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Calorie Restriction Mimetics: Examples and Mode of Action

Authors:
  • National Gerontology Centre - Cyprus

Abstract

The search for Calorie Restriction Mimetics (CRM) -compounds that mimic the genetic, biochemical and physical actions of calorie restriction -is not a search for a 'lazy dieters pill'. It is a quest aiming to clarify the basic mechanisms of calorie restriction and develop strategies in order to prevent, treat or alleviate age-related conditions. The development of CRM will add new and important assets in our armamentarium of anti-ageing therapies, with the ultimate result of increasing healthy human lifespan. This Special Supplement on CRM is an attempt to discuss some agents which may be used instead of calorie restriction itself. Agents such as resveratrol, metformin, carnosine and Rimonabant are mainstream oral therapies already used by millions of people for other clinical indications. New CRM such as NADH, gugulipids and certain drugs that interfere with glucose metabolism can be also used as oral therapy. Less easily available CRM such as oxaloacetic acid, naloxone, leptin, adiponectin, rapamycin and sirtuins are further examples of promising agents. In order for the therapy to be effective, a combination of these must be used. This paper summarises the actions of calorie restriction and then suggests several examples of possible CRM. Some of these examples can be used in everyday clinical setting.
Open Longevity Science, 2009, 3, 17-21 17
1876-326X/09 2009 Bentham Open
Open Access
Calorie Restriction Mimetics: Examples and Mode of Action
Marios Kyriazis*
British Longevity Society, UK
Abstract: The search for Calorie Restriction Mimetics (CRM) - compounds that mimic the genetic, biochemical and
physical actions of calorie restriction - is not a search for a ‘lazy dieters pill’. It is a quest aiming to clarify the basic
mechanisms of calorie restriction and develop strategies in order to prevent, treat or alleviate age-related conditions. The
development of CRM will add new and important assets in our armamentarium of anti-ageing therapies, with the ultimate
result of increasing healthy human lifespan. This Special Supplement on CRM is an attempt to discuss some agents which
may be used instead of calorie restriction itself. Agents such as resveratrol, metformin, carnosine and Rimonabant are
mainstream oral therapies already used by millions of people for other clinical indications. New CRM such as NADH,
gugulipids and certain drugs that interfere with glucose metabolism can be also used as oral therapy. Less easily available
CRM such as oxaloacetic acid, naloxone, leptin, adiponectin, rapamycin and sirtuins are further examples of promising
agents. In order for the therapy to be effective, a combination of these must be used. This paper summarises the actions of
calorie restriction and then suggests several examples of possible CRM. Some of these examples can be used in everyday
clinical setting.
Keywords: Calorie restriction, calorie restriction mimetics, health-span, hormesis.
INTRODUCTION
Calorie restriction (CR) is discussed elsewhere in this
Supplement. Its practical aim is not only to increase average
and maximum lifespan in humans, but also to prolong the
'health-span' which is the number of years an organism can
live without any major chronic diseases [1]. It may be
somewhat simplistic but practically useful to divide the ef-
fects of CR into three general categories: genetic, biochemi-
cal and physical. The following list is by no means exhaus-
tive but highlights some examples.
A. Genetic. These are effects at specific gene level which
can modulate transcription of enzymes or other fac-
tors. Perhaps the most promising CRM are those
which work on this level.
Decreases the activity of p53 [2], and therefore modu-
lates apoptosis [3].
Regulates Sir-2 [4] and activates Sirt1 [5]. Sirt1 is
activated to promote transcription of genes that deal
with the stress response and adaptation.
Regulates Daf-16. AMPK (AMP Protein Activated
Kinase) is activated in the presence of Daf-16 [6].
B. Biochemical effects are those that directly influence
macromolecules, without an identifiable genetic ori-
gin:
Reduces lipid peroxidation and generation of super-
oxides [7].
Reduces iNOS expression and COX2 expression [8],
and increases NADH concentration within the mito-
chondria [9].
*Address correspondence to this author at the British Longevity Society,
UK; E-mail: drmarios@live.it
Maintains DHEA levels [10].
Modulates PPAR [11]. Suppresses PGE-2, TNF-alpha
and CRP (thus reduces the inflammation response)
[12].
Stimulates Brain-Derived Neurotropic Factor (BDNF)
[13].
C. Physical changes include clinically relevant and
measurable parameters, at the organismic level.:
Reduces body weight and body temperature [14].
Improves diastolic function. Lowers cholesterol,
blood pressure and pulse rate, and reduces blood glu-
cose levels [15].
Increases muscle mass and reduces fat mass (includ-
ing intra-abdominal fat) [16].
Improves memory and cognition [17, 18].
CANDIDATE CRM
Calorie restriction mimetics (CRM) are drugs or chemi-
cal compounds which mimic the actions of CR. It is not suf-
ficient for a compound that mimics just one effect of CR to
be classified as a CRM. As an arbitrary guide, I propose that,
in order for a compound to be classified as a CRM, it has to
mimic at least two biochemical plus one genetic, or five bio-
chemical/physical effects of CR. This is a general attempt at
defining a CRM and further discussion is needed, although
initial attempts along these lines have already been made
[19], and in particular with regards to defining biomarkers in
calorie restriction has already taken place [20]. Examples of
CRM that are already available and currently used for other
indications are:
18 Open Longevity Science, 2009, Volume 3 Marios Kyriazis
Metformin
Metformin is a receptor sensitizer, because it enhances
the sensitivity of insulin receptors on the surface of muscle
and fat cells [21]. It can activate genes which reduce hepatic
production of glucose, thus reducing the risk of glycation
and other age-related damage. In addition, metformin re-
duces gene expression of enzymes which increase oxidation
of fatty acids. Further research is needed to clarify the ap-
proximate dose of metformin for CRM effects. Healthy peo-
ple who take metformin for its general anti-ageing benefits
use 500 mg twice a day. Side effects may include gastroin-
testinal problems and allergic reactions.
Resveratrol
This is a polyphenol with proven beneficial cardiovascu-
lar effects and a potent CRM [22]. In yeast, it stimulates Sir2
(silent information regulator), increasing DNA stability and
extending life-span by 70%. Resveratrol activates the human
homologue SIRT1 which results in reduced apoptosis in the
liver, blood and skin, and reduced risk of age-related chronic
disease. The dose of resveratrol is normally between 5 mg
and 15 mg daily, however the dose necessary to achieve
CRM effects has not yet been calculated. Long term adverse
effects are unknown, but no significant short term side ef-
fects have been reported.
Rimonabant (Acomplia)
Endocannabinoids are cannabis-like chemicals which
stimulate appetite and regulate energy balance. Overstimula-
tion of endocannabinoid receptor in the hypothalamus pro-
motes appetite and stimulates lipogenesis [23]. It also blocks
adiponectin. Rimonabant (an anti-obesity drug) is an endo-
cannabinoid-1 receptor blocker, which reduces appetite, bal-
ances energy production and increases adiponectin which, in
turn, reduces intra-abdominal fat [24]. Rimonabant improves
lipid profile, glucose tolerance, and waist measurement.
Therefore, it has effects similar to those of CR. It is taken 20
mg once daily, preferably with a mild calorie restricted diet.
The efficacy and long term adverse effects of rimonabant
have recently been questioned and further research is needed
to clarify these.
Anti-Glycators
Agents which reduce abnormal protein accumulation
(aminoguanidine and carnosine) can also be CRM. These
prevent glycation and therefore reduce AGEs (Advance Gly-
cation End-products) formation [25]. AGEs contribute to
extensive age-related damage such as accumulation of amy-
loid-beta implicated in Alzheimer's disease. CR reduces the
concentration of AGEs. The same mechanism is shared by
aminoguanidine and carnosine which prevent and eliminate
AGEs, therefore contributing towards the prevention of
chronic degenerative disease. No significant side effects
have been reported, and mild gastrointestinal problems usu-
ally improve after reducing the dose.
Exendin
The agent exendin (exanatide, exanadin) reduces plasma
glucose, suppresses food intake and regulates glucose me-
tabolism [26]. It is a GLP (Glucagon-Like Peptide) modula-
tor, able to increase brain function and protect the brain
against toxicity. Exanatide (Byetta®) was approved by the
Food and Drug Administration for treatment of Type 2 Dia-
betes in patients who are already on an oral diabetes medica-
tion. The product comes in pre-filled syringes and is injected
subcutaneously twice daily.
Olbetam (Acipimox)
This agent inhibits the release of fatty acids from adipose
tissue and reduces blood concentration of very low density
lipoproteins and low density lipoproteins with a subsequent
reduction in triglyceride and cholesterol levels [27]. It im-
proves growth hormone secretion and reduces lipid peroxi-
dation. Olbetam is indicated as adjunctive therapy to diet and
weight loss in the treatment of several lipid disorders. The
dosage is between 500-750 mg/day.
PPAR Gamma Modulators
Peroxisome proliferator-activated receptors (PPARs) are
members of the nuclear hormone receptor superfamily of
transcription factors that are related to retinoid, steroid and
thyroid hormone receptors. PPARs play an important role in
many cellular functions including lipid metabolism, cell pro-
liferation, differentiation, adipogenesis and inflammatory
signaling. Modulation of PPAR gamma generally reduces
inflammation, improves immunity and reduces blood glu-
cose. Two examples of PPAR modulators are:
a) Rosiglitazone (Avantia), an insulin-sensitizing drug
that is a ligand for PPAR-gamma [28]. The dose is 4
mg once or twice a day.
b) Gugulipids, from the plant Commiphora mukul,
which block the PPAR-mediated differentiation of
preadipocytes into mature adipocytes [29].
Two very promising CRM (NADH/oxaloacetic acid and
Naloxone) are discussed elsewhere in this Supplement. Other
candidate CRM which are not readily available are listed
below. The list is merely an example of possible CRM and it
is by no means exhaustive. Further research regarding the
CRM effects of each compound may help in establishing
their mode of action. Furthermore, the clinical adverse ef-
fects of these agents have not been clarified and are best used
under expert specialist supervision.
Leptin
This is a molecule, produced by adipocytes, that stimu-
lates fat metabolism and reduces body weight. A reduction
of dietary intake causes leptin levels to fall and this interferes
with the secretion of testosterone, progesterone, growth
hormone and thyroid hormones as a response for adaptation
[30]. Therefore, leptin mediates the clinical effects of CR. As
a result, agents which affect leptin production must also be
classified as CRM. Together with insulin and ghrelin (a
growth hormone stimulator) leptin balances the ratio of ap-
petite promoters vs. appetite blockers in the hypothalamus in
the brain and so regulates homeostasis and food intake.
Leptin is stimulated by PPAR modulators such as rosiglita-
zone. Human recombinant leptin costs approximately $140
for 0.5 mg, but nicotinic acid can help increase its concentra-
tion. However, leptin mediates the effects of diabetic car-
diomyopathy [31] and its long term effects are not clear.
Calorie Restriction Mimetics Open Longevity Science, 2009, Volume 3 19
Deoxyglucose
The first CRM described, inhibits glycolysis and mimics
some of the effects of CR, particularly increased insulin sen-
sitivity, reduced glucose levels and other biochemical
changes [32]. Research is still under way to identify more
about its possible benefits on humans. What is known about
deoxyglucose is that it can be toxic in high dosages.
Modulators of Sirtuins
Sirtuins are histone deacetylases that catalyze deacetyla-
tion reaction in an NAD(+)-dependent manner [33]. Activa-
tion of sirtuins improves longevity and health span in many
species. This can be achieved by STAC –sirtuin activating
compounds. Examples of STAC are chalchone [34], sirtinol,
which among other actions, reduces pro-inflammation me-
diators [35] and fisetin (a flavonoid, antioxidant compound).
Fisetin is a potent suppressor of some inflammatory cytoki-
nes/chemokines and an angiogenic factor [36].
4-Phenylbutyrate (PBA)
Increases median and maximum lifespan in flies. In addi-
tion, it increases histone deacetylation [37].
Hydroxycitrate
An active ingredient extracted from the Garcinia cambo-
gia, reduces caloric intake and cholesterol [38] and it is cur-
rently used in weight control [39].
Gymnemoside
Isolated from the leaves of Gymnema sylvestre [40],
gymnemoside modulates glucose metabolism.
Adiponectin
Together with leptin, it takes part in fat metabolism. It is
activated by PPAR modulators such as rosiglitazone [41]. It
enhances phosphorylation of AMPK [42], although it can
increase total and cardiovascular mortality [43]. Human re-
combinant adiponectin is available for sale costing approx
$350 per 50 mcg.
Iodoacetate
An alkylating agent, it protects against toxic metabolites
of glucose. Iodoacetate prevents formation of disulfide
bonds, is a glycolysis-inhibitor and an anti-cancer agent [44].
DPP-4 Inhibitors
Diapeptidyl peptidase-4 (DPP-4) is an enzyme that
modulates Glucagon-Like Peptide, allowing glucagon to
increase glucose concentration [45]. DPP-4 inhibitors have
the opposite effect, reducing glucose plasma levels, and are
candidate CRM.
Peptide PYY3-36
This protein fragment is released from the bowel follow-
ing a meal. It then inhibits food intake by acting on the hun-
ger centre in the hypothalamus [46]. By reducing appetite
and glucose metabolism (actions similar to those seen in
CR), it can meet some of the criteria for consideration as a
CRM.
Modulators of NPY
The neuropeptide Y (NPY) is a small protein fragment
which increases appetite, induces obesity and reduces the
metabolic rate. CR modulates the production of NPY by se-
lectively blocking receptors in the hippocampal region of the
brain and by stimulating others in the hypothalamus. Any
modulation of NPY release would result in exactly the same
clinical effects as those seen in CR [47].
Rapamycin
It is known that CR downregulates TOR (target of ra-
pamycin) [48]. Many longevity genes encode components of
TOR pathway, so rapamycin which is a TOR inhibitor, can
be classified as a CRM.
Galanin Antagonists
These block galanin (which increases appetite and re-
duces insulin) [49,50]. An example is the antagonist M35.
Aldifen (2,4-Dinitrophenol)
is a hormetic metabolic poison [51] that causes mild mi-
tochondrial uncoupling, interfering with energy production.
However, overdose is lethal. Nevertheless, metabolic poi-
sons with hormetic effects (such as oligomycin, carbonyl-
cyanide, rotenone, antimycin, and malonate) are being inves-
tigated as having not only CRM actions but also other health
benefits [52].
GENERAL CONCLUSIONS
Clearly, a CRM cannot mimic all of the actions of CR, so
it must be combined with other CRM which complement
each other, in order to cover as many actions of CR as possi-
ble.
For example, Acomplia, metformin and resveratrol can
be combined for maximum effect. It is worth noting that
Intermittent Fasting (IF) is an intervention that may mimic
the effects of CR itself. However, IF increases lifespan even
when the overall calories are not reduced. It appears that it is
the stress of fasting rather than the reduced calories that
cause the benefit. This supports the view that the stress of
fasting is a hormetic challenge which helps activate the pro-
tection pathways that are also active in CR [53]. A search for
CRM can be extended to find IF mimetics such as RHEB, a
GTPase, which is a mediator through Daf16 and TOR [54].
The increased amount of research into CR has given us
promising directions into identifying effective agents which
reproduce the exact benefits of CR, without the need to fol-
low long calorie-restricted diets. The most promising and
clinically relevant CRM are those that reproduce at least one
genetic and two biochemical, or at least five biochemi-
cal/clinical benefits of CR. While research is continuing,
many physicians who already recommend these compounds
to their patients for other indications, have now started real-
ising that their treatment has an added possible health-
extending bonus.
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Received: April 22, 2009 Revised: May 14, 2009 Accepted: October 05, 2009
© Marios Kyriazis; Licensee Bentham Open.
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... 149 DR not only prolongs lifespan but also prevents aging-related diseases. Target of rapamycin (TOR)/ribosomal protein S6 kinase (S6 K), the AMP-activated kinase (AMPK), 150 An increasing number of polyphenols in small berries have emerged as DR mimetics to activate AMPK and sirtuins in response to DR, such as fisetin and resveratrol. 151 Additionally, TOR represents another genetic signaling pathway that has become a main focus for developing DR mimetics. ...
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Aging is an inevitable, irreversible, and complex process of damage accumulation and functional decline, increasing the risk of various chronic diseases. However, for now no drug can delay aging process nor cure aging-related diseases. Nutritional intervention is considered as a key and effective strategy to promote healthy aging and improve life quality. Small berries, as one of the most common and popular fruits, have been demonstrated to improve cognitive function and possess neuroprotective activities. However, the anti-aging effects of small berries have not been systematically elucidated yet. This review mainly focuses on small berries' anti-aging activity studies involving small berry types, active components, the utilized model organism Caenorhabditis elegans (C. elegans), related signaling pathways, and molecular mechanisms. The purpose of this review is to propose effective strategies to evaluate the anti-aging effects of small berries and provide guidance for the development of anti-aging supplements from small berries.
... Ex-4 which was originally a peptide isolated from the venom of the lizard, Helodermasuspectum, shares 53% structural homology with GLP-1 [63]. Peripheral exendin-4 administration mimics the anti-aging effects through caloric restriction [18], reduces plasma glucose levels [64] and decelerates food intake and body weight gain [65]. In particular, it was shown to protect neurons against oligomerinduced dysregulation of IRS-1 phosphorylation [18]. ...
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Background: Metabolic syndromes such as insulin resistance, type 2 diabetes and obesity share common pathogenic pathways with some age-related neurodegenerative disorders. Impaired insulin signaling, inflammation, mitochondrial dysfunction and ER stress can be both causatives and consequences in both groups of the diseases. Patients with chronic metabolic disorders therefore have potential risks to develop neurological diseases in late-age phase and vice versa those who with neurodegenerative diseases also have impairments in metabolic signaling. Method: In this review, we summarize about the interrelation between pathogenic pathways, common drug targets as well as known and developing therapeutics for these "modern" diseases. Results: There are conventional medicines for insulin resistance associated metabolic disorders such as insulin analogues, insulin sensitizers and ER stress releasers which have been suggested in the treatments of some neurodegenerative diseases. Some used or tested therapeutics such as bromocriptine, memantine andα-2A adrenergic antagonists for Parkinson's and Alzheimer's diseases, vice versa, were promisingly shown as alternative or complementary drugs for metabolic syndromes. Conclusion: Therefore, it is important and possible to consider contemporary control and intervention for both diseases.
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In the face of ever-changing cellular environments during life and ageing, the nervous system ensures the coordination of behaviour and physiology. Over time, however, the nervous system declines structurally and functionally, leading to age-related cognitive and behavioural decline in humans. Aspects of nervous system ageing are being studied using C. elegans as a model system. Here we review the age-related neuronal changes that occur at the structural, cellular and functional levels in normally ageing animals, as well as how these changes relate to lifespan in healthy ageing and in neurodegenerative conditions. Understanding the cellular mechanisms that result in neuronal decline in C. elegans will help identify cellular factors that protect the nervous system structure and function during normal ageing and in disease states. Ultimately, elucidating the molecular networks and cellular processes underlying the ageing of the nervous system will fuel research and design of interventions to improve human life at old age.
Ageing is characterised by a wide variety of physiological changes and, as a consequence, an anti-ageing compound must fulfil a wide variety of roles to be effective. Carnosine is an antioxidant, antiglycating and neuroprotective compound with well-studied clinical benefits. It is becoming a clinically accepted nutritional supplement with uses across a considerable spectrum of chronic diseases, from senile cataract to dementia. In this review, the benefits and actions of carnosine are discussed in the light of current research findings.
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Context Prolonged calorie restriction increases life span in rodents. Whether prolonged calorie restriction affects biomarkers of longevity or markers of oxidative stress, or reduces metabolic rate beyond that expected from reduced metabolic mass, has not been investigated in humans.Objective To examine the effects of 6 months of calorie restriction, with or without exercise, in overweight, nonobese (body mass index, 25 to <30) men and women.Design, Setting, and Participants Randomized controlled trial of healthy, sedentary men and women (N = 48) conducted between March 2002 and August 2004 at a research center in Baton Rouge, La.Intervention Participants were randomized to 1 of 4 groups for 6 months: control (weight maintenance diet); calorie restriction (25% calorie restriction of baseline energy requirements); calorie restriction with exercise (12.5% calorie restriction plus 12.5% increase in energy expenditure by structured exercise); very low-calorie diet (890 kcal/d until 15% weight reduction, followed by a weight maintenance diet).Main Outcome Measures Body composition; dehydroepiandrosterone sulfate (DHEAS), glucose, and insulin levels; protein carbonyls; DNA damage; 24-hour energy expenditure; and core body temperature.Results Mean (SEM) weight change at 6 months in the 4 groups was as follows: controls, −1.0% (1.1%); calorie restriction, −10.4% (0.9%); calorie restriction with exercise, −10.0% (0.8%); and very low-calorie diet, −13.9% (0.7%). At 6 months, fasting insulin levels were significantly reduced from baseline in the intervention groups (all P<.01), whereas DHEAS and glucose levels were unchanged. Core body temperature was reduced in the calorie restriction and calorie restriction with exercise groups (both P<.05). After adjustment for changes in body composition, sedentary 24-hour energy expenditure was unchanged in controls, but decreased in the calorie restriction (−135 kcal/d [42 kcal/d]), calorie restriction with exercise (−117 kcal/d [52 kcal/d]), and very low-calorie diet (−125 kcal/d [35 kcal/d]) groups (all P<.008). These “metabolic adaptations” (~ 6% more than expected based on loss of metabolic mass) were statistically different from controls (P<.05). Protein carbonyl concentrations were not changed from baseline to month 6 in any group, whereas DNA damage was also reduced from baseline in all intervention groups (P <.005).Conclusions Our findings suggest that 2 biomarkers of longevity (fasting insulin level and body temperature) are decreased by prolonged calorie restriction in humans and support the theory that metabolic rate is reduced beyond the level expected from reduced metabolic body mass. Studies of longer duration are required to determine if calorie restriction attenuates the aging process in humans.Trial Registration ClinicalTrials.gov Identifier: NCT00099151 Figures in this Article Prolonged calorie restriction increases life span in rodents and other shorter-lived species.1 Whether this occurs in longer-lived species is unknown, although the effect of prolonged calorie restriction in nonhuman primates is under investigation. One hypothesis to explain the antiaging effects of calorie restriction is reduced energy expenditure with a consequent reduction in the production of reactive oxygen species (ROS).2- 3 However, other metabolic effects associated with calorie restriction, including alterations in insulin sensitivity and signaling, neuroendocrine function, stress response, or a combination of these, may retard aging.4 Total energy expenditure is made up of resting energy expenditure (50%-80% of energy), the thermic effect of feeding (~10%), and nonresting energy expenditure (10%-40%).5 Whether total energy expenditure is reduced beyond the level expected for a given reduction in the size of the metabolizing mass following calorie restriction is debated. Leibel et al6 showed that a 10% weight loss reduced sedentary 24-hour energy intake for weight maintenance between 15% and 20% in obese patients, suggesting that metabolic adaptation occurs in humans. However, the weight loss was achieved quickly with a liquid diet and, with the exception of several normal-weight patients in the study by Leibel et al, the effects of prolonged calorie restriction on energy expenditure in nonobese humans have not been assessed. In rhesus monkeys, resting energy expenditure adjusted for fat-free mass (FFM) and fat mass was lower after 11 years of calorie restriction.7 Similarly, total energy expenditure was lower in monkeys following 10 years of weight clamping.8 Studies in rodents have proven more controversial with reports of decreased, no change, or increased adjusted energy expenditure in calorie restriction vs ad libitum fed–animals.9- 13 One of the most widely accepted theories of aging is the oxidative stress theory, which hypothesizes that oxidative damage produced by ROS accumulates over time, leading to the development of disease such as cancer, aging, and ultimately death.14 Reactive oxygen species are byproducts of energy metabolism, with 0.2% to 2.0% of oxygen consumption (O2) resulting in ROS formation.15- 16 Reactive oxygen species attack lipids, proteins, and DNA, generating a number of products that affect normal cell functioning.17 Studies in rodents subjected to calorie restriction demonstrate a 30% decrease in 8-oxo-7,8-dihydroguanine (8-oxodG) in brain, skeletal muscle, and heart; similar reductions in carbonyl content in brain and muscle18- 22; and transcriptional patterns that suggest decreased oxidative stress in response to calorie restriction.23 Rhesus monkeys subjected to calorie restriction exhibit divergent responses in the expression of genes involved in oxidative stress.24 Core body temperature and levels of dehydroepiandrosterone sulfate (DHEAS) and insulin are proposed biomarkers of calorie restriction and longevity in rodents and monkeys.25 Data from the Baltimore Longitudinal Study of Aging support the association between longevity and temperature and insulin and DHEAS levels; men with plasma insulin concentration or oral temperature below the median, and DHEAS levels above the median, live longer.26 Furthermore, in a cross-sectional study that compared individuals following self-imposed nutritionally adequate calorie restriction for 6 years with normal-weight controls, Fontana et al27 found that participants in the calorie restriction group had lower levels of serum glucose, insulin, and markers of atherosclerosis. The aims of this study were to establish whether prolonged calorie restriction by diet alone or in conjunction with exercise can be successfully implemented in nonobese individuals and to determine the effects of the interventions on established biomarkers of calorie restriction, sedentary energy expenditure, and oxidative damage to DNA and proteins.
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Calorie restriction, the only non-genetic intervention known to slow aging and extend life span in organisms ranging from yeast to mice, has been linked to the down-regulation of Tor, Akt, and Ras signaling. In this study, we demonstrate that the serine/threonine kinase Rim15 is required for yeast chronological life span extension associated with the deficiencies in Tor and Ras signaling, and show that it is also required for the longevity promoting effect of both extreme (water) and standard (0.5% glucose) calorie restriction. Deletion of stress resistance transcription factors Gis1 and Msn2/4, which are positively regulated by Rim15, also caused a major although not complete reversion of the effect of calorie restriction on life span. Surprisingly, the lack of Rim15 only partially decreased the 10-fold life span extension caused by the combination of CR and the deletion of both RAS2 and SCH9/AKT. These results suggest that Rim15 functions as a central regulator of stress resistance and longevity downstream of the Ras/cAMP/PKA, Tor and Sch9 pathways during calorie restriction. Transcription factors Msn2, Msn4, and Gis1 are also important for Rim15-dependent life span extension but that additional mediators are involved.
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Caloric restriction is the most effective non-genetic intervention to enhance lifespan known to date. A major research interest has been the development of therapeutic strategies capable of promoting the beneficial results of this dietary regimen. In this sense, we propose that compounds that decrease the efficiency of energy conversion, such as mitochondrial uncouplers, can be caloric restriction mimetics. Treatment of mice with low doses of the protonophore 2,4-dinitrophenol promotes enhanced tissue respiratory rates, improved serological glucose, triglyceride and insulin levels, decrease of reactive oxygen species levels and tissue DNA and protein oxidation, as well as reduced body weight. Importantly, 2,4-dinitrophenol-treated animals also presented enhanced longevity. Our results demonstrate that mild mitochondrial uncoupling is a highly effective in vivo antioxidant strategy, and describe the first therapeutic intervention capable of effectively reproducing the physiological, metabolic and lifespan effects of caloric restriction in healthy mammals.
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Calorie restriction and reduced somatotropic (growth hormone and insulin-like growth factor-1) signaling have a widespread though not universal ability to extend life. These interventions are considered central tools to understanding the downstream events that lead to the increase in healthy life span. As these approaches have been validated, the animals phenotyped, and the mechanisms proposed, many challenges have emerged. In this article, we give several examples and propose several considerations, opportunities, and approaches that may identify major mechanisms through which these interventions exert their effects, and which may lead to drug therapy to increase "health span."