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Calorie Restriction Mimetics: Examples and Mode of Action

  • National Gerontology Centre - Cyprus


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.
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-
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:
Maintains DHEA levels [10].
Modulates PPAR [11]. Suppresses PGE-2, TNF-alpha
and CRP (thus reduces the inflammation response)
Stimulates Brain-Derived Neurotropic Factor (BDNF)
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].
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 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.
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.
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.
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.
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
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].
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].
Isolated from the leaves of Gymnema sylvestre [40],
gymnemoside modulates glucose metabolism.
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.
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
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].
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].
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-
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.
[1] Barzilai N, Bartke A. Biological approaches to mechanistically
understand the healthy life span extension achieved by calorie re-
striction and modulation of hormones. J Gerontol A Biol Sci Med
Sci 2009; 64(2): 187-91.
20 Open Longevity Science, 2009, Volume 3 Marios Kyriazis
[2] Bauer JH, Poon PC, Glatt-Deeley H, Abrams JM, Helfand SL.
Neuronal expression of p53 dominant-negative proteins in adult
Drosophila melanogaster extends life span. Curr Biol 2005; 15(22):
[3] Marzetti E, Lawler JM, Hiona A, Manini T, Seo AY, Leeuwen-
burgh C. Modulation of age-induced apoptotic signaling and cellu-
lar remodeling by exercise and calorie restriction in skeletal mus-
cle. Free Radic Biol Med 2008; 44(2): 160-8.
[4] Allard JS, Perez E, Zou S, de Cabo R. Dietary activators of Sirt1.
Mol Cell Endocrinol 2009; 299(1): 58-63.
[5] Jiang WJ. Sirtuins: novel targets for metabolic disease in drug
development. Biochem Biophys Res Commun 2008; 373(3): 341-4.
[6] Greer EL, Dowlatshahi D, Banko MR, et al. An AMPK-FOXO
pathway mediates longevity induced by a novel method of dietary
restriction in C. elegans. Curr Biol 2007; 17: 1646-56.
[7] Hyun DH, Emerson SS, Jo DG, Mattson MP, de Cabo R. Calorie
restriction up-regulates the plasma membrane redox system in brain
cells and suppresses oxidative stress during aging. Proc Natl Acad
Sci USA 2006; 103(52): 19908-12.
[8] Kim YJ, Kim HJ, No JK, Chung HY, Fernandes G. Anti-
inflammatory action of dietary fish oil and calorie restriction. Life
Sci 2006; 78(21): 2523-32.
[9] Yang H, Yang T, Baur JA, et al. Nutrient-sensitive mitochondrial
NAD+ levels dictate cell survi. J Clin Endocrinol Metab 1997;
82(7): 2093-6.
[10] Lane MA, Ingram DK, Ball SS, Roth GS. Dehydroepiandrosterone
sulfate: a biomarker of primate aging slowed by calorie restriction.
J Clin Endocrinol Metab 1997; 82(7): 2093-6.
[11] Mulligan JD, Stewart AM, Saupe KW. Downregulation of plasma
insulin levels and hepatic PPARgamma expression during the first
week of caloric restriction in mice. Exp Gerontol 2008; 43(3): 146-
[12] Bosutti A, Malaponte G, Zanetti M, et al. Calorie restriction modu-
lates inactivity-induced changes in the inflammatory markers C-
reactive protein and pentraxin-3. Clin Endocrinol Metab 2008;
93(8): 3226-9.
[13] Araya AV, Orellana X, Espinoza J. Evaluation of the effect of
caloric restriction on serum BDNF in overweight and obese sub-
jects: preliminary evidences. Endocrine 2008; 33(3): 300-4.
[14] Heilbronn LK, de Jonge L, Frisard MI, et al. Pennington CALERIE
Team. Effect of 6-month calorie restriction on biomarkers of lon-
gevity, metabolic adaptation, and oxidative stress in overweight in-
dividuals: a randomized controlled trial. JAMA 2006; 295(13):
[15] Redman LM, Ravussin E. Endocrine alterations in response to
calorie restriction in humans. Mol Cell Endocrinol 2009; 299(1);
[16] Weiss EP, Holloszy JO. Improvements in body composition, glu-
cose tolerance, and insulin action induced by increasing energy ex-
penditure or decreasing energy intake. J Nutr 2007; 137(4): 1087-
[17] Geng YQ, Guan JT, Xu MY, Xu XH, Fu YC. Behavioral study of
calorie-restricted rats from early old age. Conf Proc IEEE Eng Med
Biol Soc 2007; 2007: 2393-5.
[18] Witte AVM, Fobker R, Gellner S, Flöel KA. Caloric restriction
improves memory in elderly humans. Proc Natl Acad Sci USA
2009 [Epub ahead of print].
[19] Karasik D, Demissie S, Cupples LA, Kiel DP. Disentangling the
genetic determinants of human aging: biological age as an alterna-
tive to the use of survival measures. J Gerontol A Biol Sci Med Sci
2005; 60(5): 574-87.
[20] Ingram DK, Nakamura E, Smucny D, Roth GS, Lane MA. Strategy
for identifying biomarkers of aging in long-lived species. Exp
Gerontol 2001; 36(7): 1025-34.
[21] Anisimov VN, Berstein LM, Egormin PA, et al. Metformin slows
down aging and extends life span of female SHR mice. Cell Cycle
2008; 7(17): 2769-73.
[22] Wood JG, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric
restriction and delay ageing in metazoans. Nature 2004; 430(7000):
[23] Zyromski NJ, Mathur A, Pitt HA, et al. Cannabinoid receptor-1
blockade attenuates acute pancreatitis in obesity by an adiponectin
mediated mechanism. J Gastrointest Surg 2009; 13(5): 831-8.
[24] Loh KY, Kew ST. Endocannabinoid system and cardio-metabolic
risk. Med J Malaysia 2008; 63(4): 348-50.
[25] Sourris KC, Forbes JM, Cooper ME. Therapeutic interruption of
advanced glycation in diabetic nephropathy: do all roads lead to
Rome? Ann N Y Acad Sci 2008; 1126: 101-6.
[26] Tews D, Lehr S, Hartwig S, Osmers A, Paßlack W, Eckel J. Anti-
apoptotic action of exendin-4 in INS-1 beta cells: comparative pro-
tein pattern analysis of isolated mitochondria. Horm Metab Res
2009; 41(4): 294-301.
[27] Salgin B, Marcovecchio ML, Humphreys SM, et al. Effects of
prolonged fasting and sustained lipolysis on insulin secretion and
insulin sensitivity in normal subjects. Am J Physiol Endocrinol Me-
tab 2009; 296(3): E454-61.
[28] Holguin F, Rojas M, Hart CM. The peroxisome proliferator acti-
vated receptor gamma (PPARgamma) ligand rosiglitazone modu-
lates bronchoalveolar lavage levels of leptin, adiponectin, and in-
flammatory cytokines in lean and obese mice. Lung 2007; 185(6):
[29] Nohr LA, Rasmussen LB, Straand J. Resin from the mukul myrrh
tree, guggul, can it be used for treating hypercholesterolemia? A
randomized, controlled study. Complement Ther Med 2009; 17(1):
[30] Sirotkin AV, Chrenková M, Nitrayová S, et al. Effects of chronic
food restriction and treatments with leptin or ghrelin on different
reproductive parameters of male rats. Peptides 2008; 29(8): 1362-8.
[31] Majumdar P, Chen S, George B, Sen S, Karmazyn M, Chakrabarti
S. Leptin and endothelin-1 mediated increased extracellular matrix
protein production and cardiomyocyte hypertrophy in diabetic heart
disease. Diabetes Metab Res Rev 2009 [Epub ahead of print].
[32] Ingram DK, Zhu M, Mamczarz J, et al. Calorie restriction mimet-
ics: an emerging research field. Aging Cell 2006; 5(2): 97-108.
[33] Gan L. Therapeutic potential of sirtuin-activating compounds in
Alzheimer's disease. Drug News Perspect 2007; 20(4): 233-9.
[34] Kahyo T, Ichikawa S, Hatanaka T, Yamada MK, Setou M. A novel
chalcone polyphenol inhibits the deacetylase activity of SIRT1 and
cell growth in HEK293T cells. J Pharmacol Sci 2008; 108(3): 364-
[35] Liu FC, Day YJ, Liou JT, Lau YT, Yu HP. Sirtinol attenuates he-
patic injury and pro-inflammatory cytokine production following
trauma-hemorrhage in male Sprague-Dawley rats. Acta Anaesthe-
siol Scand 2008; 52(5): 635-40.
[36] Lee JD, Huh JE, Jeon G, et al. Flavonol-rich RVHxR from Rhus
verniciflua Stokes and its major compound fisetin inhibits inflam-
mation-related cytokines and angiogenic factor in rheumatoid ar-
thritic fibroblast-like synovial cells and in vivo models. Int
Immunopharmacol 2009; 9(3): 268-76.
[37] Kang HL, Benzer S, Min KT. Life extension in Drosophila by
feeding a drug. Proc Natl Acad Sci USA 2002; 99(2): 838-43.
[38] Vasques CA, Rossetto S, Halmenschlager G, et al. Evaluation of
the pharmacotherapeutic efficacy of Garcinia cambogia plus Amor-
phophallus konjac for the treatment of obesity. Phytother Res 2008;
22(9): 1135-40.
[39] Hayamizu K, Tomi H, Kaneko I, Shen M, Soni MG, Yoshino G.
Effects of Garcinia cambogia extract on serum sex hormones in
overweight subjects. Fitoterapia 2008; 79(4): 255-61.
[40] Zhu XM, Xie P, Di YT, Peng SL, Ding LS, Wang MK. Two new
triterpenoid saponins from Gymnema sylvestre. J Integr Plant Biol
2008; 50(5): 589-92.
[41] Kanaya AM, Harris T, Goodpaster BH, Tylavsky F, Cummings SR.
Adipocytokines attenuate the association between visceral adipos-
ity and diabetes in older adults; Health, Aging, and Body Composi-
tion (ABC) Study. Diabetes Care 2004; 27(6): 1375-80.
[42] Kondo M, Shibata R, Miura R, et al. Caloric restriction stimulates
revascularization in response to ischemia via adiponectin-mediated
activation of endothelial nitric-oxide synthase. J Biol Chem 2009;
284(3): 1718-24.
[43] Poehls J, Wassel CL, Harris TB, et al. Association of adiponectin
with mortality in older adults: the Health, Aging, and Body Com-
position Study. Diabetologia 2009 [Epub ahead of print].
[44] Fawzia A Fahim, Mady EA. Antitumor activities of iodoacetate
and dimethylsulphoxide against solid Ehrlich Carcinoma growth in
mice. Biol Res 2003; 36 (2): 253-62.
[45] Siddiqui NI. Incretin mimetics and DPP-4 inhibitors: new approach
to treatment of type 2 diabetes mellitus. Mymensingh Med J 2009;
18(1): 113-24.
[46] Karra E, Chandarana K, Batterham RL. The role of peptide YY in
appetite regulation and obesity. J Physiol 2009; 587(Pt 1): 19-25.
Calorie Restriction Mimetics Open Longevity Science, 2009, Volume 3 21
[47] Minor RK, Chang JW, de Cabo R. Hungry for life: How the arcu-
ate nucleus and neuropeptide Y may play a critical role in mediat-
ing the benefits of calorie restriction. Mol Cell Endocrinol 2009;
299(1): 79-88.
[48] Wei M, Fabrizio P, Hu J, et al. Life span extension by calorie re-
striction depends on Rim15 and transcription factors downstream
of Ras/PKA, Tor, and Sch9. PLoS Genet 2008; 4(1): e13.
[49] Tachibana T, Mori M, Khan MS, Ueda H, Sugahara K, Hiramatsu
K. Central administration of galanin stimulates feeding behavior in
chicks. Comp Biochem Physiol A Mol Integr Physiol 2008 [Epub
ahead of print].
[50] Vrontakis ME. Galanin: a biologically active peptide. Curr Drug
Targets CNS Neurol Disord 2002; 1(6): 531-41.
[51] Caldeira da Silva CC, Cerqueira FM, Barbosa LF, Medeiros MH,
Kowaltowski AJ. Mild mitochondrial uncoupling in mice affects
energy metabolism, redox balance and longevity. Aging Cell 2008;
7(4): 552-60.
[52] Jonas WB, Ives JA. Should we explore the clinical utility of hor-
mesis? Hum Exp Toxicol 2008; 27(2): 123-7.
[53] Kyriazis M. Clinical anti-aging hormetic strategies. Rejuvenation
Res 2005; 8(2): 96-100.
[54] Honjoh S, Yamamoto T, Uno M, Nishida E. Signalling through
RHEB-1 mediates intermittent fasting-induced longevity in C. ele-
gans. Nature 2009; 457(7230): 726-30.
Received: April 22, 2009 Revised: May 14, 2009 Accepted: October 05, 2009
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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. ...
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.
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 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.
Calorie restriction (CR), 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 theserine/threonine kinase Rim15 is required for yeast chronological life span extension caused by deficiencies in Ras2, Tor1, and Sch9, and by 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. The deletion of both RAS2 and the Akt and S6 kinase homolog SCH9 in combination with calorie restriction caused a remarkable 10-fold life span extension, which, surprisingly, was only partially reversed by the lack of Rim15. These results indicate that the Ras/cAMP/PKA/Rim15/Msn2/4 and the Tor/Sch9/Rim15/Gis1 pathways are major mediators of the calorie restriction-dependent stress resistance and life span extension, although additional mediators are involved. Notably, the anti-aging effect caused by the inactivation of both pathways is much more potent than that caused by CR.
We report that feeding Drosophila throughout adulthood with 4-phenylbutyrate (PBA) can significantly increase lifespan, without diminution of locomotor vigor, resistance to stress, or reproductive ability. Treatment for a limited period, either early or late in adult life, is also effective. Flies fed PBA show a global increase in histone acetylation as well as a dramatically altered pattern of gene expression, including induction or repression of numerous genes. The delay in aging may result from the altered physiological state.
Laboratory studies consistently demonstrate extended lifespan in animals on calorie restriction (CR), where total caloric intake is reduced by 10–40% but adequate nutrition is otherwise maintained. CR has been further shown to delay the onset and severity of chronic diseases associated with aging such as cancer, and to extend the functional health span of important faculties like cognition. Less understood are the underlying mechanisms through which CR might act to induce such alterations. One theory postulates that CR's beneficial effects are intimately tied to the neuroendocrine response to low energy availability, of which the arcuate nucleus in the hypothalamus plays a pivotal role. Neuropeptide Y (NPY), a neurotransmitter in the front line of the arcuate response to low energy availability, is the primary hunger signal affected by CR and therefore may be a critical mechanism for lifespan extension.
The existence of a close relationship between energy status and reproductive function is well-documented, especially in females, but its underlying mechanisms remain to be fully unfolded. This study aimed to examine the effects of restriction of daily calorie intake, as well as chronic treatments with the metabolic hormones leptin and ghrelin, on the secretion of different reproductive hormones, namely pituitary gonadotropins and prolactin, as well as testosterone, in male rats. Restriction (50%) in daily food intake for 20 days significantly reduced body weight as well as plasma PRL and T levels, without affecting basal LH and FSH concentrations and testicular weight. Chronic administration of leptin to rats fed ad libitum increased plasma PRL levels and decreased circulating T, while it did not alter other hormonal parameters under analysis. In contrast, in rats subjected to 50% calorie restriction, leptin administration increased plasma T levels and reduced testis weight. Conversely, ghrelin failed to induce major hormonal changes but tended to increase testicular weight in fed animals, while repeated ghrelin injections in food-restricted males dramatically decreased plasma LH and T concentrations and reduced testis weight. In sum, we document herein the isolated and combined effects of metabolic stress (50% food restriction) and leptin or ghrelin treatments on several reproductive hormones in adult male rats. Overall, our results further stress the impact and complex way of action of different metabolic cues, such as energy status and key hormones, in reproductive function also in the male.
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.
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.
We investigated the role of leptin and its interaction with endothelin 1 (ET-1) in fibronectin (FN) synthesis and cardiomyocyte hypertrophy, two characteristic features of diabetic cardiomyopathy. Endothelial cells [human umbilical vein endothelial cells (HUVECs)] were examined for FN production and neonatal rat cardiomyocytes for hypertrophy, following incubation with glucose, ET-1, leptin and specific blockers. FN, ET-1, leptin and leptin receptors mRNA expression and FN protein were measured. Myocytes were also morphometrically examined. Furthermore, hearts from streptozotocin-diabetic rats were analysed. Glucose caused increased FN mRNA and protein expression in HUVECs and cardiomyocytes hypertrophy along with upregulation of ET-1 mRNA, leptin mRNA and protein. Glucosemimetic effects were seen with leptin and ET-1. Leptin receptor antagonist (leptin quadruple mutant) and dual endothelin A endothelin B (ETA/ETB) receptor blocker bosentan normalized such abnormalities. Hearts from the diabetic animals showed hypertrophy and similar mRNA changes. These data indicate that in diabetes increased FN production and cardiomyocyte hypertrophy may be mediated through leptin with its interaction with ET-1.
Recent research in bio-medical science has shown an integral role of endocannabinoid system (ECS) in determining cardio-metabolic risk of human body. The mechanism is mediated through binding of endocannabinoids at the CB1 receptors. The stimulation of CB1 receptor in the brain is believed to control and mediate the effects on appetite. In normal physiology, CB1 receptors activation is responsible for energy homeostasis, govern emotions and behaviors such as anxiety, fear, appetite, food and water intake. CB1 receptors also found in peripheral tissues like liver, pancreas, skeletal muscles and adipose tissues, which play an important role in lipid and glucose metabolism. Over-activation of ECS is associated with various metabolic diseases such as dyslipidemia, insulin resistance, lipogenesis, excessive weight gain and increasing intra-abdominal obesity. All these events lead to increased cardiovascular risk. Use of selective CB1 receptor blocker such as rimonabant has shown to reduced waist circumference, better glycemic control, lower triglyceride levels, raise HDL cholesterol and over all reduction in total body fat. This drug has been recommended for patients with metabolic syndrome.
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."