig. 1
Fig. 1
Stratification of the populations by ethnic affiliation. Alu genotypes and Structure analysis were employed to assign subjects to two major strata, European and African, in the Georgia (A) and Louisiana (B) populations. The Structure analysis was carried out in two batches for Louisiana consisting of 434 and 435 samples to speed computation, the latter of which is shown, while all 650 samples from Georgia were analyzed in one batch. Dots: red (Georgia or Louisiana samples), green (African control samples), blue (European control samples), pink (Asian control samples), orange (Indian control samples). Indian refers to the Indian subcontinent. Not all samples are evident due to superposition of dots.
Fig. 2
Fig. 2
Haplotype frequencies in different age groups. The frequencies for each haplotype or haplotype combination determined for the European subpopulation (0.9 assignment probability) were normalized to the frequencies in the <60 years-old age group from Georgia or Louisiana, respectively, to facilitate comparison. Error bars denote the SD (100 bootstraps). The age groups labeled “90” and “100” are the nonagenarians and centenarians in Georgia and Louisiana, respectively. For clarity, only the haplotypes or haplotype combinations that differ significantly in frequency between age groups are shown: APOE (ATTTC), HRAS1 (CGCGCGT), and LASS1 (CCT) in A and APOE (ATTTC), HRAS1 (CGCGCGT), and LASS1 (CGT) in B. Note the difference in scale of the ordinates in A and B. The APOE and APOE·HRAS1 frequencies are identical in the two panels.
Fig. 3
Fig. 3
Survival of nonagenarians as a function of their healthy aging profile. Kaplan-Meier survival of all nonagenarians in the Louisiana sample is plotted after partitioning individuals into tertiles of deficit accumulation. Deficit count increases from tertile 1 to 3. Mortality was assessed on follow up after enrollment. Censoring is indicated by the symbols.
Fig. 4
Fig. 4
Impact of polymorphisms in LASS1 on gene expression. A luciferase reporter assay was used for determining the promoter activity in transfected HeLa cells. Error bars denote SEM for six independent experiments with at least six replicates for each of the four promoter constructs shown. The LASS1 promoter variants CCT and CGT associated with exceptional longevity were compared to an AGC variant. The control is a reporter lacking inserted promoter sequences.
Fig. 5
Fig. 5
Hypothetical model of the role of APOE, HRAS1, and LASS1 interactions. Circulating lipids are cleared by APOE and by HDL, which is aided by LASS1-generated ceramide. Metabolic (lipid) stress induces protective survival and stress responses, which are mediated/modulated by HRAS1 and LASS1. Lipotoxicity enhances LASS1 production of ceramide, which signals apoptosis removing damaged cells. These mechanisms become overwhelmed with age resulting in dysfunction and morbidity.
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References

    1. Artiga MJ, Bullido MJ, Sastre I, Recuero M, Garcia MA, Aldudo J, Vázquez J, Valdivieso F. Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene. FEBS Lett. 1998a;421:105–108. - PubMed
    1. Artiga MJ, Bullido MJ, Frank A, Sastre I, Recuero M, Garcia MA, Lendon CL, Han SW, Morris JC, Vázquez J, Goate A, Valdivieso F. Risk of Alzheimer’s disease correlates with transcriptional activity of the APOE gene. Hum. Molec. Genet. 1998b;7:1887–1892. - PubMed
    1. Bamshad MJ, Wooding S, Watkins WS, Ostler CT, Batzer MA, Jorde LB. Human population genetic structure and inference of group membership. Am. J. Hum. Genet. 2003;72:578–589. - PMC - PubMed
    1. Bergman A, Atzmon G, Ye K, MacCarthy T, Barzilai N. Buffering mechanisms in aging: a systems approach toward uncovering the genetic component of aging. PLoS Comput. Biol. 2007;3:e170. - PMC - PubMed
    1. Bonafé M, Barbi C, Olivieri F, Yashin A, Andreev KF, Vaupel JW, De Benedictis G, Rose G, Carrieri G, Jazwinski SM, Franceschi C. An allele of HRAS1 3′variable number of tandem repeats is a frailty allele: Implication for an evolutionarily-conserved pathway involved in longevity. Gene. 2002;286:121–126. - PubMed

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