Murine chromosomal regions correlated with longevity.

Abstract

In this longevity analysis of 360 BXD recombinant inbred female mice (20 different strains), 2 strains had very significantly shorter survival and 1 strain had very significantly longer survival than the other 17 strains; 4 other strains had less significant lengthening of survival compared to the other 13 strains in a proportional hazards model of survival. Mean survival on the shortest lived strain was 479 days; on the longest lived strain the mean survival was almost double (904 days). Ranges of survival within strain were very large (averaging 642 days), and strain accounted for only 29% of the variation in survival, showing that there are important environmental and/or special developmental effects on longevity even in this colony housed in a single room. Each strain had been typed for markers of 141 regions on 15 chromosomes; 101 of these markers had distinguishable distributions on the 20 strains. The two shortest lived strains had the same alleles for 63% of the markers. The single region most significantly correlated with survival (marked by P450, Coh, Xmmv-35 on chromosome 7) divided the mice into two groups with survival medians which differed by 153 days (755 days for mice with a B genotype; 602 days for mice with a D genotype). Evaluated individually, 44% of the genetic markers (including some markers on 11 of 15 chromosomes with any markers typed) were found to be significantly correlated with survival (P less than 0.05) although one would only expect 5% of the markers to be significant by chance. While studies of many markers should adjust for the multiple comparisons problem, one interpretation of these crude P values is that any experiment with only one of these "significant" markers typed would be likely to conclude that the marker was a significant predictor of survival. Two types of multiple regression models were used to examine the correlation with survival of groups of genes. When a proportional hazards model for survival was done in terms of genotype regions, a six genetic region model best correlated with survival: that marked by P450, Coh, Xmmv-35 on chromosome 7 (B allele lives longer), Ly-24 on chromosome 2 (B allele lives longer), beta 2M and H-3 on chromosome 2 (D allele lives longer) Lamb-2 on chromosome 1 (D allele lives longer), Ltw-4 on chromosome 1 (B allele lives longer), and the Igh area of chromosome 12 (Igh-Sa4, Igh-Sa2, Igh-Bgl, Igh-Nbp, Igh-Npid, Igh-Gte, Odc-8, and Ox-1; D allele lives longer).(ABSTRACT TRUNCATED AT 400 WORDS)

Lifespan-Associated Gene Expression Signatures of Recombinant BXD Mice Implicates Coro7 and Set in Longevity

“…For all of the seven datasets, we first matched each BXD mouse strain with the lifespan values from a reference QTL longevity analysis (Lang et al, 2010). We compared the Lang et al, 2010 BXD lifespans ranking (Lang et al, 2010) with a prior QTL study by Gelman et al, 1988(Gelman et al, 1988, which provided median lifespans on BXD mice, assessing the median lifespans of 20 RI BXD strains from 360 female mice (∼ 20 mice for 16 strains and 10 mice for 4 strains). The authors came to similar results for female median strains, with a correlation between the relative median lifespans of 0.73 at a P < 0.001 (Lang et al, 2010).…”

“…Although the difference in the mean lifespan of the parental strain (C57BL/6 and DBA/2) is only about 25% (Mitchell et al, 2016), these BXD inbred strains show more than twofold differences in lifespan (Roy et al, 2020). This makes them unique in order to identify longevity genes based on quantitative trait loci (QTL) mapping (Gelman et al, 1988;Haan and Zant, 1999;Lang et al, 2010;Houtkooper et al, 2013).…”

Applying hormesis in aging research and therapy

“…[16][17][18][19][20] In Drosophila, the methuselah (mth) gene, whose predicted protein sequence has homology to several GTP-binding protein coupled receptors, is also associated with increased lifespan and enhanced resistance to various forms of stress.2' Similarly, a mutation in the gene encoding an adapter protein p66shc which is involved in the oxidative stress response, extends the life span of mice.22 In the case of the mouse klotho gene, which is a membrane protein /3-glucosidase,23 and the human Werner's gene, which is a DNA helicase,24 the phenotype of premature aging is manifested along with a plethora of diseases. Additionally, genetic linkage studies for longevity in mice have identified major histocompatibility complex (MHC) regions, 25 The diversity of the genes associated with aging and longevity of different organisms indicates that whereas the genes involved in repair and maintenance pathways may be important from an evolutionary point of view (the so-called "public" genes), each species may also have additional "private" gerontogenic pathways that influence its aging phenotype.30…”

Magnetic Resonance Monitoring of Disease Progression in mdx Mice on Different Genetic Backgrounds

“…In addition, evidence in the literature supports that animal models on the DBA/2J strain are more severely affected than C57BL10 and C57BL6 backgrounds. 20,21 In recent years, mdx mice on the DBA/2J background [ie, D2.B10-Dmd mdx (D2-mdx)] mouse model has emerged as an alternative mouse model, which has been proposed to parallel human disease progression more closely than the contemporary mdx mouse model on the BL10 background (ie, B10-mdx). 18,20 In addition, disease progression varies between individual muscles and is an important factor to consider in future and especially longitudinal studies.…”