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2005
Department of Pathology, Harvard
Medical School, 77 Avenue Louis Paster, Boston, MA 02115,
USA.
The diet known as calorie restriction
(CR) is the most reproducible way to extend the lifespan
of mammals. Many of the early hypotheses to explain this
effect were based on it being a passive alteration in
metabolism. Yet, recent data from yeast, worms, flies,
and mammals support the idea that CR is not simply a passive
effect but an active, highly conserved stress response
that evolved early in life's history to increase an organism's
chance of surviving adversity. This perspective updates
the evidence for and against the various hypotheses of
CR, and concludes that many of them can be synthesized
into a single, unifying hypothesis. This has important
implications for how we might develop novel medicines
that can harness these newly discovered innate mechanisms
of disease resistance and survival.
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Department of Genetics and Medical
Genetics, University of Wisconsin, Madison, WI 53706,
USA.
To examine transcriptional alterations
associated with aging in skeletal muscle and the heart,
we and others have used DNA microarrays to compare the
gene expression profile of young and old animals. Aging
results in a differential gene expression pattern specific
to each tissue, and most alterations can be completely
or partially prevented by caloric restriction (CR) in
both heart and skeletal muscle. Transcriptional patterns
of tissues from calorie-restricted animals suggests that
CR retards the aging process by reducing endogenous damage
and by inducing metabolic shifts associated with specific
transcriptional profiles. These studies demonstrate that
DNA microarrays can be used in cardiovascular aging research
to generate panels of hundreds of transcriptional biomarkers,
providing a new tool to measure biological age of cardiac
and skeletal muscles and to test interventions designed
to retard aging in these tissues.
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Third Department of Internal Medicine,
First Faculty of Medicine, Charles University, U nemocnice
1, 128 08 Prague 2, Czech Republic.
Oxidative stress is higher in obese
diabetic than in non-diabetic subjects. This pilot study
evaluates oxidative stress during short-term administration
of a very low calorie diet in obese persons. Nine obese
Type 2 diabetic patients (age 55+/-5 years, BMI 35.9+/-1.9
kg/m2) and nine obese non-diabetic control subjects (age
52+/-6 years, BMI 37.3+/-2.1 kg/m2) were treated by a
very low calorie diet (600 kcal daily) during 8 days stay
in the hospital. Serum cholesterol, triglycerides, non-esterified
fatty acids (NEFA), beta-hydroxybutyrate (B-HB), ascorbic
acid (AA), alpha-tocopherol (AT), plasma malondialdehyde
(MDA) and superoxide dismutase (SOD) activity in erythrocytes
were measured before and on day 3 and 8 of very low calorie
diet administration. A decrease of serum cholesterol and
triglyceride concentrations on day 8 was associated with
a significant increase of NEFA (0.30+/-0.13 vs. 0.47+/-0.11
micromol/l, p<0.001) and B-HB (0.36+/-.13 vs. 2.23+/-1.00
mmol/l, p<0.001) in controls but only of B-HB (1.11+/-0.72
vs. 3.02+/-1.95 mmol/l, p<0.001) in diabetic patients.
A significant decrease of plasma MDA and serum AT together
with an increase of SOD activity and AA concentration
(p<0.01) was observed in control persons, whereas an
increase of SOD activity (p<0.01) was only found in
diabetic patients after one week of the very low calorie
diet. There was a significant correlation between NEFA
or B-HB and SOD activity (p<0.01). We conclude that
one week of a very low calorie diet administration decreases
oxidative stress in obese non-diabetic but only partly
in diabetic persons. Diabetes mellitus causes a greater
resistance to the effects of a low calorie diet on oxidative
stress.
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2004
Department of Internal Medicine,
Faculty of Medicine, University of Indonesia-Dr. Cipto
Mangunkusumo General Hospital, Jakarta.
AIM: To determine whether the Ramadan
fasting can improve metabolic control evaluated from serum
fructosamine and beta hydroxybutirate in patients with
Type 2 diabetes mellitus. METHODS: This was a prospective
one group before and after study (self-controlled study).
Twenty four patients from the outpatient clinic of the
Metabolic Endocrinology Division of the Department of
Internal Medicine, Faculty of Medicine, University of
Indonesia/ Cipto Mangunkusumo General Hospital who were
well under control underwent assessment for serum fructosamine
at weeks -1, 4, and 6 (2 weeks after the Ramadan fast)
and beta hydroxybutirate formation at week 4. RESULTS:
The mean serum fructosamine on weeks -1, 4, and 6 were
334.2 +/-45.7; 303.9 +/-34.5 dan 313.6 +/-45.9 umol/L.
The beta hydroxybutirate level was 0.3 mmol/L. CONCLUSION:
The Ramadan fasting in patients with well-controlled and
medium-controlled type 2 diabetes mellitus could cause
a reduction in serum fructosamine and does not cause formation
of beta hyroxybutirate.
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Pennington Biomedical Research Center,
Baton Rouge, Louisiana, USA.
PURPOSE OF REVIEW: The focus of
this review is on current research involving long-term
calorie restriction and the resulting changes observed
in possible biomarkers of aging. Special emphasis will
be given to the basic and clinical science studies which
are currently investigating the effects of controlled,
high-quality energy-restricted diets on both biomarkers
of longevity and on the development of chronic diseases
related to age and obesity in humans. RECENT FINDINGS:
Prolonged calorie restriction has been shown to extend
both the median and maximal lifespan in a variety of lower
species such as yeast, worms, fish, rats, and mice. Mechanisms
of this lifespan extension via calorie restriction are
not fully elucidated, but possibly involve significant
alterations in energy metabolism, oxidative damage, insulin
sensitivity, and functional changes in both the neuroendocrine
and sympathetic nervous systems. Ongoing studies of prolonged
energy restriction in humans are now making it possible
to analyze changes in these aging biomarkers to unravel
some of the mechanisms of its antiaging phenomenon. SUMMARY:
With the incremental expansion of research endeavors in
the area of energy or calorie restriction, data on the
effects of calorie restriction in animal models and humans
are becoming more accessible. Detailed analyses from controlled
human trials involving long-term calorie restriction will
allow investigators to link observed alterations in body
composition down to changes in molecular pathways and
gene expression, with their possible effects on the biomarkers
of aging.
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2003
The Children's Hospital at Westmead,
Sydney, Australia.
Treatment of metabolic disease
aims to restore homeostasis, where possible. This can
be achieved in a number of ways. For disorders of intermediary
metabolism, treatment involves a thorough understanding
of the disorder and the pathogenesis of the deleterious
effects The various approaches indicated may involve substrate
restriction, replacement of deficient products, removal
of toxic metabolites or stimulation of residual enzymes.
Newer therapies include enzyme replacement and gene therapy.
Often, the cornerstone of treatment is dietary. Substrate
restriction includes not only a diet low in the substrate
indicated by the disorder, but also strict calorie support
in times of illness to avoid catabolism. Useful levels
of substrate restriction may require the use of supplements
of "medical foods", for example amino acid mixtures.
Provision of the deficient products is important in disorders
affecting energy metabolism. To understand the problems
involved in nutritional treatment it is helpful to consider
examples of different types of disorders. In Maple syrup
urine disease (MSUD), treatment with a very strict low-protein
diet, supplemented by a branched-chain-free amino acid
mixture is successful, but each intercurrent illness is
hazardous, regimens for sick days vital, and strict lifelong
treatment is needed. Treatment for phenylketonuria is
similar in restricting a substrate but there is no tendency
for systemic illness if the phenylalanine levels are too
high. Disorders of the urea cycle are difficult dietary
challenges because while a very low-protein diet is required,
no specific amino acid needs to be avoided and there is
a fine line between adequate protein intake and chronic
catabolism. Fatty acid oxidation disorders affect energy
production and can be detected by newborn screening using
tandem mass spectrometry. For long-chain fatty acid disorders,
long chain fats must largely be avoided and medium-chain
fats must be substituted while strictly avoiding catabolism.
Glycogen storage disorders require strict attention to
providing carbohydrate, at all times including throughout
the night. Many patients with inborn errors do not need
any specific dietary therapy, (eg those with storage or
neurodegenerative disorders), although all children benefit
from an optimal diet, and sick children need this especially.
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Laboratory of Biosystems and Cancer,
Center for Cancer Research, National Cancer Institute,
Bethesda, Maryland 20892, USA.
Calorie restriction (CR) is the
most effective and reproducible intervention for increasing
lifespan in a variety of animal species, including mammals.
CR is also the most potent, broadly acting cancer-prevention
regimen in experimental carcinogenesis models. Translation
of the knowledge gained from CR research to human chronic
disease prevention and the promotion of healthy aging
is critical, especially because obesity, which is an important
risk factor for several chronic diseases, including many
cancers, is alarmingly increasing in the Western world.
This review synthesizes the key biological mechanisms
underlying many of the beneficial effects of CR, with
a particular focus on the insulin-like growth factor-1
pathway. We also describe some of the opportunities now
available for investigations, including gene expression
profiling studies, the development of pharmacological
mimetics of CR, and the integration of CR regimens with
targeted, mechanism-based interventions. These approaches
will facilitate the translation of CR research into strategies
for effective human chronic disease prevention.
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2002
International Longevity Center-USA,
New York, New York, USA.
In spite of considerable hype to
the contrary, there is no convincing evidence that currently
existing so-called "antiaging" remedies promoted
by a variety of companies and other organizations can
slow aging or increase longevity in humans. Nevertheless,
a variety of experiments with laboratory animals indicate
that aging rates and life expectancy can be altered. Research
going back to the 1930s has shown that caloric restriction
(also called dietary restriction) extends life expectancy
by 30-40% in experimental animals, presumably at least
partially by delaying the occurrence of age-dependent
diseases. Mutations that decrease production of insulin
growth factor I in laboratory mammals, and those that
decrease insulin-like signaling in nematodes and fruit
flies, have increased life expectancy as well. Other general
strategies that appear promising include interventions
that reduce oxidative stress and/or increase resistance
to stress; hormone and cell replacement therapies may
also have value in dealing with specific age-related pathologies.
This article reports the findings of a consensus workshop
that discussed what is known about existing and future
interventions to slow, stop, or reverse aging in animals,
and how these might be applied to humans through future
research.
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Department of Animal Biology-II (Animal
Physiology), Faculty of Biology, Complutense University,
28040, Madrid, Spain.
Available studies are consistent with
the possibility that oxygen radicals endogenously produced
by mitochondria are causally involved in the determination
of the rate of aging in homeothermic vertebrates. Oxidative
damage to tissue macromolecules seems to increase during
aging. The rate of mitochondrial oxygen radical generation
of post-mitotic tissues is negatively correlated with animal
longevity. In agreement with this, long-lived animals show
lower levels of oxidative damage in their mitochondrial
DNA (mtDNA) than short-lived ones, whereas this does not
occur in nuclear DNA (nDNA). Caloric restriction, which
decreases the rate of aging, also decreases mitochondrial
oxygen radical generation and oxidative damage to mitochondrial
DNA. This decrease in free radical generation occurs in
complex I and is due to a decrease in the degree of electronic
reduction of the complex I free radical generator, similarly
to what has been described in various cases in long-lived
animals. These results suggest that similar mechanisms have
been used to extend longevity through decreases in oxidative
stress in caloric restriction and during the evolution of
species with different longevities.
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2001
Department of Neurobiology, Mt. Sinai
School of Medicine, New York City, NY 10029, USA.
As part of an effort to review
current understanding of the mechanisms by which caloric
restriction (CR) extends maximum life span, the authors
of the present review were requested to develop a list
of key issues concerning the potential role of neuroendocrine
systems in mediating these effects. It has long been hypothesized
that failure of specific neuroendocrine functions during
aging leads to key age-related systemic and physiological
failures, and more recently it has been postulated that
physiological neuroendocrine responses to CR may increase
life span. However, although the acute neuroendocrine
responses to fasting have been well studied, it is not
clear that these responses are necessarily identical to
those observed in response to the chronic moderate (30%
to 50% reduction) CR that increases maximum life span.
Therefore the recommendations of this panel fall into
two categories. First, further characterization of neuroendocrine
responses to CR over the entire life span is needed. Second,
rigorous interventional studies are needed to test the
extent to which neuroendocrine responses to CR mediate
the effects of CR on life span, or alternatively if CR
protects the function of essential neuroendocrine cells
whose impairment reduces life span. Complementary studies
using rodent models, nonhuman primates, and humans will
be essential to assess the generality of elucidated mechanisms,
and to determine if such mechanisms might apply to humans.
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Department of Pathology, Nagasaki University
School of Medicine, 1-12-4 Sakamoto, Nagasaki City 852-8523,
Japan.
Evolutional theories of aging and
caloric restriction (CR) in animals predict the presence
of neuroendocrine signals to divert the limited energy
resources from energy-costly physiologic processes such
as reproduction to those essential for survival in response
to food shortage. The diversion of energy and subsequent
molecular mechanisms might extend the lifespan. A growing
body of evidence indicates that leptin, a peptide hormone
secreted from adipocytes, has a key role in neuroendocrine
adaptation against life-threatening stress such as fasting.
The present review discusses the potential role of leptin
in the anti-aging action of CR. Although several alternative
signaling pathways might also mediate the anti-aging action
of CR, leptin signaling could be a substantial pathway
in the CR action. Research on neuroendocrine mechanisms
of CR is warranted, because such efforts might provide
clues to the regulation of the aging process in humans.
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1992
Space Biospheres Ventures, Oracle,
AZ 85623.
Biosphere 2 is a 3.15-acre space
containing an ecosystem that is energetically open (sunlight,
electric power, and heat) but materially closed, with
air, water, and organic material being recycled. Since
September 1991, eight subjects (four women and four men)
have been sealed inside, living on food crops grown within.
Their diet, low in calories (average, 1780 kcal/day; 1
kcal = 4.184 kJ), low in fat (10% of calories), and nutrient-dense,
conforms to that which in numerous animal experiments
has promoted health, retarded aging, and extended maximum
life span. We report here medical data on the eight subjects,
comparing preclosure data with data through 6 months of
closure. Significant changes included: (i) weight, 74
to 62 kg (men) and 61 to 54 kg (women); (ii) mean systolic/diastolic
blood pressure (eight subjects), 109/74 to 89/58 mmHg
(1 mmHg = 133 Pa); (iii) total serum cholesterol, from
191 +/- 11 to 123 +/- 9 mg/dl (mean +/- SD; 36% mean reduction),
and high density lipoprotein, from 62 +/- 8 to 38 +/-
5 (risk ratio unchanged); (iv) triglyceride, 139 to 96
mg/dl (men) and 78 to 114 mg/dl (women); (v) fasting glucose,
92 to 74 mg/dl; (vi) leukocyte count, 6.7 to 4.7 x 10(9)
cells per liter. We conclude that drastic reductions in
cholesterol and blood pressure may be instituted in normal
individuals in Western countries by application of a carefully
chosen diet and that a low-calorie nutrient-dense regime
shows physiologic features in humans similar to those
in other animal species.
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