Common Mouse Research Models

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ILAR J. Author manuscript; available in PMC 2011 May 8.
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ILAR J. 2011 February 8; 52(1): 4–15.
Mice as a Mammalian Model for Research on the Genetics of

Aging
Rong Yuan, Ph.D., M.D.,

Research Scientist and Animal Core Leader, The Jackson Laboratory Aging Center, The Jackson
Laboratory, Bar Harbor, ME
Luanne L. Peters, Ph.D., and
Professor and Director, The Jackson Laboratory Aging Center, The Jackson Laboratory, Bar
Harbor, ME
Beverly Paigen, Ph.D.
Professor, member of the Leadership Team, The Jackson Laboratory Aging Center, The Jackson
Laboratory, Bar Harbor, ME
Abstract
Mice are an ideal mammalian model for studying the genetics of aging: considerable resources are
available, the generation time is short, and the environment can be easily controlled, an important
consideration when performing mapping studies to identify genes that influence lifespan and age-
related diseases. In this review we highlight some salient contributions of the mouse in aging
research: lifespan intervention studies in the Interventions Testing Program of the National
Institute on Aging; identification of the genetic underpinnings of the effects of calorie restriction
on lifespan; the Aging Phenome Project at the Jackson Laboratory, which has submitted multiple
large, freely available phenotyping datasets to the Mouse Phenome Database; insights from
spontaneous and engineered mouse mutants; and complex traits analyses identifying quantitative
trait loci that affect lifespan. We also show that genomewide association peaks for lifespan in
humans and lifespan quantitative loci for mice map to homologous locations in the genome. Thus,
the vast bioinformatic and genetic resources of the mouse can be used to screen candidate genes
identified in both mouse and human mapping studies, followed by functional testing, often not
possible in humans, to determine their influence on aging.
Keywords
aging; calorie restriction (CR); gene mutation; genetics; lifespan; longevity; mouse genome;
quantitative trait locus (QTL)
Introduction
Much has been learned from the study of aging in worms and flies, but it is important to test
the knowledge derived from these lower organisms in a mammalian species. For this, the
mouse is ideal. Not only does it have a relatively short lifespan but, as a mammalian
research model that shares 99% of its genes with humans (Boguski 2002), outstanding
genetic resources and sophisticated genetic engineering technology are available for
manipulating its genome (Paigen 1995). The many genetic resources of the mouse have been
Corresponding author: Beverly Paigen, The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04605, bev.paigen@jax.org.
Yuan et al. Page 2
reviewed recently (Peters et al. 2007), and new resources, such as the Collaborative Cross
(Churchill et al. 2004; Threadgill et al. 2011), are being developed at a steady pace.
Among the many aging studies that have used mouse models, we discuss testing of
interventions (especially compounds that may extend lifespan) (Harrison et al. 2009; Miller
et al. 2007; Strong et al. 2008), retardation of aging by calorie restriction, spontaneous or
genetically engineered mutations that affect lifespan, the determination of lifespan in
multiple inbred strains (Yuan et al. 2009), and quantitative trait locus (QTL1) studies to find
genomic regions associated with aging (de Haan et al. 1998; Gelman et al. 1988; Jackson et
al. 2002; Klebanov et al. 2001; Lang et al. 2010; Miller et al. 1998, 2002a; Rikke et al. 2010;
Yunis et al. 1984). Space limitations of this review prevent an in-depth discussion of the
many aspects of aging; we refer the reader to recent outstanding reviews on calorie
restriction (Fontana et al. 2010; Kemnitz 2011), the role of mitochondria (Larsson 2010) and
telomeres in aging (Sahin and Depinho 2010), pathways known to affect aging (Kenyon
2010), and other mouse models of aging (Chen et al. 2010).
As in any animal research, environmental and animal husbandry conditions may affect the
outcome of aging studies. Lifespan may be affected by husbandry issues such as
composition of food, water, type of housing, density of mice/cage, enrichment, and animal
room size and noise level, but very little is known about the impact of these factors on
lifespan.
Interventions Testing Program of the National Institute on Aging

One practical use of the mouse is to test diets and compounds for their ability to slow aging
and extend longevity in a mammalian model. The Interventions Testing Program (ITP) of
the National Institute on Aging is a three-site project with simultaneous identical lifespan
studies at the Jackson Laboratory, University of Michigan, and University of Texas Health
Science Center at San Antonio (Miller et al. 2007).2 The diets and compounds tested are
selected from proposals by the extramural research community (Nadon et al. 2008). The ITP
mice are generated by breeding two hybrids, (BALB/cByJ × C57BL/6J) F1 × (C3H/HeJ ×
DBA/2J) F1, so that all mice are genetically heterogeneous but the genetic variation of the
population is reproducible. The use of these mice avoids genotype-specific effects on
disease susceptibility while ensuring the replicability of the study.
Although all three sites follow the same standardized protocols, both control and drug-
exposed mice at the University of Michigan site were significantly smaller throughout adult
life than those at the other two sites, and researchers observed significant differences in
survival of male (but not female) mice in the control groups (Harrison et al. 2009; Strong et
al. 2008). The researchers hypothesized that such differences could be due to the sources
and formulations of food. At the start of the program, the diets used for breeders and
weanlings (before drug exposure) differed in fat content (4.5–6.5%), supplemental levels of
thiamine and other heat-sensitive vitamins, and protein source and content (18–24%).
Starting with Cohort 4 (born in 2007), however, the three ITP sites adopted a uniform
protocol for diet composition at all stages of the test process, including diets for breeder
mice and for test mice before drug administration. It is also possible that other site-specific
factors, such as minor differences in water quality, noise level, ventilation, extraneous odors,
or cage-changing frequency contribute to site-specific differences.
1Abbreviations that appear >3 × throughout this article: Chr, chromosome; CR, calorie restriction; QTL, quantitative trait locus
2Information is available at the ITP website
(www.nia.nih.gov/researchinformation/scientificresources/interventionstestingprogram.htm); this and other websites cited in this
article were accessed on December 22, 2010.

Yuan et al. Page 3
The ITP website provides the list of compounds in testing. So far, one of the major findings
of the study is that rapamycin, an inhibitor of mTOR (mammalian target of rapamycin)
signaling, significantly increased lifespan in both males and females even though treatment
did not start until mice were 600 days old (Harrison et al. 2009). However, the rapamycin-
treated mice did not differ from control mice in the pattern of diseases as shown by
pathology. Two other compounds—NDGA (p = 0.0006) and aspirin (p = 0.01), as assessed
using the log rank test, which evaluates survivorship of the entire cohort—extended the
median lifespan in male mice but not maximum lifespan as shown by comparisons of the
proportion of mice alive at the age of 90% mortality (Strong et al. 2008). This suggests that
the drugs may delay the onset or reduce the severity of specific diseases but that they do not
affect the rate of aging.
Calorie Restriction
One of the interventions most reliably associated with an extension of lifespan and a reduced
rate of aging is calorie restriction (CR1), the reduction of food intake without malnutrition.
CR has been shown to extend the lifespan of yeast, flies, worms, fish, rodents, and rhesus
monkeys (Fontana et al. 2010) and, in mammals, decrease the risk of age-related diseases
such as diabetes, cardiovascular diseases, and cancers (Fontana and Klein 2007;Morley et al.
2010).
Mouse models have been used extensively to investigate the underlying mechanisms of the
antiaging effects of CR. One of the most interesting recent studies was an investigation of
the effects of CR in different genetic backgrounds. A set of 42 recombinant inbred strains of
mice, generated by crossing strains ILS and ISS, was examined for lifespan under ad libitum
(AL) or CR conditions (Liao et al. 2010; Rikke et al. 2010). Although CR significantly
extended female lifespan in nine strains, it significantly reduced lifespan in four other strains
and had no significant effect in 29 strains, suggesting that genetic background affects the
ability of CR to alter aging. This gene-environment interaction is not surprising, nor does the
finding that CR acts only in certain genetic backgrounds contradict the widespread
observation that CR usually extends lifespan in species with mixed genetic background. The
mean lifespan under CR showed no significant correlation to lifespan under AL, suggesting
that different genes modulate lifespan under each experimental condition. The study by
Rikke and colleagues (2010) also found that increased efficiency of food utilization
correlated with longer lifespan (R = 0.34, p = 0.026) as measured by the ability to maintain
body weight, hair growth, and tail growth during CR.
The Aging Phenome Project

The Aging Center at the Jackson Laboratory characterized the lifespan and aging-related
phenotypes of 32 inbred mouse strains, providing a baseline for further use of mouse models
to improve understanding of the genetic regulation of aging. The project included both
longitudinal and cross-sectional studies. The former not only assessed lifespan (using 96
mice per strain) but also carried out noninvasive clinical assessments of neuromuscular
function at 6, 12, 18, and 24 months (Wooley et al. 2009), kidney and heart function (Tsaih
et al. 2009; Xing et al. 2009), hematology, hormone levels, and immune system parameters
(Petkova et al. 2008). The cross-sectional study euthanized 30 mice of each strain at 6, 12,
and 20 months for body composition, bone density, necropsy, and pathology (Sundberg et
al. 2008) and for the collection of tissues to evaluate apoptosis, DNA repair, and
chromosome fragility. A reproductive study evaluated the age of sexual maturity in females
of the same 32 strains (Yuan et al. manuscript in preparation). In addition to individual
reports, all of these data are available in the Mouse Phenome Database (MPD;
http://phenome.jax.org), where the Aging Center submits all data after quality control, even

Yuan et al. Page 4
before publication. The MPD also provides statistical tools to enable the assessment of
correlations of lifespan with other parameters in this and other studies (Grubb et al. 2009).
Among the 32 strains, four were recently derived from the wild and represent the major
subspecies of laboratory mice: WSB/EiJ for Mus domesticus, PWD/PhJ for M. musculus,
CAST/EiJ for M. castaneus, and MOLF/RkJ for M. molossinus. The remaining 28 strains
were chosen for genetic diversity and common use. Median lifespan varied dramatically
among the inbred strains (Table 1); the shortest was that of AKR/J (251 and 288 days for
female and male, respectively), and the longest, female WSB/EiJ (964 days) and male
C57BL/6J (901 days). These results confirmed that genetics plays an important role in
determining longevity. Median lifespans for females and males were significantly correlated
with each other (R = 0.88; p < 0.001). Proportional hazard analysis showed that sex did not
significantly affect lifespan for most strains (Yuan et al. 2009).
Among the 32 inbred strains, circulating insulinlike growth factor (IGF)-1 levels
significantly (p < 0.05) correlated with body weight at 6, 12, and 18 months in both females
and males (data available in the MPD): lower levels were associated with lighter body
weight, which in turn was associated with extended longevity in a heterogeneous mouse
population (Miller et al. 2002c). Our analysis found that IGF-1 levels at 6 months negatively
correlated with median lifespan (R = −0.33, p = 0.01) (Yuan et al. 2009). After excluding
the six short-lived strains (median lifespan less than 600 days), which presumably died of a
particular strain-specific disease (e.g., leukemia in strain AKR), the negative correlation of
IGF-1 and lifespan among long-lived strains became stronger and more significant (R =
0.53, p < 0.01).
These results underscore the importance of genetic regulation of IGF-1 signaling in

regulating body weight and longevity, as has been suggested by studies in other models. For
example, in domesticated dogs a single nucleotide polymorphism (SNP) in Igf1 significantly
correlated with body weight (Sutter et al. 2007); in human populations, genetic
polymorphisms of IGF-1 receptor (IGF-1R) (Suh et al. 2008) and phosphatidylinositol 3-
kinase catalytic beta polypeptide (PIK3CB) (Bonafe et al. 2003) associated with human
longevity. The variation in circulating IGF-1 levels among inbred strains of mice and the
correlation of these levels with longevity suggest that they may be a useful focus in research
on the genetic regulation of longevity.
Genes Implicated in Aging

Single-gene mutations that affect lifespan provide valuable tools for exploring the molecular
basis for aging mechanisms. A number of mutations, either spontaneous or genetically
engineered, that affect lifespan in the mouse are known; these are summarized in Table 2
and their location on the genome shown in Figure 1. The first of these mutants were
spontaneous dwarf mice (e.g., the Ames dwarf, the Snell dwarf) and the “little” mouse,
which have defects in the growth hormone (GH)/IGF/insulin signaling pathway (Brown-
Borg et al. 1996;Flurkey et al. 2001,2002). The little mouse has a defect in the gene Ghrhr
(growth hormone–releasing hormone receptor), and the Ames and Snell dwarf rats in the
genes Prop1 (paired-like homeodomain transcription factor 1) and Pou1f1 (POU domain,
class 1, transcription factor 1), respectively. These three mutations result in abnormal
development of the anterior pituitary gland and corresponding deficiency of pituitary
hormones such as growth hormone, thyroid-stimulating hormone, and prolactin. These
dwarf mutants all have extended lifespan compared to controls.
Mutations in several other genes (Ghr, Igf1r, Insr, Irs1, Irs2 and Pappa) reduce GH/IGF/
insulin signaling and extend lifespan. Cardiac-specific overexpression of IGF-1 significantly
prolongs lifespan, probably due to the protective effects of IGF-1 on cardiac failure.

Yuan et al. Page 5
Mutations such as knockouts of Shc1, Surf1, Adcy5, and Coq7, as well as transgenes of Mcat
and Mt, which increase resistance to stress, also successfully extend longevity. Knock-in/
transgenic models that increase the expression of Pparg, Cebpb, Pck1, and Ucp2 have
shown increased lifespan by regulating metabolism and energy expenditure (Table 2).
Mutations that extend lifespan are likely to affect the rate of aging, while those that reduce
lifespan either alter aging or increase the risk or severity of a particular disease. According
to Mouse Genome Informatics (www.informatics.jax.org), 301 mutations decrease survival
(by causing or promoting susceptibility to disease) and 46 promote features of premature
aging. In Table 3 we list genes whose mutations decrease longevity and appear to alter
aging. The roles of these genes, similar to the mutations that extend longevity, suggest that
maintaining DNA stability and antioxidative stress are important molecular mechanisms that
regulate aging and longevity. For example, a knockout of Bub1b induces chromosome
(Chr1) instability, reduced expression of PolgA increases mutations in mitochondrial DNA,
and knockouts of Msra and Prdx1 increase oxidative stress.
Aging studies in mutant gene models also provide clues for understanding the molecular
mechanisms that extend lifespan by CR. For example, mice heterozygous for a Foxo1
(forkhead box O1) knockout did not differ significantly in lifespan compared to wild-type
controls under AL or CR conditions. However, Foxo1 may play a role in CR’s
antineoplastic effect, which, as indicated by reduced incidence of tumors at death in the diet-
restricted wild-type mice, was mostly abrogated in the heterozygous knockout mice
(Yamaza et al. 2010). The noticeable increase of MIF (macrophage migration inhibitory
factor) in CR mice suggests that it may be important for CR-related lifespan extension, but
the significantly extended longevity in Mif knockout mice challenges this hypothesis
(Harper et al. 2010). Interestingly, deletion of S6k1 not only extended longevity but also
induced gene expression patterns similar to those seen in CR or with pharmacological
activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a
conserved regulator of the metabolic response to CR (Selman et al. 2009). This suggests that
therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad
protection against diseases of aging.
One problem with a lifespan extension study is that altering the risk of a disease may change
the mean or median lifespan but not reduce the rate of aging. One method to distinguish
between these outcomes is to calculate the age-specific mortality rate (de Magalhaes et al.
2005). For example, CR changes age-specific mortality and delays aging, as do mutations of
Cebpb, Msra, Shc1, Ghr, Pou1f1, and Polg, but studies in other mutants were either
insufficiently powered for such calculations or changed disease risk without changing the
rate of aging.
Lifespan Studies
QTLs in Mice
Examining spontaneous or genetically engineered mutants to determine a gene’s effect on
lifespan is one way to unravel the genetic basis of aging. Another approach, which is
unbiased and does not start with a defined hypothesis, is to conduct a quantitative trait locus
study to determine the genomic locations of genes that affect lifespan. Although all the QTL
studies performed so far on aging in the mouse were underpowered—in the number of
animals or markers genotyped or both—we think these QTLs are worthy of further
investigation, especially if they have been replicated in another mouse cross or if a human
genomewide association study has identified a peak at a homologous location. Thus, we list
all the suggestive and significant QTLs in Table 4 and depict them on the mouse genome in
Figure 1.

Yuan et al. Page 6
The earliest study was a (C57BL/6J × DBA/2) × C57BL/6 backcross using only four
markers: two coat color genes on Chrs 4 and 9, the H2 antigen on Chr 17, and sex (Yunis et
al. 1984). Subsequent studies tested 20 of the BXD (C57BL/6J × DBA/2J) recombinant
inbred (RI) lines for lifespan (de Haan et al. 1998; Gelman et al. 1988), using, as markers,
101 genes that are distinguishable between B6 and D2, but these markers were not evenly
distributed and only 14 chromosomes were covered. The QTL on Chr 17 identified in these
two studies contains the major histocompatibility complex region, and thus may be related
to the infection that occurred in the colony before the end of the study. A recent study of
longevity using BXD RI strains, a more sophisticated lifespan analysis, and 671 markers
failed to replicate the Chr 17 QTL (Lang et al. 2010). No infection occurred in the colony
during this second study, which is, to date, the QTL lifespan study with the greatest
statistical power (Lang et al. 2010) and will prove to be very useful, as considerable
infrastructure resources (e.g., genotyping, sequence, and expression data) are available for
these RI lines at GeneNetwork (www.genenetwork.org) and will enable the application of
bioinformatics and system genetics approaches to the study of aging.
Both the backcross and RI QTL designs carry homozygous alleles that may cause
deleterious effects on lifespan without affecting aging. To minimize such effects, researchers
conducted three different QTL studies using a four-way cross population. The first, using a
(BALB/cJ × C57BL/6) × (C3H/HeJ × DBA/2J) cross, showed that different loci were
involved in regulating the lifespans of female and male mice (Jackson et al. 2002). In a post
hoc study of the same population, Miller and colleagues (1998, 2002a) found that the
genotype associated with increased survival in mice dying of cancer also correlated with a
similar degree of lifespan extension in mice dying of other causes, suggesting that many
forms of late-life disease may be influenced by shared pathophysiologic mechanisms that
are under coordinated genetic control.
Miller and colleagues (2002b) suggested that wild mice or inbred strains recently derived
from the wild may carry alleles that delay sexual maturation and aging and that are missing
in domesticated inbred strains. Thus, two additional four-way cross QTL studies each
included one wild-derived inbred strain, MOLD or CAST (LP/J × MOLD/Rk) × (NZW/LacJ
× BALB/cJ) and (ST/bJ × C57BL/6J) × (CAST/EiJ × DBA/2J) (Klebanov et al. 2001).
These crosses revealed the alleles of wild-derived inbred strains that confer extended
longevity on Chr 8 and Chr 10 (Klebanov et al. 2001).
Although we have included all the suggestive and significant QTLs for lifespan in Figure 1
and Table 4, we have more confidence that replicated QTLs are true positives. Eight of these
QTLs—Chr 1, Chr 2, Chr 7 (proximal and mid-), Chr 8, Chr 10 distal, Chr 11 proximal, and
Chr 19—have been replicated in another mouse cross (Table 4). We have counted as
replicated those whose QTL peaks are within 10 Mb of each other, but further investigation
may reveal that some of these are independent QTLs.
Concordance of Human and Mouse Lifespan Peaks

A recent genomewide association study of longevity, a meta-analysis of four separate
studies by the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)
consortium, compared 1900 human subjects that lived to age 90 with an equal number of
controls that died earlier (Newman et al. 2010). Although none of the peaks reached
statistical significance, we have included the 10 highest peaks on the mouse map (arrows in
Figure 1). Remarkably, eight of the 10 are located in a mouse QTL; the probability that this
is due to chance is very low (p = 0.0025 using Fisher’s exact test, based on lifespan QTLs
covering 860 Mb of the 2700 Mb genome and each human peak being 1 Mb in size). Five of
these human peaks (Chrs 1, 9, 10, 11, 16) are located within 10 Mb of a mouse QTL peak.
Concordance of human and mouse QTLs has been reported previously (Garrett et al. 2010;

Yuan et al. Page 7
Sugiyama et al. 2001; Wang and Paigen 2005), but for traits such as plasma lipids,
hypertension, and kidney disease. Lifespan as a trait would be highly influenced by chance
and by environmental factors, so one might think that concordance would be reduced or
perhaps even nonexistent. Yet Figure 1 clearly shows concordance between humans and
mice for lifespan, suggesting that the data for both species can be integrated and that the
bioinformatic and genetic resources of the mouse can be used to narrow the QTL and test
candidate genes.
Future Directions
Mouse models are valuable for studies of the genetics of human aging not only because of
the availability of extensive mouse resources but also because of the similarity of the mouse
and human genomes. As genes are identified in humans, mouse models will continue to be
very useful in efforts to investigate underlying mechanisms of the genes that affect aging.
We expect to see growing numbers of translational studies demonstrating the relevance of
the mouse to human aging. This rise, combined with increasingly refined bioinformatic tools
and mouse models, will accelerate the identification of genes that delay human aging and
extend healthful lifespan.
Acknowledgments
The authors thank Drs. Kevin Flurkey and James Nelson for their constructive comments on the manuscript, Jesse
Hammer for preparation of the figure, and Joanne Currer for editing of the manuscript. This work was supported by
grants from the Glenn Foundation (BP), the Ellison Medical Foundation (BP), and the Nathan Shock Center (grant
AG038070; LLP).
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Figure 1.
Quantitative trait loci (QTLs) for mouse longevity and genomewide association (GWA)
peaks for human longevity, both depicted on the mouse genome (mapped in Mb). The length
of the colored bars represents the 95% confidence interval if reported or an estimated 40 Mb
if not reported; the black bars across the colored bars represent QTL peaks. We determined
the Mb position using a recently revised mouse map (Cox et al. 2009) and the Mouse Map
Converter from the Center for Genome Dynamics (http://cgd.jax.org/mousemapconverter/).
Arrows on the left of chromosomes represent human GWA peaks at the homologous mouse
genome locations. Chr, chromosome, Mb, megabase (millions of base pairs).

NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Table 1
Lifespan characteristics of 32 inbred mouse strainsa
Strain Female Male

Yuan et al.
Age (in days) of… 20% longest- Age (in days) of… 20% longest-
lived (mean ± lived (mean ±
SEM) SEM)b
25% 50% 75% 25% 50% 75%
death death death death death death
AKR/J 224 254 308 395 ± 24 244 288 336 415 ± 18

PL/J 373 471 596 736 ± 17 365 469 558 674 ± 19
SJL/J 393 515 632 740 ± 30 330 505 555 632 ± 21
MRL/MpJ 455 555 626 681 ± 9 549 645 669 711 ± 10
NZO/H1LtJ 418 575 700 782 ± 18 286 423 637 762 ± 26
CAST/EiJ 219 589 754 n.a. 239 591 754 n.a.
KK/H1J 564 608 653 720 ± 13 545 616 700 826 ± 43
BTBR T+tf/J 550 611 668 743 ± 19 444 575 728 822 ± 20
BUB/BnJ 392 621 755 876 ± 23 354 493 873 906 ± 23
SWR/J 499 630 814 n.a. 411 726 904 1020 ± 29
CBA/J 476 637 786 855 ± 11 532 679 808 872 ± 10
A/J 505 639 739 806 ± 19 541 623 708 785 ± 18
P/J 546 660 791 n.a. 439 607 673 n.a.
NOD.B10-H2b 599 667 770 827 ± 13 501 696 878 954 ± 11
C3H/HeJ 532 683 797 833 ± 7 623 728 834 894 ± 15

DBA/2J 443 687 823 872 ± 7 410 701 759 825 ± 17
MOLF/EiJ 590 705 n.a.c n.a. 503 686 730 n.a.
C57L/J 700 721 749 800 ± 5 658 736 768 806 ± 9

NZW/LacJ 600 732 866 950 ± 16 607 792 1013 1126 ± 14
SM/J 650 733 817 902 ± 15 730 783 833 873 ± 6
FVB/NJ 518 760 952 1023 ± 13 553 591 708 879 ± 56
129S1/SvImJ 651 791 920 1012 ± 25 798 882 992 1044 ± 12
BALB/cByJ 700 795 877 936 ± 10 512 714 840 927 ± 13
NON/ShiLtJ 631 806 861 887 ± 5 793 847 919 958 ± 11
RIIIS/J 691 813 883 938 ± 5 779 886 940 970 ± 12
Page 13
Strain Female Male
Age (in days) of… 20% longest- Age (in days) of… 20% longest-
lived (mean ± lived (mean ±
SEM) SEM)b
25% 50% 75% 25% 50% 75%
Yuan et al.
death death death death death death
LP/J 715 833 966 1047 ± 17 721 822 862 984 ± 28

PWD/PhJ 600 839 929 993 ± 12 575 813 905 956 ± 12
C57BR/CDJ 757 861 917 973 ± 7 737 849 943 993 ± 21
C57BLKS/J 672 867 926 989 ± 12 770 826 932 983 ± 21
WSB/EiJ 629 886 1148 n.a. 470 1005 1110 1213 ± 19
C57BL/10J 692 889 1035 1135 ± 9 677 792 852 893 ± 13
C57BL/6J 782 914 1006 1075 ± 13 838 901 971 1061 ± 17
n.a., not available; SEM, standard error of the mean

a
Lifespan traits reported by Yuan and colleagues (2009) and updated in August 2009. Age of 25%, 50%, and 75% at death and mean lifespan of the 20% longest-lived mice were calculated using JMP 6.0.4
software.
b
Mean lifespan of the 20% longest-lived mice is not available for strains for which mice are still alive.
c
Age at death of 75% MOLF/EiJ was not available because there were too few mice to evaluate.

Page 14
Table 2
Mutations in mouse genes that increase longevity
Gene information Type of Target gene

Yuan et al.
mutation expression
Symbola Full name Chr Mb Effect on lifespan (sex) Reference
Adcy5 Adenylate cyclase 5 16 35 Knockout Reduces Increases (pooled) Yan et al. 2007
Cebpb CCAAT/enhancer binding protein (C/EBP), beta 2 168 Knock-in Increases Increases (female, male) Chiu et al. 2004
Coq7 Demethyl-Q 7 5 126 Knockout Reduces Increases (female, male) Liu et al. 2005
Ghr Growth hormone receptor 15 3 Knockout Reduces Increases (female, male) Coschigano et al. 2003
Ghrhr Growth hormone–releasing hormone receptor 6 55 Spontaneous Reduces Increases (pooled) Flurkey et al. 2001
Igf1b Insulin-like growth factor 1 10 88 Transgene Increases Increases (male) Li and Ren 2007
Igf1r Insulin-like growth factor I receptor 7 75 Knockout Reduces Increases (female) Holzenberger et al. 2003
Insr Insulin receptor 8 3 Knockout Reduces Increases (female, male) Bluher et al. 2003
Irs1 Insulin receptor substrate 1 1 82 Knockout Reduces Increases (female) Selman et al. 2008a
Irs2c Insulin receptor substrate 2 8 11 Knockout Reduces Increases (pooled) Taguchi et al. 2007
Kld Klotho 5 152 Transgene Increases Increases (female, male) Kurosu et al. 2005
Mcatb Malonyl CoA:ACP acyltransferase (mitochondrial) 15 83 Transgene Increases Increases (female, male) Schriner et al. 2005
Mtb Metallothionein 8 97 Transgene Increases Increases (male) Yang et al. 2006
Pappa Pregnancy-associated plasma protein A 4 65 Knockout Reduces Increases (female, male) Conover and Bale 2007
Pck1 Phosphoenolpyruvate carboxykinase 1, cytosolic 2 103 Transgene Increases Increases (female, male) Hakimi et al. 2007
Pou1f1 POU domain, class 1, transcription factor 1 16 66 Spontaneous Reduces Increases (female, male) Flurkey et al. 2002

Pparg Peroxisome proliferator–activated receptor gamma 6 115 Knock-in Increases Increases (male) Heikkinen et al. 2009
Prop1 Paired-like homeodomain transcription factor 1 11 51 Spontaneous Reduces Increases (female, male) Brown-Borg et al. 1996
Rps6kb1 Ribosomal protein S6 kinase, polypeptide 1 11 86 Knockout Reduces Increases (female) Selman et al. 2009
Shc1 Src homology 2 domain–containing transforming protein C1 3 89 Knockout Reduces Increases (not specified) Migliaccio et al. 1999
Surf1 Surfeit gene 1 2 27 Knockout Reduces Increases (female, male) Dell’agnello et al. 2007
Ucp2e Uncoupling protein 2 7 108 Transgene Increases Increases (female, male) Conti et al. 2006
Mif Macrophage migration inhibitory factor 10 75 Knockout Reduces Increases (female) Harper et al. 2010
Chr, chromosome; Mb, megabase (millions of base pairs)

a
Gene names and symbols are according to the Mouse Genome Informatics database (www.informatic.jax.org).
Page 15
b
Models were generated by transferring the human gene.
c
Irs2 knockout heterozygotes showed an extended lifespan in Taguchi’s study (Taguchi and White 2008) but failed to extend lifespan in a study by Selman and colleagues (2008a). The authors of the two
studies discuss possible reasons for the different results: differences in the lifespan of controls, number of times the knockout was backcrossed to C56BL/6, diet, and housing conditions.
d
Kurosu’s model is a transgenic model that overexpresses Klotho.
e
Yuan et al.
The transgenic model overexpresses Ucp2 in hypocertin neurons, which causes elevated temperature in the thermostat center and results in a lowering of core body temperature.

Page 16
Table 3
Mutations in mouse genes that reduce longevity
Gene information Type of Target gene Effect on

Yuan et al.
mutation expression lifespan (sex)
Symbola Full name Chr Mb Reference
Bub1b Budding uninhibited by benzimidazoles 1 homolog, beta 2 118 Knockout Reduces Reduces (female, male) Baker et al. 2004
Kl Klotho 5 152 Transgeneb Reduces Reduces (female, male) Kuro-o et al. 1997
Lmna Lamin A 3 88 Knock-in n.a.c Reduces (not specified) Mounkes et al. 2003
Msra Methionine sulfoxide reductase A 14 65 Knockout Reduces Reduces (female, male) Moskovitz et al. 2001
PolgA Polymerase (DNA directed), gamma 7 87 Knock-in Reduces Reduces (pooled) Trifunovic et al. 2004
Prdx1 Peroxiredoxin 1 4 116 Knockout Reduces Reduces (not specified) Neumann et al. 2003
Top3b Topoisomerase (DNA) III beta 16 17 Knockout Reduces Reduces (not specified) Kwan and Wang 2001
Chr, chromosome; Mb, megabase (millions of base pairs); n.a, not available
a
Gene names and symbols are according to Mouse Genome Informatics database (www.informatic.jax.org).
b
he transgene causes an insertional mutation in the Klotho gene that suppresses its expression.
c
his knock-in model introduces a nucleotide polymorphism that results in the substitution of proline for leucine at amino acid 530 in the Lmna gene.

Page 17
Table 4
Significant and suggestive lifespan quantitative trait loci (QTLs) detected in the mouse
Peak High allele strain Replicated Replicated

Yuan et al.
Chra (Mb) Cross (sex) Reference in mice in humans
1 34 B6 × D2 RI strains D2 (male) Lang et al. 2010

120 B6 × D2 RI strains D2 (female) Gelman et al. 1988 X
128 B6 × D2 RI strains D2 (female) Lang et al. 2010 X
163 B6 × D2 RI strains B6 (female) Gelman et al. 1988 X
2 65 B6 × D2 RI strains B6 (female) Lang et al. 2010
108 (BALB/cJ × B6) × (C3H × D2) C3H (female) Jackson et al. 2002; Miller et al. 2002a X
121 B6 × D2 RI strains D2 (female) Gelman et al. 1988
4 80 (B6 × D2) × D2 B6 (female) Yunis et al. 1984
5 80 B6 × D2 RI strains D2 (female) Lang et al. 2010
6b 77 B6 × D2 RI strains D2 (male) Lang et al. 2010
98 B6 × D2 RI strains D2 (male) Lang et al. 2010

113 B6 × D2 RI strains D2 (male) Lang et al. 2010
3 B6 × D2 RI strains B6 (female) Lang et al. 2010 X
66 (BALB/cJ × B6) × (C3H × D2) BALB (male) Miller et al. 1998 X X
73 B6 × D2 RI strains B6 (female) Lang et al. 2010 X X
92 B6 × D2 RI strains B6 (female and male) Lang et al. 2010

111 (BALB/cJ × B6) × (C3H × D2) BALB (male) Miller et al. 1998
8 15 B6 × D2 RI strains B6 (female) Lang et al. 2010 X X
26 (LP × MOLD) × (NZW × BALB) MOLD (pooled) Klebanov et al. 2001 X X
111 B6 × D2 RI strains B6 (female) Lang et al. 2010
9 91 (BALB/cJ × B6) × (C3H × D2) C3H (male) Jackson et al. 2002; Miller et al. 2002a X
10 48 (BALB/cJ × B6) × (C3H × D2) D2 (male) Miller et al. 1998 X
66 (BALB/cJ × B6) × (C3H × D2) D2 (male) Jackson et al. 2002; Miller et al. 2002a
109 B6 × D2 RI strains D2 (male) Lang et al. 2010 X
119 (ST × B6) × (CAST × D2) CAST (pooled) Klebanov et al. 2001 X
11a 15 B6 × D2 RI strains B6 (female) de Haan et al. 1998 X

Page 18
Peak High allele strain Replicated Replicated

Chra (Mb) Cross (sex) Reference in mice in humans
18 B6 × D2 RI strains B6 (male) Lang et al. 2010 X

Yuan et al.

12 60 D2 (female) Gelman et al. 1988
105 (BALB/cJ × B6) × (C3H × D2) B6/C3H (female and male) Jackson et al. 2002; Miller et al. 2002a
16 6 (BALB/cJ × B6) × (C3H × D2) BALB (female) Jackson et al. 2002; Miller et al. 1998, 2002a
17 34 (B6 × D2) × D2 B6 (male) Yunis et al. 1984
18 53 (BALB/cJ × B6) × (C3H × D2) D2 (male) Miller et al. 1998
19 30 (BALB/cJ × B6) × (C3H × D2) BALB (female) Miller et al. 1998 X
32 ILS × ISS ILS (female) Rikke et al. 2010 X
47 (BALB/cJ × B6) × (C3H × D2) D2 (male) Miller et al. 1998
X 49 B6 × D2 RI strains D2 (female) Lang et al. 2010
126 B6 × D2 RI strains D2 (female) Lang et al. 2010
Chr, chromosome; RI, recombinant inbred
Each suggestive and significant QTL is listed with the chromosomal peak in Mb (derived from the corrected mouse map [Cox et al. 2009] and the Mouse Map Converter from the Center for Genome
Dynamics [http://cgd.jax.org/mousemapconverter/]), the cross in which the QTL was found, the allele conferring longer lifespan, and the reference. The QTL near the bottom of Chr 7 was originally
reported with D12Mit38 as peak marker (Miller et al. 1998), but this particular marker was incorrectly mapped; it properly belongs on Chr 7 at Mb 111 and is now called D7Mit1000.
a
Chromosomes 3 and 13–15 are missing because no QTLs affecting lifespan have been reported on them.

b
Although Lang and colleagues (2010) reported QTLs for males and females separately, we combined the two examples for which QTLs were found in both sexes at the same spot (Chr 6 at 96 Mb and Chr
11 at 18 Mb).
Page 19

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ILAR J. 2011 February 8; 52(1): 4–15.

Mice as a Mammalian Model for Research on the Genetics of

Rong Yuan, Ph.D., M.D.,

Interventions Testing Program of the National Institute on Aging

ILAR J. Author manuscript; available in PMC 2011 May 8.

The Aging Phenome Project

ILAR J. Author manuscript; available in PMC 2011 May 8.

These results underscore the importance of genetic regulation of IGF-1 signaling in

Genes Implicated in Aging

ILAR J. Author manuscript; available in PMC 2011 May 8.

ILAR J. Author manuscript; available in PMC 2011 May 8.

Concordance of Human and Mouse Lifespan Peaks

ILAR J. Author manuscript; available in PMC 2011 May 8.

ILAR J. Author manuscript; available in PMC 2011 May 8.

ILAR J. Author manuscript; available in PMC 2011 May 8.

Genes Dev. 2005; 19:2424–2434. [PubMed: 16195414]

ILAR J. Author manuscript; available in PMC 2011 May 8.

ILAR J. Author manuscript; available in PMC 2011 May 8.

homeostasis. Science. 2007; 317:369–372. [PubMed: 17641201]

ILAR J. Author manuscript; available in PMC 2011 May 8.

ILAR J. Author manuscript; available in PMC 2011 May 8.

Lifespan characteristics of 32 inbred mouse strainsa

Strain Female Male

AKR/J 224 254 308 395 ± 24 244 288 336 415 ± 18

ILAR J. Author manuscript; available in PMC 2011 May 8.

C57L/J 700 721 749 800 ± 5 658 736 768 806 ± 9

Strain Female Male

death death death death death death

LP/J 715 833 966 1047 ± 17 721 822 862 984 ± 28

n.a., not available; SEM, standard error of the mean

ILAR J. Author manuscript; available in PMC 2011 May 8.

Gene information Type of Target gene

Symbola Full name Chr Mb Effect on lifespan (sex) Reference

Mtb Metallothionein 8 97 Transgene Increases Increases (male) Yang et al. 2006

ILAR J. Author manuscript; available in PMC 2011 May 8.

Chr, chromosome; Mb, megabase (millions of base pairs)

ILAR J. Author manuscript; available in PMC 2011 May 8.

Gene information Type of Target gene Effect on

mutation expression lifespan (sex)

Symbola Full name Chr Mb Reference

ILAR J. Author manuscript; available in PMC 2011 May 8.

Peak High allele strain Replicated Replicated

Chra (Mb) Cross (sex) Reference in mice in humans

1 34 B6 × D2 RI strains D2 (male) Lang et al. 2010

6b 77 B6 × D2 RI strains D2 (male) Lang et al. 2010

98 B6 × D2 RI strains D2 (male) Lang et al. 2010

ILAR J. Author manuscript; available in PMC 2011 May 8.

11a 15 B6 × D2 RI strains B6 (female) de Haan et al. 1998 X

Peak High allele strain Replicated Replicated

18 B6 × D2 RI strains B6 (male) Lang et al. 2010 X

56 B6 × D2 RI strains B6 (male) Lang et al. 2010 X

Chr, chromosome; RI, recombinant inbred

ILAR J. Author manuscript; available in PMC 2011 May 8.

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