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Perspective
MICHAEL RAE
3
4 RAE
at 35%, CR6 – and 6 weeks’ CR feeding, when position of CR,10,11 leaving the question of CR’s
initiated at 18–22 months, was unable to reduce effects in older organisms open.
mitochondrial protein carbonyls or loss of A new report by Spindler’s group12 is there-
sulfhydryl groups.7 The results overall dem- fore of considerable significance. Using a care-
onstrate a rapid reduction in oxidative stress, ful experimental design reflecting the insights
but confirm the expectation that much pre- of Weindruch and Walford’s groundbreaking
existing, accumulating oxidative damage is left experiment,2 these investigators initiated CR at
unaffected by at least short- to medium-term 19 months of age and achieved decisive exten-
CR implemented in older animals. Simultane- sions of mean and maximal lifespan, relative to
ously, the shift in steady-state REDOX tone both intraexperimental (extensions of 15%)
underlying these results would be expected and historical13 controls, accompanied by sig-
to reduce the secondary age-related shifts in nificant early reductions in cancer-associated
REDOX-sensitive gene transcription (briefly re- mortality.
viewed in Ref. 8) And indeed, Dr. Stephen Additionally, Dhahbi et al.12 performed a mi-
Spindler’s laboratory at UC Riverside recently croarray analysis on hepatic gene expression of
issued an important report of the predicted late-onset CR animals after 2, 4, and 8 weeks of
rapid shift in gene expression in older mice intervention, and found that CR rapidly in-
subjected to CR.9 duced shifts in gene expression away from the
But the strongest reason to regard the search AL profile which parallel 72% of the changes
for CR mimetics as a dubious endeavor has observed in animals maintained on CR from
been a series of reported failures of late-life CR the age of 7 months onward.
to clearly extend lifespan. Yet these studies In principle, this design should lead to in-
could not be considered to be definitive refu- formation of considerable value. As the inves-
tations of late-life CR’s efficacy, because all of tigators note, most previous gene expression
them repeated methodological errors high- studies have been cross-sectional comparisons
lighted by Weindruch and Walford2 with re- of expression profiles of young AL vs. old AL
spect to provision of nutrients and gradual im- and CR animals. This method produces data of
CALORIE RESTRICTION IN OLDER MAMMALS 5
little ultimate value, as the results do not allow sponses of those organisms to CR. For instance,
one to distinguish expression shifts which are considerably older animals may fail to make
causal in the anti-aging action of CR from those some of the metabolic adaptations necessary
which are its effects—a fact that has often been for the manifestation of retarded aging, or the
glossed over in previous discussion of these time course of that shift may be considerably
findings. Indeed, examining the gene chip pro- altered. The fact that CR fails when initiated in
file of an aged organism would reasonably be older organisms unless special care is taken to
predicted to primarily reveal compensatory impose the regimen gradually and to ensure
adaptations to the primary, accumulated mo- the nutrient quality of diet appears to testify to
lecular lesions that define the aging process, just such a reduction in the metabolic flexibil-
and to confirm that CR animals have been less ity required for adaptation to the diet.
subject to those lesions over their lifetimes. We cannot, in fact, even be confident that
By demonstrating a panel of gene expression animals this old are even capable of making
changes which are closely temporally linked to such a shift and, therefore, that their gene ex-
extension of lifespan, the results of Dhahbi et pression profiles will accurately reflect those
al.’s could, in principle, allow for both greater changes essential to the process—precisely be-
confidence in assigning a causal role for those cause we do not have lifespan data for such a
changes in the resulting lifespan (LS) gains, and study.
for the use of this profile as a positive control A second, more minor methodological weak-
snapshot against which to test putative CR ness of the new study12 relates to the decision
mimetics (a task to which Spindler’s group has to have all animals at the full level of restric-
already begun to apply these data).12 However, tion ultimately achieved in the LS study at the
the design of the gene chip study necessitates time of sacrifice for microarray analysis.11 This
caution in accepting the data for this purpose. protocol led to CR being implemented on a
One group of methodological concerns re- time scale different from that actually used for
lates to the age of the animals used in the two the lifespan study, which, in turn, may be pre-
arms of the studies. Whereas CR was initiated dicted to distort the results obtained.
at 19 months for the LS study [a time point Following the example set by Weindruch and
which, as the authors take care to point out, Walford’s successful protocols,2 the animals
was 2 months before the visible acceleration used in the LS study had their caloric intake re-
of age-related mortality in the animals—the duced in two steps: caloric intake was reduced
“knee” in the survival curve], animals used for by 17% for two weeks, following which the full
gene expression studies were all sacrificed for 44% CR regimen was imposed. By contrast, in
that purpose after 2, 4, or 8 weeks’ CR initiated order to have animals fully on CR in time for
at age 32 mo, to create what is in fact a short the gene chip studies, the animals sacrificed at
cross-sectional series rather than a truly longi- 2 weeks underwent the first reduction in caloric
tudinal investigation. intake for one week, followed by a second week
The considerably greater age of the animals at the fully restricted intake. This accelerated
used for the gene expression study can be ex- initiation of CR may have altered the magni-
pected to distort the results. On the one hand, tude, time-course, or even the fact of some
the basal gene expression profile to which the genes’ differential expression under CR. This
post-CR profile is ultimately compared can seems particularly likely in the case of genes re-
only be expected to differ in magnitude, and ported as “oscillators.”
perhaps even in its very existence, as in the case A possible counterargument to all of the
of age-related hypo- or de novo hyper-methyla- above objections would be that 72% of the dif-
tion.14 If so, then the relative (“-fold”) changes ferences in gene expression observed in life-
in expression observed upon implementation long CR vs. AL animals were recapitulated in
of CR—and perhaps even the fact of those the late-onset CR animals. But to take the op-
changes—can only be predicted to be partially posing view, the fact that over a quarter of all
artifacts of this aspect of the design. the gene changes observed following long-term
On the other hand, the greater age of the an- CR are not reproduced in the late-onset group
imals may also be expected to alter the re- leaves open the possibility that at least some of
6 RAE
the gene expression changes essential to the metabolism in its anti-aging action, and a pu-
anti-aging effects of CR are among their num- tative CR mimetic which had no effect on lev-
ber. (Valuable insight into these issues might els of expression of these inflammatory genes
be gained by repeating the current study’s pro- would be judged either effective or not, de-
tocol in weanling mice, in whom LS-prolong- pending on which tissue was used as the ref-
ing CR is readily and consistently induced.) erence standard.
An additional caveat is that the microarray These methodological issues call into ques-
data collected was that of a particular organ, tion the utility of the expression profile as a
the liver. While (as previous studies have screen for candidate CR mimetics.
shown) many of the effects of CR on gene ex- The finding that CR can rapidly impact aging
pression are broadly similar across tissues, and cancer, and video footage of the aged AL
there are some clearly tissue-specific effects of and late-onset CR animals (which strongly pre-
CR—and some of these may be critical to its ef- sents a picture of more robust health in the CR
fects on survivorship and physiology. group)17 combine to give reason for optimism
As one example of difficult-to-unravel issues regarding the efficacy of late-life CR, or of late-
of tissue specificity and/or cause vs. effect, con- life use of CR mimetics, which are heartening
sider the findings of Lee et al.,15 who have findings for the growing body of human CR
observed that genes associated with stress re- practitioners,18 and for biopharma labs and ven-
sponse are upregulated with age in gastrocne- ture capitalists seeking to produce extremely
mius muscle and in two regions of the brain useful CR-mimetic compounds. It would be ex-
(neocortex and cerebellum),16 but only the for- tremely useful in this context, to have a fuller
mer demonstrated increases in expression of characterization of the effects of late-life CR on
inflammation-associated transcripts. In yet molecular disorder and physiology.
greater contrast, long-term CR animals’ mus- There remains, however, the question of the
cles manifest increases in the expression of degree of clinical impact to be anticipated from
genes involved in carbohydrate metabolism, CR-based interventions when implemented in
while the carbohydrate-metabolic class is down- persons in late middle age, such as the postwar
regulated in their brains. A snapshot of the “baby boom” cohort whose entry into senior-
short-term effects of CR in these tissues might ity is in large part responsible for increasing in-
lead to opposite inferences regarding a possi- terest in truly interventional biogerontology.
ble causal role of a CR-induced anti-inflamma- It is widely held that the effectiveness of CR
tory response or alterations in carbohydrate lessens at later ages. While Dhahbi et al’s data12
Life extension
Lifespan % Remaining
Energy intake (mo.) % ALa % Historical13 LSb
Age
Study initiated kcal/wk % ALa Mean Maxc Mean Maxc Mean Maxc Mean Maxc
*All studies used similar, longevous hybrid genotypes: C3B10RF120,22; B6C3 F112; C57BL/622.
NB: The known strain variability of the response to CR: Ref. 2 reported lower absolute lifespans, but greater rela-
tive extensions, in B6 mice than in C3B10RF1; cf. Ref. 21.
CALORIE RESTRICTION IN OLDER MAMMALS 7
19. Merry BJ. Molecular mechanisms linking calorie re- 24. de Grey AD, Ames BN, Andersen JK, Bartke A, Camp-
striction and longevity. Int J Biochem Cell Biol 2002;34: isi J, Heward CB, McCarter RJM, Stock G. Time to talk
1340–1354. SENS: critiquing the immutability of human aging.
20. Weindruch R, Walford RL, Fligiel S, Guthrie D. The Ann NY Acad Sci 2002;959:452–462.
retardation of aging in mice by dietary restriction: 25. de Grey AD. Challenging but essential targets for
longevity, cancer, immunity and lifetime energy in- genuine anti-ageing drugs. Expert Opin Ther Targets
take. J Nutr 1986;116:641–654. 2003;7:1–5..
21. Turturro A, Witt WW, Lewis S, Hass BS, Lipman
RD, Hart RW. Growth curves and survival charac-
teristics of the animals used in the Biomarkers of Ag-
ing Program. J Gerontol A Biol Sci Med Sci 1999;
54:B492–B501. Address reprint requests to:
22. Pugh TD, Oberley TD, Weindruch R. Dietary inter- Michael Rae
vention at middle age: caloric restriction but not de- The Calorie Restriction Society
hydroepiandrosterone sulfate increases lifespan and 1827 W. 145th Street
lifetime cancer incidence in mice. Cancer Res 1999;59:
1642–1648.
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23. Mair W, Goymer P, Pletcher SD, Partridge L. De- Gardena, CA 90249
mography of dietary restriction and death in
Drosophila. Science 2003;301:1731–1733. E-mail: michaelrae@cadvision.com