Mice as a Mammalian Model for Research on the Genetics of Aging

Rong Yuan, Luanne L. Peters, and Beverly Paigen

Abstract

Key Words: aging; calorie restriction (CR); gene mutation;

genetics; lifespan; longevity; mouse genome; quantitative
trait locus (QTL)

Introduction

uch 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

Rong Yuan, PhD, MD, is a research scientist and Animal Core Leader;
Luanne L. Peters, PhD, is a professor and Director; and Beverly Paigen,
PhD, is a professor and member of the Leadership Team, all at the Jackson
Aging Center of the Jackson Laboratory in Bar Harbor, Maine.
Address correspondence and reprint requests to Dr. Beverly Paigen, The
Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609 or email bev.
paigen@jax.org.

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

1Abbreviations used in 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.

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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.

sophisticated genetic engineering technology are available

for manipulating its genome (Paigen 1995). The many genetic resources of the mouse have been 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.

Table 1 Lifespan characteristics of 32 inbred mouse strainsa

Female

Male

Age (in days) of

Age (in days) of

Strain

25%
death

50%
death

75%
death

20% longestlived (mean

SEM)

AKR/J

224

254

308

395 24

25%
death

50%
death

75%
death

20% longestlived (mean

SEM)b

244

288

336

415 18

373

471

596

736 17

365

469

558

674 19

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

705

n.a.c

n.a.

503

686

730

n.a.

MOLF/EiJ

590

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

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

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PL/J
SJL/J

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

aLifespan 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.
bMean lifespan of the 20% longest-lived mice is not available for strains for which mice are still alive.
cAge at death of 75% MOLF/EiJ was not available because there were too few mice to evaluate.

Volume 52, Number 1

2011

ILAR Journal

Full name

Adenylate cyclase 5

CCAAT/enhancer binding
protein (C/EBP), beta

Demethyl-Q 7

Growth hormone receptor

Growth hormonereleasing
hormone receptor

Insulin-like growth factor 1

Insulin-like growth factor I receptor

Insulin receptor

Insulin receptor substrate 1

Insulin receptor substrate 2

Klotho

Malonyl CoA:ACP acyltransferase

(mitochondrial)

Metallothionein

Pregnancy-associated plasma
protein A

Phosphoenolpyruvate
carboxykinase 1, cytosolic

POU domain, class 1, transcription

factor 1

Peroxisome proliferatoractivated
receptor gamma

Paired-like homeodomain
transcription factor 1

Ribosomal protein S6 kinase,

polypeptide 1

Src homology 2 domaincontaining

transforming protein C1

Surfeit gene 1

Symbola

Adcy5

Cebpb

Coq7

Ghr

Ghrhr

Igf1b

Igf1r

Insr

Irs1

Irs2c

Kld

Mcatb

Mtb

Pappa

Pck1

Pou1f1

Pparg

Prop1

Rps6kb1

Shc1

Surf1

Gene information

11

11

16

15

10

15

16

Chr

27

89

86

51

115

66

103

65

97

83

152

11

82

75

88

55

126

168

35

Mb

Table 2 Mutations in mouse genes that increase longevity

Knockout

Knockout

Knockout

Spontaneous

Knock-in

Spontaneous

Transgene

Knockout

Transgene

Transgene

Transgene

Knockout

Knockout

Knockout

Knockout

Transgene

Spontaneous

Knockout

Knockout

Knock-in

Knockout

Type of
mutation

Reduces

Reduces

Reduces

Reduces

Increases

Reduces

Increases

Reduces

Increases

Increases

Increases

Reduces

Reduces

Reduces

Reduces

Increases

Reduces

Reduces

Reduces

Increases

Reduces

Target gene
expression

Increases (female, male)

Increases (not specified)

Increases (female)

Increases (female, male)

Increases (male)

Increases (female, male)

Increases (female, male)

Increases (female, male)

Increases (male)

Increases (female, male)

Increases (female, male)

Increases (pooled)

Increases (female)

Increases (female, male)

Increases (female)

Increases (male)

Increases (pooled)

Increases (female, male)

Increases (female, male)

Increases (female, male)

Increases (pooled)

Effect on lifespan (sex)

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Dellagnello et al. 2007

Migliaccio et al. 1999

Selman et al. 2009

Brown-Borg et al. 1996

Heikkinen et al. 2009

Flurkey et al. 2002

Hakimi et al. 2007

Conover and Bale 2007

Yang et al. 2006

Schriner et al. 2005

Kurosu et al. 2005

Taguchi et al. 2007

Selman et al. 2008a

Bluher et al. 2003

Holzenberger et al. 2003

Li and Ren 2007

Flurkey et al. 2001

Coschigano et al. 2003

Liu et al. 2005

Chiu et al. 2004

Yan et al. 2007

Reference

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

aGene names and symbols are according to the Mouse Genome Informatics database (www.informatics.jax.org).
bModels were generated by transferring the human gene.
cIrs2 knockout heterozygotes showed an extended lifespan in Taguchis 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.
dKurosus model is a transgenic model that overexpresses Klotho.
eThe transgenic model overexpresses Ucp2 in hypocertin neurons, which causes elevated temperature in the thermostat center and results in a lowering of core body temperature.

Harper et al. 2010

Conti et al. 2006

Increases (female, male)

Increases (female)
Reduces

Increases
Transgene

Knockout
Macrophage migration inhibitory
factor
Mif

108
7

10

Uncoupling protein 2
Ucp2e

75

Reference
Effect on lifespan (sex)
Target gene
expression
Type of
mutation
Mb
Chr
Symbola

Gene information

Table 2 (continued)

Full name

2011

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.
7

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Volume 52, Number 1

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 (4.56.5%), 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 cagechanging frequency contribute to site-specific differences.
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 compoundsNDGA (p = 0.0006) and aspirin
(p = 0.01), as assessed using the log rank test, which evaluates survivorship of the entire cohortextended 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.

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 crosssectional 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
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
8

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 strainspecific 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 hormonereleasing hormone receptor), and the Ames and Snell
dwarf mice 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
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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.

2011

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).

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Volume 52, Number 1

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 CRs 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 agespecific mortality and delays aging, as do mutations of Cebpb,

Table 3 Mutations in mouse genes that reduce longevity

Gene information
Symbola Full name

Chr

Mb

Type of
mutation

Target gene
expression

Effect on
lifespan (sex)

Reference

Bub1b

Budding uninhibited by
benzimidazoles 1
homolog, beta

118

Knockout

Reduces

Reduces
(female, male)

Baker et al. 2004

Kl

Klotho

152

Transgeneb

Reduces

Reduces
(female, male)

Kuro-o et al. 1997

Lmna

Lamin A

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

87

Knock-in

Reduces

Reduces (pooled)

Trifunovic et al. 2004

Prdx1

Peroxiredoxin 1

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
aGene names and symbols are according to Mouse Genome Informatics database (www.informatics.jax.org).
bThe transgene causes an insertional mutation in the Klotho gene that suppresses its expression.
cThis knock-in model introduces a nucleotide polymorphism that results in the substitution of proline for leucine at amino acid 530 in the Lmna gene.

10

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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. 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.

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

Volume 52, Number 1

2011

Concordance of Human and Mouse

Lifespan Peaks
A recent genomewide association study of longevity, a metaanalysis 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 Fishers 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; 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
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Examining spontaneous or genetically engineered mutants

to determine a genes 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 underpoweredin the number of animals or markers genotyped
or bothwe 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.
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 QTLsChr 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.

Table 4 Significant and suggestive lifespan quantitative trait loci (QTLs) detected in the mouse
Chra

Peak
(Mb)

Cross

High allele strain

(sex)

Reference

34

B6 D2 RI strains

D2 (male)

Lang et al. 2010

120

B6 D2 RI strains

D2 (female)

Gelman et al. 1988

128

B6 D2 RI strains

D2 (female)

Lang et al. 2010

163

B6 D2 RI strains

B6 (female)

Gelman et al. 1988

65

B6 D2 RI strains

B6 (female)

Lang et al. 2010

103

B6 D2 RI strains

B6 (female)

Gelman et al. 1988

108

(BALB/cJ B6)
(C3H D2)

C3H (female)

Jackson et al. 2002;

Miller et al. 2002a

Replicated
in mice

Replicated
in humans

B6 D2 RI strains

D2 (female)

Gelman et al. 1988

80

(B6 D2) D2

B6 (female)

Yunis et al. 1984

80

B6 D2 RI strains

D2 (female)

Lang et al. 2010

6b

77

B6 D2 RI strains

D2 (male)

Lang et al. 2010

96

B6 D2 RI strains

D2 (male and female)

Lang et al. 2010

113

B6 D2 RI strains

D2 (male)

Lang et al. 2010

B6 D2 RI strains

B6 (female)

Lang et al. 2010

11

B6 D2 RI strains

B6 (female)

Gelman et al. 1988

66

(BALB/cJ B6)
(C3H D2)

BALB (male)

Miller et al. 1998

73

B6 D2 RI strains

B6 (female)

Lang et al. 2010

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

15

B6 D2 RI strains

B6 (female)

Lang et al. 2010

26

(LP MOLD)
(NZW BALB)

MOLD (pooled)

Klebanov et al. 2001

111

B6 D2 RI strains

B6 (female)

Lang et al. 2010

91

(BALB/cJ B6)
(C3H D2)

C3H (male)

Jackson et al. 2002;

Miller et al. 2002a

10

48

(BALB/cJ B6)
(C3H D2)

D2 (male)

Miller et al. 1998

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

119

(ST B6)
(CAST D2)

CAST (pooled)

Klebanov et al. 2001

15

B6 D2 RI strains

B6 (female)

de Haan et al. 1998

18

B6 D2 RI strains

B6 (male and female)

Lang et al. 2010

35

B6 D2 RI strains

B6 (female)

Lang et al. 2010

56

B6 D2 RI strains

B6 (male)

Lang et al. 2010

60

B6 D2 RI strains

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

11a

12

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121
4

ILAR Journal

Table 4 (continued)

Chra

Peak
(Mb)

16

(BALB/cJ B6)
(C3H D2)

BALB (female)

Jackson et al. 2002;

Miller et al. 1998,
2002a

32

B6 D2 RI strains

B6 (male)

Lang et al. 2010

Cross

High allele strain

(sex)

Reference

Replicated
in mice

B6 D2 RI strains

B6 (female)

Lang et al. 2010

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

32

ILS ISS RI strains

ILS (female)

Rikke et al. 2010

47

(BALB/cJ B6)
(C3H D2)

D2 (male)

Miller et al. 1998

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.
aChromosomes 3 and 13-15 are missing because no QTLs affecting lifespan have been reported on them.
bAlthough 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).

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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