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Abstract Caloric (or dietary) restriction (CR)
extends lifespan and lowers risk for age associated
diseases in a phylogenetically diverse group of
species. Whether prolonged CR increases average or
maximum lifespan or promotes a more youthful
physiology in humans at advanced ages is not yet
known. However, available epidemiological evi-
dence indicates that CR may already have contrib-
uted to an extension of average and maximum life
span in one human population and appears to have
lowered risk for age associated chronic diseases in
other human populations. We review the human
studies in the context of a special human population,
older Okinawans, who appear to have undergone a
mild form of prolonged CR for about half their adult
lives.
Keywords Caloric restriction Æ Okinawa Æ
Maximum life span Æ Healthy aging Æ Diet Æ
Longevity
Introduction
Caloric (or dietary) restriction (CR) is the only con-
sistently reproducible experimental means of
extending mean and maximum lifespan and markedly
decreasing morbidity in a phylogenetically diverse
group of short lived laboratory mammals. Studies
underway with longer-lived species such as non-
human primates are also showing promising early
results regarding the life-extending physiological
effects seen in rodents and other animals (Roth et al.
2001; Mattison et al. 2003; Lane et al. 2004). The
question of whether or not CR would work in humans
may be one of the most significant unanswered
questions in biogerontology.
We take the position that CR not only will work
but in fact available epidemiological evidence indi-
cates that CR may already have contributed to an
extension of average and maximum life span in one
human population and appears to have lowered risk
D. C. Willcox (&)
College of Nursing, Okinawa Prefectural University,
1-24-1 Yogi, Naha, Okinawa 902-0076, Japan
e-mail: willcox@okinawa-nurs.ac.jp
B. J. Willcox Æ J. D. Curb Æ D. C. Willcox
Pacific Health Research Institute, 846 South Hotel Street,
Suite 301, Honolulu, HI 96813, USA
B. J. Willcox Æ J. D. Curb
Departments of Geriatric Medicine and Medicine, John A.
Burns School of Medicine, University of Hawaii, 1356
Lusitana Street, 7F, Honolulu, HI 96813, USA
H. Todoriki
Faculty of Medicine, University of the Ryukyus,
Department of Environmental and Preventive Medicine,
207 Vehara, Nishihara, Okinawa 903-0215, Japan
M. Suzuki
Professor Emeritis, University of the Ryukyus, 207
Uehara, 903-0215, Nishihara-Cho, Okinawa, Japan
Biogerontology (2006) 7: 173–177
DOI 10.1007/s10522-006-9008-z
123
OPINION
Caloric restriction and human longevity: what can we learn
from the Okinawans?
D. Craig Willcox Æ Bradley J. Willcox Æ
Hidemi Todoriki Æ J. David Curb Æ
Makoto Suzuki
Received: 20 January 2006 / Accepted: 20 January 2006 / Published online: 30 June 2006
Ó Springer Science+Business Media B.V. 2006
for age associated chronic diseases in other human
populations. We review the human studies in the
context of a special human population that we believe
has undergone prolonged CR while also maintaining
a high quality diet—a necessary condition for CR to
manifest its beneficial effects.
CR studies and effects in humans
Short-term studies of humans under various CR par-
adigms have shown dramatic changes in biology
similar to prior studies in other animals. While some
effects appear partly mediated by reduction of fat
mass, multiple mechanisms have been proposed
including altered insulin signaling, reduced free rad-
ical damage, and hormesis, among others. This evi-
dence has been reviewed elsewhere and we will
concentrate on long term human studies (Heilbronn
and Ravussin 2003; Masoro 2005; Dirks and
Leeuwenburgh 2006).
Recent data from individuals (18 subjects) under-
taking a voluntary long-term CR regimen supports
what would be expected by the short term studies.
Long term caloric restriction for periods of 3–15 years
(average of 6 years) has shown it to be highly effec-
tive in reducing the risk for atherosclerotic arterial
disease, the leading cause of morbidity and mortality
in Western societies, by changing key biochemical,
hormonal and metabolic parameters (Fontana et al.
2004). CR also appears to ameliorate the decline in
diastolic heart function that occurs with human aging
(Meyer et al. 2006). A key question is whether or not
these systemic changes are reflective of a more
youthful physiology and will enhance health and
lifespan if continued over a longer time period.
A recently published 25 years follow-up report
from the Baltimore Longitudinal Study of Aging
(BLSA) suggests that this might indeed be the case.
The BLSA noted that healthy men who displayed
three ‘‘biomarkers of the CR phenotype’’—lower
insulin levels, lower body temperature and a slower
decline in levels of the hormone dehydroepiandros-
terone sulfate (DHEA-S) also had significantly longer
survival (Roth et al. 2002). Furthermore, similar
findings have also been seen in the Honolulu Heart
Program cohort where blood glucose in middle age
strongly predicts late life survival (Rodriguez et al.
1999). More human studies are needed to confirm
these preliminary findings and are currently under-
way, such as the CALERIE trials, but they do not
address longevity as an outcome (Heilbronn and
Ravussin 2003).
Only one long-term epidemiological prospective
study (>30 years) has directly addressed the issue of
caloric intake and human longevity. This 36-year
follow-up study reported a weak trend for lower all-
cause mortality in healthy non-smoking Japanese-
American men suggesting that those who consumed a
modestly low energy intake (85% of group mean) had
the lowest risk for all-cause mortality (Willcox et al.
2004). There was higher mortality risk when caloric
intake dropped below 50% of the group mean. This is
consistent with previous animal findings that show
decreased risk for mortality from age associated
diseases and increased life span under a CR regimen
of up to 50% restriction.
The Okinawa findings
Older Okinawans exhibit the CR phenotype
Low caloric intake was first reported in the Okinawan
population by Hokama et al. (1967) who showed that
Okinawan school children consumed only 62% of the
calories of other Japanese school children. Kagawa
(1978) confirmed low caloric intake (83% of Japan
average) in the Okinawa adult population from the
1972 Japan National Nutrition Survey and docu-
mented anthropometric and morbidity data from
older Okinawans that were consistent with CR.
Kagawa (1978) hypothesized that this may have been
partly responsible for the long and healthy lives of
Okinawans. Death rates from heart disease, cancer
and cerebral vascular disease were found to be only
60 to 70% of that of the Japan average and the all-
cause mortality rate for 60–64 year olds was only half
that of other Japanese. A later study published by
Chan et al. (1997) also reported dietary and pheno-
typic data in Okinawan septuagenarians and cente-
narians consistent with CR.
Our recent analysis of long-term trends in whole
population caloric intake and energy balance for the
years beginning in 1949 demonstrates that the
Okinawan septuagenarian population appeared to be
in a relative ‘‘energy deficit’’ consistent with CR
until the late 1960s, eating approximately 11% fewer
174 Biogerontology (2006) 7: 173–177
123
calories (approximately 1,785 kcal per day) than
would normally be recommended for maintenance of
body weight according to the Harris-Benedict equa-
tion (Willcox et al. Unpublished data). The body
mass index (BMI) of adult Okinawans also remained
stable at a very lean 21 kg/m
2
and peak body weight
was reached in young adulthood and appeared rela-
tively stable until elderly ages (Willcox et al.
Unpublished data). These dietary and anthropometric
data are consistent with adaptation to a long-term
energy deficit and fit proposed epidemiologic defini-
tions by a recent US National Institutes of Health
panel (see Lee et al. 2001) of the human CR pheno-
type (i.e. no weight gain after early adulthood).
Moreover, nutritional studies suggest that the tra-
ditional Okinawan diet, with its high intake of green
leafy and yellow root vegetables, sweet potatoes as a
dietary staple, and soy as a principle protein supple-
mented by small amounts of fish and meat, was
adequate in most nutrients and particularly high in
antioxidant vitamins (Sho 2001; Suzuki et al. 2001;
Todoriki et al. 2004; Willcox 2005).
Was there a CR effect?
If a CR phenomenon occurred for the current gen-
eration of elderly Okinawans then there should be
biomarker evidence of CR-linked delayed physio-
logical aging. Thus, it is of keen interest that recent
findings from our ongoing study of Okinawa’s elderly
population show that Okinawan septuagenarians, who
would have undergone CR until at least middle age
according to the previous population data, exhibit
higher DHEA levels when compared to age-matched
Americans not subjected to CR (Willcox et al.
Unpublished data). In addition, if delayed aging oc-
curred in Okinawans, then there should be a right-
ward shift in the survival curve, with increases in
both average lifespan and maximum lifespan. Indeed,
survival curves for Okinawan, Japanese and U.S.
populations calculated based on life table data for the
year 1995 do show increases in both average and
maximum lifespan in the Okinawan population
compared to Japanese and American populations,
consistent with CR. Average lifespan (measured as
50th percentile survival) and maximum lifespan
(measured as 99th percentile survival) in the Okina-
wan, Japanese and U.S. populations were 83.8 and
104.9 years, 82.3 and 101.1 years, and 78.9 and
101.3 years, respectively (Willcox et al. Unpublished
data).
Finally, age-adjusted mortality for specific age-
related diseases (especially cardiovascular diseases)
is extremely low in elderly Okinawans compared to
other age-matched Japanese or Americans (Kagawa
1978; Suzuki et al. 2001).Thus, life expectancy at
older ages is extremely long in Okinawa. For the
septuagenarian cohort, life expectancy from age 65 is
the longest in Japan, and possibly the world, at
24.1 years for females and 18.5 years for males (Ja-
pan Ministry of Health, Labor and Welfare, 2005).
This compares to 22.5 years and 17.6 years for the
same birth cohort in mainland Japan (Japan Ministry
of Health, Labor and Welfare 2000) and 19.3 years
and 16.2 years for corresponding U.S. birth cohorts
of females and males respectively (U.S. Centers for
Disease Control and Prevention 2003). Also consis-
tent with a longer life expectancy at older ages is the
high numbers of centenarians at approximately 50 per
100,000 or about 4–5 times the average for most
industrialized countries (Japan Ministry of Health,
Labor and Welfare 2005).
Other factors may also be contributing to the
exceptional longevity of the Okinawans such as ge-
netic factors, specific nutritional components of the
diet (high anti-oxidants), social support and/or health
care (Takata et al. 1987; Goto et al. 2003; Todoriki
et al. 2004; Suzuki et al. 2001, 2004; Willcox 2005;
Willcox et al. 2006). However, the forces of mor-
bidity and mortality act most strongly at older ages
and it is at these ages one would expect to see the
most marked phenotypic differences and the most
marked survival advantage, had CR occurred in the
Okinawans, and indeed this is the case.
Should we restrict our calories?
Some scientists who study the mechanisms of aging
suggest that it is unlikely that the maximum lifespan
of humans can be extended by any intervention,
including caloric restriction (Hayflick 2004). It has
also been argued that while CR is likely to be almost
universal in its beneficial effects on longevity, the
benefit to humans is likely to be small, even if hu-
mans restrict their caloric intake substantially and
over long periods of time (Phelan and Rose 2005).
The latter argument derives from observations of
Biogerontology (2006) 7: 173–177 175
123
complex differences between species (such as amount
of energy allocated to reproduction) and the fact that
underlying physiological mechanisms that determine
longevity are not necessarily the same between spe-
cies. Furthermore, there are potential health concerns,
particularly if practiced incorrectly (too severe) or at
vulnerable (too young, too old, pregnancy) life stages
(Le Bourg 2005; Dirks and Leeuwenburgh 2006).
While fully acknowledging that the nature of the
life-extending action of CR may differ among spe-
cies, we believe these views to be overly pessimistic
and not reflective of the available evidence. However,
we believe that people should not attempt to restrict
calories to the extreme levels seen in animal studies
(up to 60%) because human studies, although prom-
ising, have not fully addressed issues such as quality
of life and other potential side effects. With that
caveat in mind, cautious approaches to lowering
calories (mild CR) among adults while maintaining
optimal nutrient intakes would still likely result in
significant health benefits. In fact, recent findings
show that even 8% CR has beneficial effects on
specific biochemical and inflammatory biomarkers
(Dirks and Leeuwenburgh 2006).
We cite the following reasons for a more optimistic
view of the potential benefits of the CR lifestyle for
human beings: First, the accumulated evidence of
70 years of CR studies suggests that CR is an ex-
tremely ancient and very important survival mecha-
nism which appeared early in the evolution of
eukaryotes. Therefore it appears to be strongly con-
served throughout the phylogenetic scale (from yeast
to mammals). As such, it would be unusual if it did not
work in some positive capacity in humans as well.
Second, studies in progress with non-human primates
(who share over 95% of our genes and have similar
reproductive physiology) on a CR regimen, while not
yet conclusive, are showing early results consistent
with previous animal data. Third, short-term and
longer-term studies of humans under a true CR para-
digm have shown dramatic changes in physiology and
metabolic shifts similar to other animals. Fourth, our
research shows that older Okinawans (ages-65 plus)
exhibit a CR-like phenotype and ate a low calorie diet
over a prolonged period of time. Calories in the
Okinawan population were approximately 11% fewer
than what would usually be recommended for their
body weight and activity levels (based on the Harris-
Benedict equation) but only for half their adult lives.
Yet, even with this mild CR-like regimen older
Okinawans have gained an additional 6% survival
time from age 65 (1.3 years) versus other Japanese
and an additional 20% survival time (3.6 years) ver-
sus Americans. Given the large number of factors that
influence human lifespan, this is also surprisingly
similar to the gain in lifespan observed in prior ani-
mal studies (i.e. 10–20% calorie reduction leads to a
10–20% increase in lifespan). Most importantly, the
Okinawans appear to have gained an increased health
span, with almost a decade of disability-free life
expectancy beyond what typical Western populations
experience.
Lastly, while Okinawans were not consciously
practicing CR, they did develop cultural habits that
led to the kind of prudent food choices that maximize
nutritional properties of foods while minimizing
caloric density as would be the favored strategy for
anyone who attempts a CR regimen. Simply avoiding
calorie-dense refined sugars, saturated fats and pro-
cessed foods and replacing them with nutrient-dense
but calorie poor vegetables, fruits and legumes will
not only likely lead to spontaneous weight loss
through lower caloric intake but would also result in a
vastly increased intake of health-enhancing phytonu-
trients, including key vitamins and minerals, antioxi-
dants and flavonoids. Practicing a little restraint at the
dinner table may also have its benefits. ‘‘Eat until you
are 80% full’’ (or hara hachi-bu) is the advice that
Okinawan grandmothers have given for years and the
science of CR appears to be proving that the wisdom
of the elders still rings as true as ever.
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