Within the Center

Research Performed within the Shock Center

The Shock Center has extensively characterized 32 commonly used inbred strains for aging-related phenotypes – greatly increasing the genetic diversity of the mouse models available for aging research. Center investigators have analyzed these data using complex trait methods pioneered at the Jackson Laboratory, including predictive quantitative trait loci (QTL) and haplotype association mapping (HAM) to support their independent, grant-funded research.

This work has 1) accelerated genetic analyses of aging processes and disease, 2) uncovered lifespan loci, 3) revealed tantalizing correlations between lifespan and susceptibility for age-related disorders, such as osteoporosis and cancer, and 4) provided evidence for concordance of genomic loci influencing lifespan and aging phenotypes between mouse and humans, suggesting promising leads for translational research.

Median Lifespans and Insulin-like Growth Factor 1 (IGF1) levels

To better characterize aging in mice, the Jackson Aging Center carried out a lifespan study of 31 genetically-diverse inbred mouse strains housed in a specific pathogen-free facility. Clinical assessments were carried out every 6 months, measuring multiple age-related phenotypes including neuromuscular, kidney and heart function, body composition, bone density, hematology, hormonal levels, and immune system parameters. In a concurrent cross-sectional study of the same 31 strains at 6, 12, and 20 months, more invasive measurements were carried out followed by necropsy to assess apoptosis, DNA repair, chromosome fragility, and histopathology. In this report, which is the initial paper of a series, the study design, median lifespans, and circulating insulin-like growth factor 1 (IGF1) levels at 6, 12, and 18 months are described for the first cohort of 32 females and 32 males of each strain. Survival curves varied dramatically among strains with the median lifespans ranging from 251 to 964 days. Plasma IGF1 levels, which also varied considerably at each time point, showed an inverse correlation with a median lifespan at 6 months (R = -0.33, P = 0.01). This correlation became stronger if the short-lived strains with a median lifespan < 600 days were removed from the analysis (R = -0.53, P < 0.01). These results support the hypothesis that the IGF1 pathway plays a key role in regulating longevity in mice and indicates that common genetic mechanisms may exist for regulating IGF1 levels and lifespan.

Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels
Yuan R, Tsaih SW, Petkova SB, de Evsikova CM, Xing S, Marion MA, Bogue MA, Mills KD, Peters LL, Bult CJ, Rosen CJ, Sundberg JP, Harrison DE, Churchill GA, Paigen B.
Aging Cell (2009) 8(3): 277-87. [ Full Text ] [ Datasets 1 ] [ Datasets 2 ]

Kidney Disease

Aging in the kidney can cause albuminuria, and discovering molecular mechanisms responsible for this might offer a new perspective on the etiology of this abnormality. Haplotype association mapping in the mouse is a novel approach which uses the haplotypes of the relatively closely related mouse inbred strains and the phenotypic variation among these strains to find associations between haplotypes and phenotype. The albumin-to-creatinine ratios, a measure of urinary albumin excretion, were determined in 30 inbred mouse strains at 12, 18, and 24 months of age. Mapping was performed for males and females separately at all three time points using a high density set of 63,222 single-nucleotide polymorphisms to determine genetic loci involved in albuminuria. One significant and eight suggestive loci were found, some of which map to previously identified loci for traits associated with kidney damage in the mouse, but with a much higher resolution thus narrowing their chromosomal location. These nine loci were then compared with genome-wide association scans for diabetic nephropathy (DN) in human type I diabetes. Our study found that two of the nine mouse loci for age-related albuminuria were significantly associated with DN and consistent across male and female strata. This suggests common underlying genes predispose to kidney disease in mice and humans.

Genetic analysis of albuminuria in aging mice and concordance with loci for human diabetic nephropathy found in a genome-wide association scan
Tsaih SW, Pezzolesi MG, Yuan R, Warram JH, Krolewski AS, Korstanje R.
Kidney Int. (2010) 77(3):201-10.  [ Full Text ] [ Datasets ]

Immune System Function

Inbred mouse strains are routinely used as genetically defined animal models for studying a wide assortment of biological and pathological processes, including immune system function. However, no studies have presented large-scale data on the immune cell populations among the inbred strains in physiological conditions. Here we present a systematic, quantitative analysis of peripheral blood cell phenotypes of 30 mouse strains assessed by flow cytometry. This cohort of mice represents a wide range of genetic origins and includes most of the strains used in genetic, physiological, and immunological studies. We evaluated the relative percentages of peripheral blood leukocyte subtypes (lymphocytes, granulocytes, and monocytes) and lymphocyte subpopulations (CD4+ T, CD8+ T, B220+ B, and natural killer cells) of mature (6-mo-old) mice. Our comprehensive study demonstrated: 1) marked differences in the relative proportions of blood cell populations among the strains at this age, 2) considerable variation of each immune trait with more than twofold difference between strains with the highest and the lowest trait values, and 3) haplotype analysis revealed a strong correlation between eosinophil percentage and a single region on chromosome 14 containing two candidate genes. The strain differences described here provide important information for researchers applying immunophenotyping of peripheral blood in immunological and genetic studies.

Genetic influence on immune phenotype revealed strain-specific variations in peripheral blood lineages
Petkova SB, Yuan R, Tsaih SW, Schott W, Roopenian DC, Paigen B.
Physiol Genomics (2008) 34(3): 304-14.  [ Full Text ] [ Datasets ]

Cardiac Conduction Activity

Understanding the genetic influence on electrocardiogram (ECG) time intervals and heart rate (HR) is important for identifying the genes underlying susceptibility to cardiac arrhythmias. The objective of this study was to determine the genetic influence on ECG parameters and their age-related changes in mice. ECGs were recorded in lead I on 8 males and 8 females from each of 28 inbred strains at the ages of 6, 12, and 18 mo. Significant interstrain differences in the P-R interval, QRS complex duration, and HR were found. Age-related changes in the P-R interval, QRS complex duration, and HR differed among strains. The P-R interval increased with age in 129S1/SvlmJ females. The QRS complex duration decreased with age in C57BR/J males and DBA2/J females but increased in NON/ShiLtJ females. HR decreased in C57L/J females and SM/J and P/J males but increased in BALB/cByJ males. Differences between males and females were found for HR in SJL/J mice and in the P-R interval in 129S1/SvlmJ mice. Broad-sense heritability estimates of ECG time intervals and HR ranged from 0.31 for the QRS complex duration to 0.52 for the P-R interval. Heritability estimates decreased with age for the P-R interval. Our study revealed that genetic factors play a significant role on cardiac conduction activity and age-related changes in ECG time intervals and HR.

Genetic influence on electrocardiogram time intervals and heart rate in aging mice
Xing S, Tsaih SW, Yuan R, Svenson KL, Jorgenson LM, So M, Paigen BJ, Korstanje R.
Am J Physiol Heart Circ Physiol (2009) 296(6): H1907-13.  [ Full Text ] [ Datasets ]

Insulin-like Growth Factor 1 (IGF1) levels

The IGF-1 signaling pathway plays an important role in regulating longevity. To identify the genetic loci and genes that regulate plasma IGF-1 levels, we intercrossed MRL/MpJ and SM/J, inbred mouse strains that differ in IGF-1 levels. Quantitative trait loci (QTL) analysis of IGF-1 levels of these F2 mice detected four QTL on chromosomes (Chrs) 9 (48 Mb), 10 (86 Mb), 15 (18 Mb), and 17 (85 Mb). Haplotype association mapping of IGF-1 levels in 28 domesticated inbred strains identified three suggestive loci in females on Chrs 2 (13 Mb), 10 (88 Mb), and 17 (28 Mb) and in four males on Chrs 1 (159 Mb), 3 (52 and 58 Mb), and 16 (74 Mb). Except for the QTL on Chr 9 and 16, all loci co-localized with IGF-1 QTL previously identified in other mouse crosses. The most significant locus was the QTL on Chr 10, which contains the Igf1 gene and which had a LOD score of 31.8. Haplotype analysis among 28 domesticated inbred strains revealed a major QTL on Chr 10 overlapping with the QTL identified in the F2 mice. This locus showed three major haplotypes; strains with haplotype 1 had significantly lower plasma IGF-1 and extended longevity (P < 0.05) than strains with haplotype 2 or 3. Bioinformatic analysis, combined with sequencing and expression studies, showed that Igf1 is the most likely QTL gene, but that other genes may also play a role in this strong QTL.

Identification of genetic determinants of IGF-1 levels and longevity among mouse inbred strains.
Leduc MS, Hageman RS, Meng Q, Verdugo RA, Tsaih SW, Churchill GA, Paigen B, Yuan R.
Aging Cell. (2010) 823-36. doi: 10.1111/j.1474-9726.2010.00612.x. [ Full Text ] [ Datasets ]

Salt Regulation

In central osmoregulation, a 1-2% rise in plasma osmolality is detected by specialized osmoreceptors located in the circumventricular organs of the hypothalamus. A disturbance in this tightly regulated balance will result in either hyponatremia or hypernatremia, which are both common electrolyte disorders in hospitalized patients. Despite the high clinical importance of hypo- and hypernatremia and the fact that this vital process has been studied for many years, the genes and corresponding proteins involved in this process are just beginning to be identified. To identify novel genes involved in the (patho-)physiology of osmoregulation, we therefore employed haplotype association mapping on an aging group of 27 inbred mouse strains. Serum sodium concentrations were determined in all strains at 6, 12, and 18 mo of age, and high-resolution mapping was performed for males and females separately. We identified a total of five loci associated with the serum sodium concentration of which the locus on chromosome 14, containing only one known gene (Nalcn), showed the strongest correlation. Within this locus three different haplotypes could be distinguished, which associated with different average serum sodium levels. The association of Nalcn with sodium levels was confirmed by analysis of heterozygous Nalcn knockout mice, which displayed hypernatremia compared with wild-type littermates. Our study demonstrates that Nalcn associates with serum sodium concentrations in mice and indicates that Nalcn is an important novel player in osmoregulation.

Genetic analysis of mouse strains with variable serum sodium concentrations identifies the Nalcn sodium channel as a novel player in osmoregulation.
Sinke AP, Caputo C, Tsaih SW, Yuan R, Ren D, Deen PM, Korstanje R.
Physiol Genomics. (2011) 43(5):265-70. [ Full Text ] [ Datasets ]

Histopathology of Diseases Associated with Aging

Inbred mice provide a unique tool to study aging populations because of the genetic homogeneity within an inbred strain, their short life span, and the tools for analysis which are available. A large-scale longitudinal and cross-sectional aging study was conducted on 30 inbred strains to determine, using histopathology, the type and diversity of diseases mice develop as they age. These data provide tools that when linked with modern in silico genetic mapping tools, can begin to unravel the complex genetics of many of the common chronic diseases associated with aging in humans and other mammals. In addition, novel disease models were discovered in some strains, such as rhabdomyosarcoma in old A/J mice, to diseases affecting many but not all strains including pseudoxanthoma elasticum, pulmonary adenoma, alopecia areata and many others. This extensive data set is now available online and provides a useful tool to help better understand strain-specific background diseases that can complicate interpretation of genetically engineered mice and other manipulatable mouse studies that utilize these strains.

The mouse as a model for understanding chronic diseases of aging: the histopathologic basis of aging in inbred mice
Sundberg JP, Berndt A, Sundberg BA, Silva KA, Kennedy V, Bronson R, Yuan R, Paigen B, Harrison D, Schofield PN.
Pathobiology of Aging & Age-related Diseases (2011) 1: 7179 – DOI: 10.3402/pba.v1i0.7179
[ Full Text ] [ Datasets ]

DNA Damage

One theory of aging posits that accumulation of DNA damage or chromosomal abnormalities with age leads to decline or derangement of normal cellular processes. In support of this hypothesis, mice deficient for DNA damage response or repair often show phenotypes resembling accelerated aging, especially tumor development. However, natural aging and age-specific pathologies, such as cancer, are complex and variable phenomena that may be considered quantitative traits.

We have taken advantage of a comprehensive collection of aging inbred mouse strains that were generated at The Jackson Laboratory—with support from The Ellison Foundation and the NIH Nathan Shock Center of Excellence in the Basic Biology of Aging—to probe the connection between DNA damage and natural aging. We have found that endogenous genotoxic stress, and the magnitude of the resulting apoptotic response, varies dramatically among different inbred strains of mice, at least in the tissues we tested. This suggests that either the underlying susceptibility to DNA damage or the nature of the response is under genetic control. Intriguingly, we have found that apoptosis and spontaneous chromosomal instability appear to be inversely correlated, suggesting that some strains more effectively avoid genomic instability by mounting a stronger apoptotic reaction to damage. Moreover, we have found that this apoptosis/instability relationship also correlates with the average lifespan characteristics of individual strains, suggesting that DNA damage, chromosomal instability and cellular genotoxicity may relate to some aspects of overall organismal aging. We are now taking a genetics approach to begin dissecting the pathways governing these phenotypes.

Mills, KD. unpublished
[ Datasets ]