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3
3
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Department of Medicine, University of Wisconsin-Madison and Veterans Administration Hospital, Geriatric Research, Education and Clinical Center, Madison, WI 53705;
Wisconsin Regional Primate Research Center, University of Wisconsin, Madison, WI 53715;
**
Environmental Toxicology Center, University of Wisconsin, Madison, WI 53706 and
Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, WI 53706
3To whom correspondence should be addressed. E-mail: rhweindr{at}facstaff.wisc.edu or taprolla{at}facstaff.wisc.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONGene expression changes induced...Oligonucleotide microarrays as a...The gene expression profile...Implications for aging and...REFERENCES |
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KEY WORDS: • caloric restriction • aging • gene expression • oligonucleotide microarrays • muscle
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONGene expression changes induced...Oligonucleotide microarrays as a...The gene expression profile...Implications for aging and...REFERENCES |
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, Fishbein 1991
, Yu 1994
). This retardation of aging by CR is manifested by a
delayed occurrence or complete prevention of a broad spectrum of
age-associated pathophysiological changes and a 30–50% increase
in maximum life span. CR also lengthens the maximum life span of fish,
rotifers, spiders and other nonmammals (Weindruch and Walford 1988
).
Because no other intervention has been shown to retard the aging
process in mammals, an active research area in biological gerontology
concerns the mechanisms by which CR retards aging in laboratory
rodents. These are challenging studies because CR induces hundreds (if
not hundreds of thousands) of biological changes, making it difficult
to identify those that are causal. Five classes of interrelated and
nonexclusive explanations for the mechanism of CR are: 1)
decreases in oxidative stress (Sohal and Weindruch 1996
); 2) decreases in glycation or glycoxidation
(Kristal and Yu 1992
); 3) decreases in body
temperature and circulating thyroid hormone levels associated with a
hypometabolic state (Walford and Spindler 1997
);
4) alterations in gene expression and protein degradation
(Van Remmen et al. 1995
); and 5)
neuroendocrine changes (Nelson et al. 1995
).
This brief article discusses changes in gene expression induced by CR
in laboratory mice. We first discuss earlier work using Northern
hybridization and then summarize our recent study (Lee et al. 1999
) of mouse gastrocnemius muscle using oligonucleotide
microarrays. The latter approach provides a powerful tool to evaluate
nutritional interventions at the transcriptional level because it
produces a broad assessment of gene expression patterns.
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Gene expression changes induced by CR as measured by Northern hybridization |
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TOPABSTRACTINTRODUCTIONGene expression changes induced...Oligonucleotide microarrays as a...The gene expression profile...Implications for aging and...REFERENCES |
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. Most information is available for liver. Studies from Stephen
Spindler’s laboratory suggest that CR may lower enzyme capacity for
glycolysis and increase enzyme capacity for gluconeogenesis and
disposal of by-products of muscle protein catabolism. Also, the
mRNA levels of hepatic endoplasmic reticulum chaperones were reduced by
CR. Other studies show decreased expression of viral genes in
calorie-restricted mice. The mRNA levels for several antioxidant
enzymes, in most cases, were not influenced by CR. A striking feature
of this dataset is the scarcity of information in brain, heart and
other organs.
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Oligonucleotide microarrays as a tool to evaluate nutritional interventions |
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TOPABSTRACTINTRODUCTIONGene expression changes induced...Oligonucleotide microarrays as a...The gene expression profile...Implications for aging and...REFERENCES |
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). Large-scale analysis of
transcriptional responses has already proven to be useful in the
analysis of complex biological phenomena such as metabolism in
Saccharomyces cerevisiae (DeRisi et al. 1997
)
and tumorigenesis in humans (Perou et al. 1999
). Because
such arrays are synthesized based on sequence information, they provide
a direct link between differential gene expression patterns and
information readily available in public genomic databases.
DNA microarrays can be broadly divided into two classes, cDNA-based
and oligonucleotide-based arrays. cDNA-based arrays are simpler
to construct, and several devices are commercially available that spot
cDNAs onto glass slides (Brown and Botstein 1999
). These
slides can be used to quantify mRNA abundance after hybridization with
tissue-specific cDNA pools obtained through reverse transcription
of polyA mRNA. A disadvantage of this approach is that a large fraction
of mammalian genes are members of gene families, and family members can
easily cross-hybridize, causing spurious results. In contrast,
oligonucleotide arrays contain tens of thousands of gene-specific
oligonucleotides synthesized in situ using light-directed,
solid-phase combinatorial chemistry (Lipshutz et al. 1999
). This technology was introduced by Affymetrix (Santa
Clara, CA) whose arrays contain 40 specific oligonucleotide probes,
which are 25 base pairs long, for each gene represented in the array.
Twenty of these oligonucleotides represent perfect matches (PM probes)
to the gene of interest along its length. Another 20 oligonucleotides
contain a single mismatch (MM probes) compared with the PM probes. To
calculate an average signal intensity, hybridization intensity from
each MM probe is subtracted from that of its PM counterpart and the
values are averaged for the 20 pairs.
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The gene expression profile of aging and CR in mouse gastrocnemius muscle |
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TOPABSTRACTINTRODUCTIONGene expression changes induced...Oligonucleotide microarrays as a...The gene expression profile...Implications for aging and...REFERENCES |
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). Skeletal muscle was studied
because it is primarily composed of long-lived, high
oxygen-consuming postmitotic cells, a feature shared with other
critical aging targets such as heart and brain. Loss of muscle mass
(sarcopenia) and associated motor dysfunction is a leading cause of
frailty and disability in older persons (Dutta and Hadley 1995
). The gene expression profile of aging.
A comparison of gastrocnemius muscle from 5- and 30-mo-old male C57BL/6 mice revealed that aging is associated with alterations at the mRNA level, which may reflect changes in gene expression, mRNA stability or both. Of the 6347 genes surveyed in the oligonucleotide microarray, only 58 (0.9%) displayed a > twofold increase in gene expression levels as a function of aging, whereas 55 (0.9%) displayed a > twofold decrease in expression. Therefore, gene expression patterns seem to be remarkably stable during the adult mammalian life span, a finding that contrasts with the hypothesis that aging is due to large and widespread alterations in gene expression.
Based on a literature search, functional classes were assigned and
regulatory mechanisms inferred for specific sets of alterations. Of the
58 genes that increased > twofold in expression with age, 16%
(9/58) could be assigned to stress responses. Genes in this category
included the heat shock factors Hsp71 and Hsp27, protease Do and the
DNA damage-inducible gene GADD45. Interestingly, the largest
differential expression between young and aged animals (3.8-fold) was
the mitochondrial sarcomeric creatine kinase, a critical target for
peroxynitrite-induced inactivation (Stachowiak et al. 1998
). Peroxynitrite is a strong oxidant generated in
mitochondria through the reaction of superoxide with nitric oxide.
Possibly, the induction of mitochondrial sarcomeric creatine kinase is
a compensatory response to the increased production of reactive oxygen
species (ROS) in mitochondria of aged animals (Sohal and Weindruch 1996
). Taken as a whole, these observations provide
support at the transcriptional level for a state of increased ROS
production with aging, resulting in macromolecular damage.
A well-known consequence of both aging and muscle injury is
reinnervation of motor neuron units (Larsson 1995
).
Genes involved in neuronal growth accounted for 9% (5/58) of genes
highly induced in 30-mo-old animals, including neurotrophin-3
(Copray and Brouwer 1997
), a growth factor induced
during reinnervation, and synaptic vesicle protein-2, implicated in
neurite extension (Marazzi and Buckley 1993
). An
age-associated disturbance in calcium homeostasis, which may play a
major role in aging of the central nervous system, has been linked to
increased activity of voltage-activated calcium channels
(Disterhoft et al. 1994
). Interestingly, we observed an
increase in the expression of the dihydropyridine-sensitive
L-type calcium channel in muscle from 30-mo-old animals, a
finding that suggests altered calcium homeostasis in aged skeletal
muscle. An increased catabolic state in aged muscle is suggested by the
induction of the beta lysosomal protein-encoding gene. PEA3, a
transcriptional factor induced in the response to muscle injury and
previously shown to be highly expressed in muscle from old rats
(Peterson and Houle 1997
) was also induced in aged
muscle. We also observed interesting parallels between our results and
data obtained in fibroblasts undergoing in vitro replicative
senescence. For example, HIC-5, an oxidative damage-induced
transcriptional factor (Fujita et al. 1998
) and
insulin-like growth factor binding protein, both associated with in
vitro senescence (Wang et al. 1996
), are induced in aged
skeletal muscle.
Taken as a whole, these results provide evidence that the aging process is characterized by the activation of an adaptive stress response consistent with increased production of ROS in aging muscle. Additionally, gene expression patterns suggest that secondary responses involve the activation of neuronal and myogenic responses to injury.
Transcriptional evidence for an age-related decline in metabolic capacity, biosynthesis and protein metabolism.
Fifty-five of the 6347 genes assayed (0.9%) displayed a > twofold age-related decrease in expression. Genes involved
in energy metabolism accounted for 13% (7/55) of these alterations.
Several transcriptional alterations suggest a decrease in mitochondrial
function or turnover, including reduced expression of the ATP synthase
A chain and NADP transhydrogenase genes (both involved in mitochondrial
bioenergetics), the LON protease implicated in mitochondrial biogenesis
and the ERV1 gene involved in mtDNA maintenance. Presumably, this
transcriptional pattern reflects either decreased mitochondrial
biogenesis or turnover, secondary to cumulative ROS-inflicted
mitochondrial damage (Sohal and Sohal 1991
,
Beckman and Ames 1998
). These observations lend support
to the concept that mitochondrial dysfunction plays a central role in
aging of postmitotic tissues. Additionally, a metabolic deficit is
suggested by a decline in the expression of genes involved in
glycolysis, glycogen metabolism and the glycerophosphate shunt.
Aging was also characterized by large reductions (twofold or
more) in the expression of biosynthetic enzymes such as
cytochrome P450 IIC12 (steroid biosynthesis), squalene synthase (fatty
acid and cholesterol synthesis), stearoyl-CoA desaturase
(polyunsaturated fatty acid synthesis) and EF-1-gamma (protein
synthesis). This suppression in biosynthetic genes was accompanied by a
concerted decrease in the expression of genes involved in protein
turnover, such as the 20S proteasome subunit, the 26S proteasome
component TBP1, ubiquitin-thiolesterase and the Unp
ubiquitin-specific protease, all of which are involved in the
ubiquitin-proteasome pathway of protein turnover (Schwartz and Ciechanover 1999
). When taken as a whole, these
observations suggest that as the induction of a stress response
associated with damaged proteins and other macromolecules ensues, the
very systems required for the turnover of such molecules are declining
with age, perhaps due to an energetic deficit in the cell.
We also observed an intriguing and strong age-related
downregulation (3.7-fold decrease) of a gene thought to be
involved in gene silencing, MeCP2 [an abundant CpG binding protein
(Nan et al. 1998
)]. Although we have no clear
understanding of the significance of this change, it is noteworthy due
to the postulated role of DNA methylation alterations in aging
(Cooney 1993
) and cancer (Lengauer et al. 1997
). In contrast to the consistent gene expression patterns
observed for stress response genes (increased with age) and energy
metabolism (decreased with age), the directions of changes in other
categories, such as signal transduction, transcriptional and growth
factors did not present a consistent age-related trend.
Age-related changes in gene expression are reversed by CR.
If differential gene expression patterns in tissues of aged animals
represent biological (as opposed to chronological) markers of
organismal senescence, a significant fraction of these markers should
be affected by CR, the only experimental intervention shown to extend
the maximum life span of mammals (Weindruch and Walford 1988
). Further, CR-mediated attenuation of specific
age-related changes in gene expression would confirm the
significance of the data obtained using high density oligonucleotide
arrays and would validate their utility as markers of biological age.
To study the effects of CR on the gene expression profile of aging, caloric intake of C57BL/6 mice was reduced to 76% of control animals in early adulthood (2 mo of age), and this dietary regimen was maintained until the age of death at 30 mo. Age-related changes in gene expression profiles were remarkably attenuated by CR. Of the largest age-associated alterations (2.0-fold or higher), 29% (33/113) were completely prevented by CR and 34% (38/113) were partially suppressed. Of the four major gene classes that displayed consistent age-associated alterations (i.e., stress response, biosynthesis, protein metabolism and energy metabolism), 84% (26/31) were either completely or partially suppressed by CR. The striking effect of CR on age-related changes in gene expression patterns validates the conclusion that most of these reflect biological age and can serve as biomarkers of aging. Also, these observations imply that some molecular aspects of the aging process are markedly suppressed by CR, suggesting that elucidation of molecular mechanisms will provide opportunities for intervention.
Aging retardation by CR is associated with a metabolic shift.
A global view of alterations in gene expression in CR mice suggests a
metabolic reprogramming characterized by a transcriptional shift toward
energy metabolism, increased biosynthesis and protein turnover. CR
resulted in the induction of 51 genes (1.8-fold or higher) compared
with age-matched controls. Nineteen percent of genes (10/51) in
this class are related to energy metabolism. Modulation of carbohydrate
metabolism was evident through the induction of glucose-6-phosphate
isomerase (glycolysis), fructose 1,6-biphosphatase (gluconeogenesis),
IPP-2 (an inhibitor of glycogen synthesis) and transketolase. Fructose
1,6-biphosphatase switches the direction of a key regulatory step in
glycolysis, reversing glycolysis toward a biosynthetic precursor,
glucose-6-phosphate. Remarkably, this same adaptation has been observed
as part of the transcriptional reprogramming of Saccharomyces
cerevisiae accompanying the diauxic switch from anaerobic growth
to aerobic respiration upon depletion of glucose (DeRisi et al. 1997
). Transketolase, which controls the nonoxidative branch of
the pentose phosphate pathway, provides NADPH for biosynthesis and
reducing power for several antioxidant systems. CR also induced
transcripts associated with fatty acid metabolism, such as fatty acid
synthase and PPAR-delta, a mediator of peroxisome proliferation.
Interestingly, CR may act to increase insulin sensitivity through the
induction of glucose-dependent insulinotropic peptide and
PPAR-gamma, a potent insulin sensitizer (Zierath et al. 1998
, Wu et al. 1999
). Possibly, alterations in
insulin signaling by CR in mice and through life-extending alleles
of Caenorhabditis elegans daf-2 (which encodes an insulin
receptor) are mediated through a similar pathway that senses the
energetic state of the cell (Ogg et al. 1997
,
Tissenbaum and Ruvkun 1998
).
Perhaps due to the reduced availability of dietary sources,
biosynthetic ability also seems to be induced in CR mice based on
higher expression of glutamine synthase, purine nucleoside
phosphorylase (purine turnover) and thymidylate kinase. Remarkably,
16% of transcripts (8/51) highly induced by CR encode proteins
involved in protein synthesis and turnover, including elongation factor
1-gamma, proteasome activator PA28, translocon-associated protein
delta, 60S ribosomal protein L23 and the 26S proteasome subunit TBP-1.
The overt shift in gene expression profile toward protein turnover and
biosynthesis in CR mice contrasts with the evidence for reduced protein
turnover and the accumulation of altered proteins in age-matched
animals receiving the control diet. These findings agree with previous
observations of a reduced level of oxidatively modified proteins in CR
animals (Lass et al. 1998
, Zainal et al., unpublished
results) and provide transcriptional evidence for a central mechanism
of action of CR in aging retardation of postmitotic tissues involving
shifts in energy metabolism and increases in protein turnover.
Gene expression profile in calorie-restricted mice suggests decreased macromolecular damage.
CR was associated with a 1.6-fold or greater reduction in
expression of 57 genes. Twelve percent of these (7/57) were clearly
associated with stress responses and/or DNA repair. The most
substantial suppression of gene expression by CR among the 6347 genes
examined was for a murine DnaJ homolog (3.4-fold), a pivotal and
inducible heat shock factor that senses and transduces the presence of
misfolded proteins in bacteria (Tomoyasu et al. 1998
).
Presumably, reduced generation of toxic by-products of metabolism
in CR mice results in a lower steady-state level of modified
proteins, triggering a down-regulation of this gene. The hypothesis
of lower steady-state levels of toxic metabolic by-products is
also supported by the observation that CR lowers the expression of
cytochrome P450 isoforms IIIA and Cyp1b1 (involved in detoxification),
Hsp105 (a heat shock factor), aldehyde dehydrogenase (an inducible
enzyme involved in detoxification of metabolic by-products) and an
oxidative stress-induced protein of unknown function.
Reduction of endogenous damage by CR is apparently not limited to
proteins, because CR reduced the expression of several DNA repair genes
including XPE [a factor that recognizes multiple DNA adducts
(Payne and Chu 1994
)], RAD50 [involved in
double-strand break repair (Petrini 1999
)] and DNA
polymerase beta [a DNA damage inducible polymerase (Fornace et al. 1989
)]. Because skeletal muscle is largely a postmitotic
tissue, a reduction in the expression of DNA repair genes is most
consistent with a decrease in endogenous damage, as opposed to reduced
mitotic activity. These observations are in agreement with the
reduction in oxidative damage to DNA in calorie-restricted rodents
(Sohal and Weindruch 1996
), but contrast with the
hypothesis that CR delays aging through an upregulation of DNA repair.
How does CR reduce the generation of toxic by-products of
metabolism? One putative mechanism of action is lowered metabolic rate
due to reduced substrate availability for mitochondrial electron
transport and subsequent ROS production, a view that is controversial
based on observations of whole animal oxygen consumption measurements
in CR rodents (Sohal and Weindruch 1996
). We find
molecular evidence to support a state of lower basal metabolic rate in
CR mice through lowered expression of the thyroid hormone receptor
alpha gene, a key mediator of metabolism (Fraichard et al. 1997
).
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Implications for aging and nutritional research |
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TOPABSTRACTINTRODUCTIONGene expression changes induced...Oligonucleotide microarrays as a...The gene expression profile...Implications for aging and...REFERENCES |
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). The
development of higher density gene arrays is now providing a more
complete analysis of gene expression patterns of organismal senescence
and the impact of specific nutritional interventions on this process.
The observed collection of gene expression alterations in aging
skeletal muscle is complex, reflecting the presence of myocyte,
neuronal and vascular components. Additionally, changes in mRNA levels
may not always result in a parallel alteration in protein levels;
however, the complete or partial prevention of the majority of the
observed aging alterations by CR suggests that gene expression patterns
can be used to assess the biological age of the tissue under study.
Extension of our study to other organs should result in the
identification of hundreds of tissue-specific biomarkers of aging,
facilitating the elucidation of aging mechanisms and the development of
interventions. Importantly, the method described here is readily
applicable to the investigation of aging in both nonhuman primates and
humans through the use of small tissue biopsies (100 mg or less with
current technology).
Because the pathophysiology of aging is complex, it is likely that a
detailed analysis of gene expression patterns will reveal
organ-specific alterations. This prediction is supported by our
recently reported findings from two brain regions (neocortex,
cerebellum) in this mouse model, which shared an age-associated
up-regulation of stress response genes with the gastrocnemius but
differed from muscle in showing increased expression of genes involved
in the inflammatory response (Lee et al. 2000
). Also,
microarray analysis of senescence in replicative tissues (Ly et al. 2000
) has revealed aging patterns differing markedly from
those which we have observed in muscle and brain. Genetic analysis of
replicative senescence in Saccharomyces cerevisiae has been
linked to the accumulation of extrachromosmal rDNA gene circles
(Sinclair and Guarente 1997
), whereas replicative
senescence of human cells in vitro is associated with telomere
shortening (Bodnar et al. 1998
). Nevertheless, the
approach outlined here should allow the identification of common
patterns of transcriptional alterations among postmitotic tissues,
providing a framework for investigating nutritional and pharmacological
interventions.
How does our analysis fit with the prevailing theories of aging and the
postulated mechanisms of aging retardation by CR? A summary of global
changes induced by aging and the contrasting effects of CR are shown in
Table 2
. The obvious transcriptional activation of stress response genes that
play a role in the processing of damaged or misfolded proteins during
aging and the prevention of this induction by CR suggest a central role
for protein modifications in aging of skeletal muscle. In fact, aging
is characterized by an exponential increase of oxidatively damaged
proteins that is indicated by loss of sulfhydryl groups, carbonylation
and loss of catalytic activity (Berlett and Stadtman 1997
). Previous analyses of metabolic rates in CR animals have
led to the suggestion that this life-extending regimen acts through
a reduction in metabolic rate, resulting in a lower production of toxic
by-products of metabolism (Sohal and Weindruch 1996
). The CR-mediated reduction of mRNA encoding inducible
genes involved in metabolic detoxification, DNA repair and the response
to oxidative stress support this view, because it implies lower
substrate availability for these systems. Additionally, our analysis
strongly suggests that an equally important mechanism of action may be
a metabolic shift toward increased biosynthesis and macromolecular
turnover. A hormonal trigger for this shift may be an alteration in the
insulin-signaling pathway, a finding that links our observations to
those obtained through the genetic analysis of aging in the nematode
Caenorhabditis elegans. A consistent theme that emerges from
our study is the importance of highly conserved pathways, such as the
heat shock response and DNA repair, in understanding the aging process.
Therefore, continued research in model organisms such as
Escherichia coli and Saccharomyces cerevisiae, as
well as multicellular organisms, will provide key insights to guide the
interpretation of information obtained in mammals through DNA
microarray technology.
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FOOTNOTES |
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2 Supported by National Institutes of Health Grants P01 AG11915 (to R.W.), R01 AG18922 (to R.W.) and R01 CA78723 (to T.A.P.). T.A.P. is a recipient of the Shaw Scientist (Milwaukee Foundation), Burroughs Wellcome Young Investigator and Basil O’Connor (March of Dimes) awards.
4 Abbreviations used: CR, caloric restriction; PM, perfect matches; MM, mismatch; ROS, reactive oxygen species.
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