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Toward a cancer-specific diet.

Bozzetti F, Zupec-Kania B.

Clin Nutr. 2016 Oct;35(5):1188-95. doi: 10.1016/j.clnu.2015.01.013. Epub 2015 Jan 23.

PMID: 25707910




It is widely acknowledged that the energy metabolism of cancer cells mainly relies on anaerobic glycolysis and this has prompted many researchers to try to reduce the malignant cells growth of experimental tumours through a programme of calorie restriction. Recently this approach has been proposed also to cancer patients. In the meantime it was demonstrated that the effects of calorie restriction on tumour growth are mediated through the toxic effect of ketone bodies on cancer cells which have a defective mitochondrial function, while these substrates are well-utilized by the normal cells.


Despite the paucity of data it appears that modulation of tumour growth by the calorie restriction/nutritional support is unlikekly in humans for several reasons: the different tumour cells growth rate and different tumour/host carcass ratio and duration of treatment, between tumour-bearing animals and patients.


There is a large consensus in literature that maintaining a normal body weight and preserving the lean body mass through an adequate nutrition is beneficial in cancer patients. The nutritional approach through a ketogenic diet which may be toxic for the cancer cells while is well utilized and tolerated by the patient seems promising in a next future.

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The below paper is not pdf-availed.


Practical alternatives to chronic caloric restriction for optimizing vascular function with aging.

Martens CR, Seals DR.

J Physiol. 2016 Sep 19. doi: 10.1113/JP272348. [Epub ahead of print]

PMID: 27641062




Calorie restriction (CR) in the absence of malnutrition exerts a multitude of physiological benefits with aging in model organisms and in humans including improvements in vascular function.  Despite the well-known benefits of chronic CR, long-term energy restriction is likely not a feasible healthy lifestyle strategy in humans due to poor sustained adherence, and presents additional concerns if applied to normal weight older adults.  The purpose of this review will be to summarize what is known about the effects of CR on vascular function with aging including the underlying molecular "energy- and nutrient-sensing" mechanisms, and to discuss the limited but encouraging evidence for alternative pharmacological and lifestyle interventions that may improve vascular function with aging by mimicking the beneficial effects of long-term CR.

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Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress.

Huang, Li T, Wang L, Zhang L, Yan R, Li K, Xing S, Wu G, Hu L, Jia W, Lin SC, Dang CV, Song L, Gao P, Zhang H.

Cell Res. 2016 Sep 20. doi: 10.1038/cr.2016.109. [Epub ahead of print]

PMID: 27644987


ketone catabolism or ketolysis is re-activated in hepatocellular carcinoma (HCC) cells under nutrition deprivation conditions. … 3-oxoacid CoA-transferase 1 (OXCT1) … is re-induced by serum starvation-triggered mTORC2-AKT-SP1 signaling in HCC cells. … analysis of clinical HCC samples reveals that increased OXCT1 expression predicts higher patient mortality.


Short-term starvation attenuates liver ischemia-reperfusion injury (IRI) by Sirt1-autophagy signaling in mice.

Qin J, Zhou J, Dai X, Zhou H, Pan X, Wang X, Zhang F, Rao J, Lu L.

Am J Transl Res. 2016 Aug 15;8(8):3364-3375. eCollection 2016.

PMID: 27648127

[pdf-availed from the http://www.ajtr.org/V8_No8.html site.]

[Eye-balled liver ALT levels after liver injury were about a tenth that of control after CR.]

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Calorie Restricted High Protein Diets Downregulate Lipogenesis and Lower Intrahepatic Triglyceride Concentrations in Male Rats.

Margolis LM, Rivas DA, Ezzyat Y, Gaffney-Stomberg E, Young AJ, McClung JP, Fielding RA, Pasiakos SM.

Nutrients. 2016 Sep 15;8(9). pii: E571.

PMID: 27649241

Free Article


hepatic de novo lipogenesis (DNL) … CR (40% restriction), adequate (10%), or high (32%) protein (PRO) milk-based diets [“10% protein, 20% fat, and 70% carbohydrate (Adequate); and 32% protein, 22% fat, and 46% carbohydrate (PRO)”] for 16 weeks. ... Independent of calorie intake, 32% PRO tended to result in lower homeostatic model assessment of insulin resistance (HOMA-IR) values compared to 10% PRO, while insulin and homeostatic model assessment of β-cell function (HOMA-β) values were lower in CR than AL, regardless of protein intake. Intrahepatic triglyceride concentrations were 27.4 ± 4.5 and 11.7 ± 4.5 µmol·g-1 lower (p < 0.05) in CR and 32% PRO compared to AL and 10% PRO, respectively.


[The below paper is not pdf-availed.]

Energy restriction at young age, genetic variants in the insulin-like growth factor pathway and colorectal cancer risk in the Netherlands Cohort Study.

Simons CC, Schouten LJ, Godschalk RW, van Engeland M, van den Brandt PA, van Schooten FJ, Weijenberg MP.

Int J Cancer. 2016 Sep 20. doi: 10.1002/ijc.30439. [Epub ahead of print]

PMID: 27649841


The energy restriction (ER)-colorectal cancer (CRC) ... Individuals living in a Western city during the Hunger Winter (1944-45) or Western rural versus non-Western area were exposed to (severe) ER at young age. … showed increasing CRC risks in men, but confidence intervals were wide. … the IGF pathway might be involved in the ER-CRC association in men, but not women


Ghrelin is the metabolic link connecting calorie restriction to neuroprotection.

Bayliss JA, Andrews ZB.

Neural Regen Res. 2016 Aug;11(8):1228-1229. No abstract available.

PMID: 27651762


Calorie restriction (CR), or reducing calories without

causing malnutrition is beneficial in a number of pathological

conditions including diabetes, cancer and neurodegeneration.

Primates with a chronic overall 30% reduction in food

intake were found to be resistant to the MPTP model of PD

(Maswood et al., 2004). This study highlights that CR is neuroprotective

however, the difficulty to adhere to CR necessitates

an alternate method to recapitulate the neuroprotective

benefits of CR. Evidence from cells treated with serum from

CR rats suggests that a hormonal factor improves mitochondrial

function and cell viability (Lopez-Lluch et al., 2006).

One hormone that is elevated with prolonged fasting and

promptly falls post-prandially is ghrelin.


Ghrelin is neuroprotective in Parkinson's disease: molecular mechanisms of metabolic neuroprotection.

Bayliss JA, Andrews ZB.

Ther Adv Endocrinol Metab. 2013 Feb;4(1):25-36. doi: 10.1177/2042018813479645.

PMID: 23515333

Free PMC Article



Acylated but not des-acyl ghrelin is neuroprotective in an MPTP mouse model of Parkinson's disease.

Bayliss JA, Lemus M, Santos VV, Deo M, Elsworth JD, Andrews ZB.

J Neurochem. 2016 May;137(3):460-71. doi: 10.1111/jnc.13576. Epub 2016 Mar 11.

PMID: 26872221




Starving cancer from the outside and inside: separate and combined effects of calorie restriction and autophagy inhibition on Ras-driven tumors.

Lashinger LM, O'Flanagan CH, Dunlap SM, Rasmussen AJ, Sweeney S, Guo JY, Lodi A, Tiziani S, White E, Hursting SD.

Cancer Metab. 2016 Sep 16;4:18. eCollection 2016.

PMID: 27651895


30 % CR diet, relative to control diet, in nude mice resulted in significant decreases in body fat, blood glucose, and serum insulin, insulin-like growth factor-1, and leptin levels concurrent with increased adiponectin levels. In a xenograft … with (Atg5 +/+ ) and without (Atg5 -/-) autophagic capacity… tumor volume was greatest for Atg5 +/+ tumors in control-fed mice, intermediate for Atg5 +/+ tumors in CR-fed mice and Atg5 -/- tumors in control-fed mice, and lowest for Atg5 -/- tumors in CR mice. … the prosurvival effects of autophagy induction may mitigate the tumor suppressive effects of CR.

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Effect of Intermittent versus Chronic Calorie Restriction on Tumor Incidence: A Systematic Review and Meta-Analysis of Animal Studies.

Chen Y, Ling L, Su G, Han M, Fan X, Xun P, Xu G.

Sci Rep. 2016 Sep 22;6:33739. doi: 10.1038/srep33739.

PMID: 27653140


Both chronic calorie restriction (CCR) and intermittent calorie restriction (ICR) have shown anticancer effects. … Compared to CCR, ICR decreased tumor incidence in genetically engineered models (RR = 0.57; 95% CI: 0.37, 0.88) but increased the risk in chemically induced models (RR = 1.53, 95% CI: 1.13, 2.06). It appears that ICR decreases IGF-1 and leptin and increases adiponectin in genetically engineered models.


Fibroblast growth factor 21 has no direct role in regulating fertility in female mice.

Singhal G, Douris N, Fish AJ, Zhang X, Adams AC, Flier JS, Pissios P, Maratos-Flier E.

Mol Metab. 2016 May 18;5(8):690-8. doi: 10.1016/j.molmet.2016.05.010. eCollection 2016 Aug.

PMID: 27656406


fibroblast growth factor 21 (FGF21) was implicated as a signal from the liver to the hypothalamus that directly inhibits the hypothalamic-gonadotropin axis during fasting and starvation. However, FGF21 itself increases metabolic rate and can induce weight loss, which suggests that the effects of FGF21 on fertility may not be direct and may reflect changes in energy balance.

… ketogenic diet fed mice remain fertile despite significant elevation in serum FGF21 levels. Absence of FGF21 does not alter transient infertility induced by fasting. Centrally infused FGF21 does not suppress fertility despite its efficacy in inducing browning of inguinal white adipose tissue.

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Effects of long-term heat stress and dietary restriction on the expression of genes of steroidogenic pathway and small heat-shock proteins in rat testicular tissue.

Bozkaya F, Atli MO, Guzeloglu A, Kayis SA, Yildirim ME, Kurar E, Yilmaz R, Aydilek N.

Andrologia. 2016 Sep 23. doi: 10.1111/and.12668. [Epub ahead of print]

PMID: 27659778


small heat-shock proteins (sHSPs) ... Group I and II were kept at an ambient temperature of 22°C, while Groups III and IV were reared at 38°C for 9 weeks. Feed was freely available for Group I and Group III, while Group II and Group IV were fed 60% of the diet consumed by their ad libitum counterparts. … 9 weeks ... https://en.wikipedia.org/wiki/Steroidogenic_acute_regulatory_protein (StAR) … heat stress decreased the expression of StAR and HspB10 genes while dietary restriction upregulated StAR gene expression. The results suggested that long-term heat stress negatively affected the expression of StAR and HspB10 genes and the dietary restriction was able to reverse negative effect of heat stress on the expression of StAR gene in rat testis.

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Calorie restriction protects against experimental abdominal aortic aneurysms in mice
Yue Liu, Ting-Ting Wang, Ran Zhang, Wen-Yan Fu, Xu Wang, Fang Wang, Peng Gao, Yang-Nan Ding, Yan Xie, De-Long Hao, Hou-Zao Chen, De-Pei Liu
Journal of Experimental Medicine Sep 2016, jem.20151794; DOI: 10.1084/jem.20151794


Abdominal aortic aneurysm (AAA)... we subjected Apoe−/− mice to 12 wk of CR and then examined the incidence of angiotensin II (AngII)–induced AAA formation. We found that CR markedly reduced the incidence of AAA formation and attenuated aortic elastin degradation in Apoe−/− mice. ... ablation of SIRT1 in smooth muscle cells abolished the preventive effect of CR on AAA formation in Apoe−/− mice.

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Ultradian feeding in mice not only affects the peripheral clock in the liver, but also the master clock in the brain.

Sen S, Raingard H, Dumont S, Kalsbeek A, Vuillez P, Challet E.

Chronobiol Int. 2016 Sep 26:1-20. [Epub ahead of print]

PMID: 27668547


central clock in the suprachiasmatic nucleus (SCN) … clock (PER1) and clock-controlled (vasopressin) proteins. … ultradian 6-meals schedule (1 food access every 4 h) to abolish the daily periodicity of feeding. Mice fed with ultradian feeding that lost <10% body mass (i.e. isocaloric) displayed 1.5-h phase-advance of body temperature rhythm, but remained mostly nocturnal, together with up-regulated vasopressin and down-regulated PER1 and PER2 levels in the SCN. Hepatic expression of clock genes (Per2, Rev-erbα, and Clock) and Fgf21 was, respectively, phase-advanced and up-regulated by ultradian feeding. Mice fed with ultradian feeding that lost >10% body mass (i.e. hypocaloric) became more diurnal, hypothermic in late night, and displayed larger (3.5 h) advance of body temperature rhythm, more reduced PER1 expression in the SCN, and further modified gene expression in the liver (e.g. larger phase-advance of Per2 and up-regulated levels of Pgc-1α). While glucose rhythmicity was lost under ultradian feeding, the phase of daily rhythms in liver glycogen and plasma corticosterone (albeit increased in amplitude) remained unchanged. In conclusion, the additional impact of hypocaloric conditions on the SCN are mainly due to the metabolic and not the timing effects of restricted daytime feeding.

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Ultradian feeding in mice not only affects the peripheral clock in the liver, but also the master clock in the brain.

Sen S, Raingard H, Dumont S, Kalsbeek A, Vuillez P, Challet E.

Chronobiol Int. 2016 Sep 26:1-20. [Epub ahead of print]

PMID: 27668547


central clock in the suprachiasmatic nucleus (SCN) … clock (PER1) and clock-controlled (vasopressin) proteins. … ultradian 6-meals schedule (1 food access every 4 h) to abolish the daily periodicity of feeding. Mice fed with ultradian feeding that lost <10% body mass (i.e. isocaloric) displayed 1.5-h phase-advance of body temperature rhythm, but remained mostly nocturnal, together with up-regulated vasopressin and down-regulated PER1 and PER2 levels in the SCN. Hepatic expression of clock genes (Per2, Rev-erbα, and Clock) and Fgf21 was, respectively, phase-advanced and up-regulated by ultradian feeding. Mice fed with ultradian feeding that lost >10% body mass (i.e. hypocaloric) became more diurnal, hypothermic in late night, and displayed larger (3.5 h) advance of body temperature rhythm, more reduced PER1 expression in the SCN, and further modified gene expression in the liver (e.g. larger phase-advance of Per2 and up-regulated levels of Pgc-1α). While glucose rhythmicity was lost under ultradian feeding, the phase of daily rhythms in liver glycogen and plasma corticosterone (albeit increased in amplitude) remained unchanged. In conclusion, the additional impact of hypocaloric conditions on the SCN are mainly due to the metabolic and not the timing effects of restricted daytime feeding.

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[it is an abstract.]

Caloric Restriction Augments the Molecular Effects of Radiation in Both Hormone-Sensitive and Hormone-Insensitive Prostate Cancers by Decreasing Inflammation.

Simone B, Dan T, Palagani A, DeAngelis T, Schiewer M, Knudsen KE, Dicker AP, Simone NL.

Int J Radiat Oncol Biol Phys. 2016 Oct 1;96(2S):S76. doi: 10.1016/j.ijrobp.2016.06.193. No abstract available.

PMID: 27676012


CR was associated with significant reduction in tumor formation. After PC3 tumor injection, compared with AL, the mice had a 22% reduction in tumor size with radiation, 77% with CR (P < 0.01) and an 80% reduction with CR + RT (P < 0.01). After LNCaP tumor injection, compared with AL, CR mice had a 49% reduction in tumor size and a 55% reduction with CR + RT (P < 0.01). ... Treatment with CR and CR + RT also prolonged time to metastases from 86 days in the AL group to 112 days and 108 days in the CR and CR + RT groups, respectively. …




"Normal Tension Glaucoma (NTG) patients tend to suffer "dips", sudden and unnoticed drops in blood pressure during sleep."


Caloric restriction promotes cell survival in a mouse model of normal tension glaucoma.

Guo X, Kimura A, Azuchi Y, Akiyama G, Noro T, Harada C, Namekata K, Harada T.

Sci Rep. 2016 Sep 27;6:33950. doi: 10.1038/srep33950.

PMID: 27669894


retinal ganglion cells (RGCs) … glutamate transporters (EAAC1 or GLAST) … every-other-day fasting (EODF) … EAAC1-/- mice. EODF suppressed RGC death and retinal degeneration without altering intraocular pressure. Moreover, visual impairment was ameliorated with EODF … EODF upregulated blood β-hydroxybutyrate levels and increased histone acetylation in the retina. …

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"And intriguingly, palmiteolate may be linked to caloric restriction: mice that had been genetically modified in a way that mimicked some aspects of caloric restriction (a drastic reduction in caloric intake that has been show to lengthen lifespan in many animals) began to release the fat in large quantities. That led to the initial discovery of the molecule at HSPH. Whether molecules like palmiteolate may actually be responsible for some of the beneficial effects of caloric restriction, says Hotamışlıgil, will require further investigation."


Prevention of atherosclerosis by bioactive palmitoleate through suppression of organelle stress and inflammasome activation.

Çimen I, Kocatürk B, Koyuncu S, Tufanlı Ö, Onat UI, Yıldırım AD, Apaydın O, Demirsoy Ş, Aykut ZG, Nguyen UT, Watkins SM, Hotamışlıgil GS, Erbay E.

Sci Transl Med. 2016 Sep 28;8(358):358ra126. doi: 10.1126/scitranslmed.aaf9087.

PMID: 27683551

De novo lipogenesis (DNL), the conversion of glucose and other substrates to lipids, is often associated with ectopic lipid accumulation, metabolic stress, and insulin resistance, especially in the liver. ... Palmitoleate (PAO)… prevents macrophage ER stress and IL-1β production in atherosclerotic plaques in vivo, resulting in a marked reduction in plaque macrophages and protection against atherosclerosis in mice. …

"… male ApoE−/− mice were placed on a hypercholesterolemic diet at 6 weeks of age for a total of 16 weeks. ... Starting at 12 weeks on diet, PAO was administered daily by oral gavage, whereas control mice received vehicle for a total of 4 weeks (Fig. 5A). Chronic oral PAO treatment resulted in a significant (P < 0.01) decrease (−33%) in the development of atherosclerotic lesions in en face aorta analysis when compared to control mice (Fig. 5B). The impact of PAO on atherosclerosis development was also evaluated in cross-sectional lesions of the aortic root. The foam cell area in the plaques (visualized with Oil Red O staining) was significantly (P < 0.05) decreased (−29.4%) in the aortic sinus sections (Fig. 5C). In parallel, there was a significant (P < 0.01) reduction in the necrotic core area in the lesions of the PAO-treated group when compared to control mice (−31%) (Fig. 5D). …"


Effect of nine diets on mRNAs of phase-II conjugation enzymes in livers of mice.

Guo Y, Cui JY, Lu H, Klaassen CD.

Xenobiotica. 2016 Aug 10:1-10. [Epub ahead of print]

PMID: 27686132


1. Phase-II enzymes are important in metabolizing many xenobiotics including prescription drugs and chemical carcinogens. ... Diet restriction altered the hepatic expression of the most genes encoding phase-II enzymes (27), followed by lab chow (15), atherogenic diet (13), high-fat diet (10), western diet (7), high-fructose diet (5), and essential fatty acid-deficient diet (3), whereas the low n-3 fatty acid diet had no effect on the hepatic expression of these phase-II enzymes. 3. …


[The below paper is pdf-availed.]


Interstitial glucose concentrations and hypoglycemia during 2 d of caloric deficit and sustained exercise: a double-blind, placebo-controlled trial.

Smith TJ, Wilson MA, Karl JP, Austin K, Bukhari A, Pasiakos SM, O'Connor KL, Lieberman HR.

J Appl Physiol (1985). 2016 Sep 29:jap.00432.2016. doi: 10.1152/japplphysiol.00432.2016. [Epub ahead of print]

PMID: 27687559

energy expenditure (EE) … normoglycemia (3.9-7.8 mmol/L) … continuous glucose monitoring (CGM). … For 2 days during a double-blind, placebo-controlled, crossover study, 23 volunteers (17M/6F; age: 21.3±3.0 years; BMI: 25±3 kg/m2) increased habitual daily EE ([mean±SD] 2300±450 kcals/d) by 1647±345 kcals/d through prescribed exercise (~3 hr/d; 40-65% VO2peak), and consumed diets designed to maintain energy balance (FED) or induce 93% energy deficit (DEF). … Interstitial glucose concentrations were 1.0±0.9 mmol/L lower during DEF versus FED (p<0.0001). The percentage of time spent in mild (3.1-3.8 mmol/L) hypoglycemia was higher during DEF compared to FED (mean difference = 20.5%, [95% CI: 13.1%, 27.9%], P=0.04), while time spent in severe (<3.1 mmol/L) hypoglycemia was not different between interventions (mean difference = 4.6% [95% CI: -0.6%, 9.8%], P=0.10). Three of 23 participants spontaneously reported symptoms (e.g., nausea) potentially related to hypoglycemia during DEF, and, an additional participant reported symptoms during both interventions.

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[The below paper is not pdf-availed.]

Effects of aerobic exercise performed in fasted v. fed state on fat and carbohydrate metabolism in adults: a systematic review and meta-analysis.

Vieira AF, Costa RR, Macedo RC, Coconcelli L, Kruel LF.

Br J Nutr. 2016 Oct;116(7):1153-1164.

PMID: 27609363


... There was a significant increase in fat oxidation during exercise performed in the fasted, compared with fed, state (-3·08 g; 95 % CI -5·38, -0·79; I 2 39·1 %). The weighted mean difference of NEFA concentrations was not significantly different between states (0·00 mmol/l; 95 % CI -0·07, 0·08; I 2 72·7 %). However, the weighted mean differences of glucose (0·78 mmol/l; 95 % CI 0·43, 1·14; I 2 90·8 %) and insulin concentrations (104·5 pmol/l; 95 % CI 70·8, 138·2; I 2 94·5 %) were significantly higher for exercise performed in the fed state.


[The below paper is not pdf-availed.]

n-3 Fatty acids preserve muscle mass and insulin sensitivity in a rat model of energy restriction.

Galmiche G, Huneau JF, Mathé V, Mourot J, Simon N, Le Guillou C, Hermier D.

Br J Nutr. 2016 Oct;116(7):1141-1152.

PMID: 27619894


… rats fed a high-fat diet (4 weeks) rich in 18 : 1 n-9 (oleic acid, OLE-R), 18 : 3 n-3 (α-linolenic acid, ALA-R) or n-3 long-chain (LC-R) fatty acid and then energy restricted (8 weeks). A control group (OLE-ad libitum (AL)) was maintained with AL diet throughout the study. ... All energy-restricted rats lost weight and fat mass, but only the OLE-R group showed a significant muscle loss. ... In conclusion, dietary n-3 PUFA prevent the loss of muscle mass associated with energy restriction, probably by an improvement in the insulin-signalling pathway activation …


Increased Bone Marrow Adiposity in a Context of Energy Deficit: The Tip of the Iceberg?

Ghali O, Al Rassy N, Hardouin P, Chauveau C.

Front Endocrinol (Lausanne). 2016 Sep 16;7:125.

PMID: 27695438


Elevated bone marrow adiposity (BMA) … bone marrow (BM) ... BMA increases with age in a bone-site-specific manner. This increase may be linked to certain pathophysiological situations. Osteoporosis or compromised bone quality is frequently associated with high BMA. ... Here, we review evidence that in a context of energy deficit (such as anorexia nervosa (AN) and restriction rodent models) bone alterations can occur in the absence of an increase in BMA. In severe cases, bone alterations are even associated with gelatinous BM transformation. … we propose that competition between differentiation into osteoblasts and differentiation into adipocytes might trigger bone loss at least in moderate-to-severe AN and in some calorie restriction models. …

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Stimulating S-adenosyl-l-methionine synthesis extends lifespan via activation of AMPK.

Ogawa T, Tsubakiyama R, Kanai M, Koyama T, Fujii T, Iefuji H, Soga T, Kume K, Miyakawa T, Hirata D, Mizunuma M.

Proc Natl Acad Sci U S A. 2016 Oct 3. pii: 201604047.

PMID: 27698120


… Here we show that stimulating S-adenosyl-l-methionine (AdoMet) synthesis extended the lifespan of the budding yeast Saccharomyces cerevisiae The AdoMet synthesis-mediated beneficial metabolic effects, which resulted from consuming both Met and ATP, mimicked CR. Indeed, stimulating AdoMet synthesis activated the universal energy-sensing regulator Snf1, which is the S. cerevisiae ortholog of AMP-activated protein kinase (AMPK), resulting in lifespan extension. Furthermore, our findings revealed that S-adenosyl-l-homocysteine contributed to longevity with a higher accumulation of AdoMet only under the severe CR (0.05% glucose) conditions. …


How long can people live? New study suggests there's a limit

Some aging specialists disagree with finding that human life span likely tops out at about 115 years

The Associated Press Posted: Oct 05, 2016 5:12 PM ET



Nature | News

Human age limit claim sparks debate

Analysis suggests people will never live much beyond 115 but some scientists say that it's too soon to assume a fixed shelf-life.

Linda Geddes

05 October 2016



Nature | Editorial

The limits to human lifespan must be respected

Lengthening our lives will come at a cost.

05 October 2016

Nature 538, 6 (06 October 2016) doi:10.1038/538006a


Why do animals grow old and die at characteristic ages? Even if maintained in peak condition and not eaten by your cat, your hamster is unlikely to make it much past its second birthday. And your cat might live for ten times that. Yet neither cat nor hamster will ever match the average healthy human for longevity.


See: Evidence for a limit to human lifespan

Xiao Dong, Brandon Milholland & Jan Vijg



Nature | News & Views

Ageing: Measuring our narrow strip of life

S. Jay Olshansky              

Nature (2016) doi:10.1038/nature19475

Published online 05 October 2016


In line with previous research, a demographic analysis corroborates the presence of a limit to human lifespan, indicating that increases in life expectancy are likely to slow down or stop over the coming years.


Driven by technological progress, human life expectancy has

increased greatly since the nineteenth century. Demographic

evidence has revealed an ongoing reduction in old-age mortality and

a rise of the maximum age at death, which may gradually extend

human longevity1,2. Together with observations that lifespan in

various animal species is flexible and can be increased by genetic or

pharmaceutical intervention, these results have led to suggestions

that longevity may not be subject to strict, species-specific genetic

constraints. Here, by analysing global demographic data, we show

that improvements in survival with age tend to decline after age 100,

and that the age at death of the world’s oldest person has not increased

since the 1990s. Our results strongly suggest that the maximum

lifespan of humans is fixed and subject to natural constraints.


    Ageing: Dietary protection for genes

A study published online in Nature this week uses demographic data to reveal a lifespan that human beings cannot exceed, simply by virtue of being human (see X. Dong et al. Nature http://dx.doi.org.qe2a-proxy.mun.ca/10.1038/nature19793;2016). It’s like running, as an accompanying News and Views article points out (see S. J. Olshansky Nature http://dx.doi.org.qe2a-proxy.mun.ca/10.1038/nature19793; 2016). Elite athletes might shave a few milliseconds off the world record for the 100-metre sprint, but they’ll never run the same distance in, say, five seconds, or two. Human beings are simply not made that way. The same is true for longevity. The consequences of myriad factors related to our genetics, metabolism, reproduction and development, all shaped over millions of years of evolution, means that few humans will make it past their 120th birthdays. The name of Jeanne Calment, who died in 1997 at the age of 122, is likely to remain as long in the memory in the Methuselah stakes as that of Usain Bolt on the Olympic track.

Maximum lifespan is a bald measure of years accumulated. It is not the same as life expectancy, which is an actuarial measure of how long one is expected to live from birth, or indeed from any given age. Life expectancy at birth has increased in most countries over the past century, not because people have longer lifespans, but mainly because infectious disease does not kill as many infants as it once did. Factors such as poverty and warfare conspire to decrease life expectancy. Although life expectancy at birth has risen steadily for both men and women in France since 1900, for example, there are dramatic and poignant drops that coincide with the two world wars.

In Britain in the early twentieth century, many children still died from infectious diseases, and men would die shortly after retiring from physically demanding jobs. The National Health Service was the political response. It has become, in some ways, the victim of its own success. People live longer than they did even a few decades ago, and die (eventually) of different (and more expensive) complaints. As any beginning medical student is soon taught, gerontology is far from a dying discipline. So if we owe our increases in life expectancy to better public health, nutrition, sanitation and vaccination, is it not fair to ask whether more-effective treatments for diseases such as cancer, Parkinson’s disease and Alzheimer’s might also yield dividends in maximum lifespan? Will 120th birthday parties become routine, outmatched by a small yet increasing number of sesquicentenarians? The demographic data say no. People are living longer, and the population as a whole is greying, but the rate of increase in the number of centenarians is slowing, and might even have peaked.

Could it be possible, in some science-fictional future, to break free from the bonds of human life expectancy and increase lifespan indefinitely? An unquenchable desire for eternal life has preoccupied humanity from the earliest times, as attested by the earliest passages of the Bible, the Gilgamesh epic and many other stories from our past. Perhaps the chilliest evocation of mortality comes in Bede’s seventh-century Ecclesiastical History of the English People, in which a chieftain remarks that the ‘few moments of comfort’ offered by human life are as the brief flight of a sparrow through a warm and lighted mead hall, in through one door, and out through the other, back into a dark, storm-tossed and demon-haunted night of which we know nothing. No wonder we’d all like a little more light. Technological solutions might one day transcend the limitations of the human body, but transcend them they must — mere extension is already yielding diminishing returns.The risks of transcendence are twofold. First, it might be that to extend our lives beyond our normal span, we must somehow become other than human. After all, what would a 50-year-old hamster be like? The unintended consequences of immortality are graphically and grimly illustrated in Aldous Huxley’s 1939 novel After Many A Summer, in which people fed on a life-extending diet of carp intestines live for centuries — at the cost of turning into witless apes. Second, there is a risk that life wouldn’t really be that much longer — it would only feel like it.

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Altered gut microbiota in female mice with persistent low body weights following removal of post-weaning chronic dietary restriction.

Chen J, Toyomasu Y, Hayashi Y, Linden DR, Szurszewski JH, Nelson H, Farrugia G, Kashyap PC, Chia N, Ordog T.

Genome Med. 2016 Oct 3;8(1):103.

PMID: 27716401


Four-week-old female BALB/c mice (n = 12/group) were fed ad libitum (AL) or offered limited food to abolish weight gain (LF). A subset of restricted mice was treated with an insulin-like growth factor 1 (IGF1) analog. Food access was restored in a subset of untreated LF (LF-RF) and IGF1-treated LF mice (TLF-RF) on day 97. ... body weight change (Δbwt) ... On day 120, Δbwt in AL, LF, LF-RF, and TLF-RF mice was 52 ± 3, -6 ± 1*, 40 ± 3*, and 46 ± 2 % (*, P < 0.05 versus AL). Age and diet, but not Δbwt, were associated with gut microbiota composition. Age explained a larger proportion of the microbiota variability than diet or Δbwt. Random Forests predicted chronological age based on the microbiota and indicated microbiota immaturity in the LF mice before, but not after, refeeding. However, on day 120, the microbiota community structure of LF-RF mice was significantly different from that of both AL and LF mice. IGF1 mitigated the difference from the AL group. Refed groups had a higher abundance of Bacteroidetes and Proteobacteria and a lower abundance of Firmicutes than AL mice.

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Nutrigenomics at the Interface of Aging, Lifespan, and Cancer Prevention.

Riscuta G.

J Nutr. 2016 Oct;146(10):1931-1939. Review.

PMID: 27558581


``Bioenergetics as a Link between Aging

and Cancer Prevention

    Historically, calorie restriction without malnutrition has been

associated with an increased life span in a variety of lower

species (30). Some studies in animal models concluded that

caloric restriction not only increases life span, but also decreases

the risk of certain diseases. A study initiated in 1989 at

the National Primate Research Center at the University of

Wisconsin, Madison, reported a delayed onset of diseases

and decreased mortality in a calorie-restricted group of rhesus

monkeys compared with a control group (31). Interestingly, a

National Institute of Aging intramural study reported no

significant difference in survival between control-fed and

calorie-restricted monkeys (32). The 2 studies admittedly used

different diets and cohort compositions, which may account for

some of the differences. In addition, the body weights of the

National Institute of Aging control animals consistently were

lower than average for both sexes; thus, additional restrictions

did not make a difference (33). Therefore, calorie restriction

would not automatically lead to an increase in lifespan under all

conditions, but calorie restriction may be beneficial for subjects

consuming a high number of calories.``


Alternate-day versus daily energy restriction diets: which is more effective for weight loss? A systematic review and meta-analysis.

Alhamdan BA, Garcia-Alvarez A, Alzahrnai AH, Karanxha J, Stretchberry DR, Contrera KJ, Utria AF, Cheskin LJ.

Obes Sci Pract. 2016 Sep;2(3):293-302. Review.

PMID: 27708846


Alternate-day-fasting (ADF) ... very-low-calorie dieting (VLCD) ... Meta-analysis: 10/28 studies (four ADF and six matched VLCD) ... After adjustment for BMI and duration, there was no significant difference in mean body weight loss (VLCD 0.88 kg more weight loss than ADF, 95% CI: -4.32, 2.56) or fat-free mass (VLCD 1.69 kg more fat-free mass loss than ADF, 95% CI: -3.62, 0.23); there was a significant difference observed in fat mass (ADF 3.31 kg more fat mass loss than VLCD, 95% CI: 0.05, 6.56). Meta-analysis showed that, among ADF studies, the pooled change in body weight, fat mass and fat-free mass was 4.30 kg (95% CI: 3.41, 5.20), 4.06 kg (95% CI: 2.99, 5.13) and 0.72 kg (95% CI: -0.07, 1.51), respectively, while among VLCD studies, the pooled change was 6.28 kg (95% CI: 6.08, 6.49), 4.22 kg (95% CI: 3.95, 4.50) and 2.24 kg (95% CI: 1.95, 2.52), respectively. ...

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The effect of dietary restriction on reproduction: a meta-analytic perspective.

Moatt JP, Nakagawa S, Lagisz M, Walling CA.

BMC Evol Biol. 2016 Oct 7;16(1):199.

PMID: 27717308


... In general, DR reduced reproduction across taxa, but several factors moderated this effect. The effect of DR on reproduction was greater in well-studied model species (yeast, nematode worms, fruit flies and rodents) than non-model species. This mirrors recent results for longevity and, for reproduction, seems to result from a faster rate of decline with decreasing resources in model species. Our results also suggested that not all reproductive traits are affected equally by DR. High and moderate cost reproductive traits suffered a significant reduction with DR, but low cost traits, such as ejaculate production, did not. Although the effect of DR on reproduction was stronger in females than males, this sex difference reduced to near zero when accounting for other co-factors such as the costliness of the reproductive trait. ...


Mouse models of ageing and their relevance to disease.

Kõks S, Dogan S, Tuna BG, González-Navarro H, Potter P, Vandenbroucke RE.

Mech Ageing Dev. 2016 Oct 4. pii: S0047-6374(16)30214-7. doi: 10.1016/j.mad.2016.10.001.

PMID: 27717883


... Ageing is a process that gradually increases the organism's vulnerability to death. It affects different biological pathways, and the underlying cellular mechanisms are complex. ... We review some mouse models commonly used in studies on ageing, highlight the advantages and disadvantages of the different strategies, and discuss their relevance to disease susceptibility. In addition to addressing the genetics and phenotypic analysis of mice, we discuss examples of models of delayed or accelerated ageing and their modulation by caloric restriction ...


Differential Regulation of Hippocampal IGF-1-Associated Signaling Proteins by Dietary Restriction in Aging Mouse.

Hadem IK, Sharma R.

Cell Mol Neurobiol. 2016 Oct 7.

PMID: 27718093


... Dietary restriction (DR) ... Results showed a decrease in the levels of IGF-1, IGF1R, PI3K, and pAkt, while pFoxO level increased with respect to age. Under DR, these protein levels are maintained in adult mice, but old mice displayed diminished expression levels of these proteins as compared to ad libitum-fed mice. Maintenance of PI3K/Akt pathway results in the phosphorylation of FoxOs, necessary for the enhancement of neural proliferation and survival in adult mice. The down-regulation of IGF-I signaling, as observed in old mice, leads to increasing the activity of FoxO factors that may be important for the neuroprotective effects seen with DR ...

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Gifford, Bill (AUTHOR)

Source: Scientific American. Sep2016, Vol. 315 Issue 3, p62-69.






In March, officials from Guinness World Records traveled to Haifa, Israel, to visit a retired candymaker named Israel Kristal. They came to proclaim him, at the age of 112 years and 178 days, the world’s oldest man. Kristal has led an extraordinary life. When he was born, in 1903, life expectancy for a boy in Poland was only about 45 years. As a child, he remembers throwing candies to Emperor Franz Josef of Austria-Hungary. As an adult, he ran a candy factory near Lodz. He lived through two world wars and survived nearly a year in various concentration camps, including a three-month stint at Auschwitz. His wife and two children were killed. After remarrying, he immigrated to Israel, where he made artisanal confections by hand. He now has something like 20 great-grandchildren. Born in the era of gas lamps, the centenarian now lives in the age of Twitter.


“Mr. Kristal’s achievement is remarkable,” said Marco Frigatti, head of records for Guinness, in an official statement. Indeed, the average life expectancy of a male in the developed world is close to 80 years. Only about two in 10,000 people live to age 100, and the vast majority of centenarians are female. At 112 and change, Kristal is near the limit of maximum observed life span for men. No human being has ever outlived Jeanne Calment of France, who died in 1997 at the age of 122.


What if, instead of dying at 80 or 85, the average person lived to be 100 or even 112 like Kristal? False promises of longer lives, even immortality, date back to the days of the alchemists, of course. So far there has not been much evidence to support such optimism. But some scientists believe centenarians such as Kristal really do age more slowly than the average person. Legitimate findings of current biological research hint that periods of extreme calorie restriction—perhaps like those experienced by the candymaker—affect the life spans of cells. This research is showing more precise ways to stretch those limits, not with diets, but with drugs.


Half a dozen medications or supplements, all of which have already been approved for human use for other purposes, turn out to target mechanisms within our cells that seem to improve internal damage control and thus help to prolong life. Some of these substances, including an anticancer drug, have already been shown to increase average and maximum life span in mice and other laboratory animals. This year a popular diabetes drug called metformin is headed for the first clinical trial ever designed to reveal whether a medication works to slow aging in people.


Because of this activity, a small coterie of well-established aging researchers is beginning to say that serious life extension could become a reality within the lifetimes of people reading this magazine. “There’s been so much crazy talk about living forever and ‘hacking’ aging that it kind of drowns out what we know is possible now,” says Matt Kaeberlein, a leading biogerontologist at the University of Washington. “The way the research is going, I see maybe 25 to 50 percent increases in healthy longevity as plausible in the next 40 or 50 years.”


“There’s been a huge response and huge interest, and a feeling that something big is going to happen,” says Nir Barzilai, a leader of the metformin trial and the director of aging research at the Albert Einstein College of Medicine. “I think we’ll get significant results. And the next drugs will be better.”




AGING, AT LEAST IN PART, is rooted in our appetites. Scientists have known since the 1930s that underfeeding lab animals such as mice and rats can enable them to live longer—in some experiments, as much as 40 percent longer. Even nonscientists like Kristal think that the episodes of hunger in his life, during and after World War II, may have contributed to his longevity. In an interview with the newspaper Haaretz, he said, “I eat to live, and I don’t live to eat. You don’t need too much. Anything that’s too much isn’t good.”


Unfortunately—or fortunately, depending on one’s point of view—experiments with extreme caloric restriction in monkeys, animals more similar to people, have had mixed results. Low calorie consumption seemed to work well in one study, but then another well-designed trial showed that simply eating a more natural, whole-foods based diet, with a low sugar content, seemed to help just as much, regardless of calorie count. And in any event, very few humans can stick to a diet that requires cutting calories by 25 percent.


But experiments in lower organisms have revealed specific, beneficial cellular pathways—chains of molecular interactions—that are triggered when nutrients are scarce. These pathways evolved to allow organisms to survive long periods without food. In theory, activating such pathways with drugs could yield the same benefit without the pain of starving oneself. One example involves the enzyme AMPK, which acts as a kind of cellular fuel gauge. When nutrients are low, as happens during intense exercise or caloric restriction, AMPK jumps into action, transporting glucose into cells for energy and increasing cells’ sensitivity to hormones that aid in this transport, such as insulin. It also helps break down fat for more energy. During exercise, AMPK stimulates the creation of new mitochondria, the energy producers within cells. All of these things improve health.


There is compelling evidence that aging and the rate of metabolism—the process by which a body converts food to energy—are directly linked. In 1993 Cynthia Keny on of the University of California, San Francisco, discovered that mutations in just one specific gene called DAF-2 could double the life span of the Caenorhabditis elegans worm. That gene is also linked to metabolic rates. But scientists still know relatively little about the genetics of aging, so for now their preferred targets are the higher-level mechanics of the cell.


One of the most promising antiaging mechanisms was discovered by accident. In 2001 biologist Valter Longo of the University of Southern California went away for a weekend and forgot to feed yeast cells that he was using in an experiment. He was surprised to discover that starving them completely for a time made them live longer than usual. The reason, he learned, lay in a cascade of molecular actions usually referred to by the enzyme at its center, which is called mTOR.


This pathway was originally discovered years earlier thanks to a drug called rapamycin, which was found in soil bacteria. The drug, scientists learned, affected a major pathway regulating growth and division in the cell, like the circuit breaker in a tiny factory. Researchers named the path mTOR because it is a “mechanistic target of rapamycin.” When mTOR is activated, the “factory” (that is, the cell) is humming along, producing new proteins, growing and ultimately dividing. When mTOR is blocked, such as by rapamycin—or by short-term fasting—cell growth and replication slow down or stop. This is why rapamycin has been effective as an immunosuppressor to protect transplanted organs and more recently as a cancer therapy; these conditions involve runaway cell division.


Longo’s work led to the revelation of mTOR’s crucial role in aging. When nutrients are scarce, mTOR is inhibited, and the factory goes into a more efficient mode, recycling old proteins to make new ones, ramping up the production of cellular cleaning and repair mechanisms and hunkering down to wait out the famine. Cell division slows down. And the animal is better able to survive until its next meal.


“What mTOR really does is, it senses the environment, and if there’s lots of food around, then it gets cranked up—and in simple organisms, it causes them to develop really quickly and reproduce,” Kaeberlein explains. “That makes a lot of sense because when there’s lots of food, that’s a really good time to make babies.” No wonder the mTOR mechanism has been such a big evolutionary hit, used and reused by creatures up and down the tree of life, from single-celled yeast all the way up to humans and whales.


The activity change affects survival. In 2009 a team of scientists reported in Nature that rapamycin made lab mice live longer. This was a stunning finding: No other drug had ever lengthened the life span of mammals in this way in a controlled experiment. And this was not just one group of mice but three sets of genetically heterogeneous animals. All groups lived longer and not only on average: the animals’ maximum life span was lengthened, which some considered clear evidence that the drug was slowing the aging process itself.


The mice given rapamycin generally seemed to stay healthier and more youthful for longer than rodents that did not get the drug. Their tendons, for example, stayed more flexible and elastic. So did their hearts and blood vessels. Even their livers were in better shape than the control mice’s. They remained more active, even as they got older. What is more, rapamycin extended average and maximum life span even though mice only got it starting at the age of 20 months. It was like giving 70-year-old women a pill that let them live past 95. Or to put it another way, imagine a drug that would have let Kristal live into his 130s.


Other labs were able to reproduce the results and to extend them. Mice given rapamycin throughout their adult lives ended up living 25 percent longer— about the same as if they had been calorically restricted. Mice are not people, of course, but rapamycin raised the possibility, at least, that something might slow aging and delay the onset of age-related diseases. “Rapamycin was the first robust hit, the first drug that everybody said that this might be the real thing,” says Brian Kennedy, CEO of the Buck Institute for Research on Aging in Novato, Calif.


Rapamycin is not without drawbacks, however. It can have unpleasant side effects, notably the appearance of mouth sores in some patients, and more frequent infections (because it suppresses immune response). In the mouse studies, the males appeared to suffer from testicular shrinkage. Those effects were acceptable for cancer and transplant patients, who were already quite sick, but they might disqualify it as an antiaging drug for otherwise healthy people. The cure might actually be worse than the disease. But what if you gave it to those healthy people in a different way or in lower doses? Could it, somehow, extend human life span as well?


To try and answer those questions, Kaeberlein and his colleague Daniel Promislow are starting an unusual clinical trial of low-dose rapamycin in middleaged pet dogs. Our canine companions, they figure, are reasonable stand-ins for us: “They share our environment, and they get all the same diseases we get as they get older,” Kaeberlein says. According to their preliminary data, dogs treated with rapamycin for just a few weeks displayed more youthful cardiac function, as measured by an echocardiogram. “We can clearly see that the heart is contracting better in the dogs that have gotten rapamycin than in the ones that haven’t,” Kaeberlein says. “In aging animals, poor blood flow is probably a factor in the decline of other body tissues.”


One encouraging sign for the drug’s potential as an antiaging agent, Kaeberlein says, is that in small amounts rapamycin may be working more as an immune modulator rather than a suppressor. It actually appears to enhance some kinds of immune function at these lower doses. A small human trial by Novartis, which markets a version of rapamycin as a cancer treatment called Afinitor, showed that older adults who took the drug actually responded better to a flu vaccine. This would indicate that it might enhance the immune response in some cases. One other interesting piece of evidence: a Dutch study found that healthy nonagenarians had lower levels of mTOR activity.


The next step, funds permitting, is to do a longerterm longitudinal study of rapamycin in older dogs, tracking their progress as they age. If the results reflect those achieved in mice—if the dogs live longer and healthier lives—they could justify a human clinical trial. “We could know, five years from now, to what extent it is actually working,” Kaeberlein says.




CONNECTING “HEALTHIER” to “longer” is key. Our life spans have been stretching out, but the latter part of our lives is prone to periods of disease and disability. As demographers James W. Vaupel and Jim Oeppen demonstrated in a 2002 Science paper, life expectancy for the longest-lived populations has been growing more or less linearly since the 1840s (currently Japanese females are at the top of the list). People have been living longer than ever before in human history.


At the same time, however, health span—defined as the length of healthy life—has not been growing quite as fast. This means that the period of disease and disability at the end of life, the dreaded decline of old age, has actually been getting longer. The only thing that changes, as we live longer and longer, is that we fall victim to different ailments. As mortality rates from heart disease and cancer drop, more of us become vulnerable to Alzheimer’s disease. One in nine Americans older than 65 is affected by Alzheimer’s or other forms of cognitive decline, with risk rising drastically after age 80.


“The rise of Alzheimer’s disease has been astonishing, but it’s exactly what you would expect if you push people into age windows where this disease is common, the late 70s and 80s,” says S. Jay Olshansky, a demographer at the University of Illinois at Chicago. “If we continue this path, I think that it will get worse. The alternative is to slow aging and compress morbidity and mortality into a shorter time period.”


Olshansky has not met Kristal, but the Guinness record holder seems to be the kind of old person he has in mind. At 112, Kristal is still sharp mentally and a witty conversationalist. He has managed to resist the deadly illnesses of aging—not only cancer and heart disease but also Alzheimer’s and diabetes, which together account for about half of deaths in the developed world. In centenarians like him, researchers find, the period of sickness at the end of life is often much shorter than for people who die in their 70s. A successful antiaging drug would need to mimic the same effect, rather than merely prolong life at the expense of health and well-being, Olshansky says.


But until very recently, investigators have faced a formidable stumbling block to developing that kind of drug: the U.S. Food and Drug Administration has not considered aging to be a disease. Therefore, it would not approve any drug that targeted the aging process itself. From the agency’s point of view, this policy made sense: There is no objective way to “measure” aging—no blood test, for example, that can determine whether a person is aging more quickly or slowly than normal. So how would we know if an antiaging drug was working? That official stance eliminated any incentive for a drug company to invest in research into aging and drugs that might slow it down. There was simply no path to approval and to market.


The path began to clear in 2015, however, when the agency gave approval to a clinical trial meant to assess the antiaging properties of metformin. Approved for type 2 diabetes (the most common form) in the U.K. in the 1950s, metformin passed fda review in the U.S. in 1994. It has since been prescribed to millions of patients as a first-line treatment. Now available as a cheap generic, it is one of the world’s most common prescriptions, so much so that the World Health Organization has declared it an “essential” medication. It increases cells’ sensitivity to insulin, the hormone that signals them to take in sugar (glucose) from the blood.


Because so many people take the drug, researchers have been able to detect intriguing patterns among patients. In particular, epidemiological studies have found that those on metformin seem to have a lower incidence of cancer. Other studies have suggested that metformin may have beneficial cardiovascular effects. Moreover, whereas diabetics generally lose several years of life expectancy, a 2014 analysis of British patient data found that older diabetics who were taking metformin were actually living 18 percent longer than matched nondiabetic controls. They also lived longer than diabetics using another common class of medications, the sulfonylureas, indicating that it was the metformin itself, and not just control of diabetes, that conferred a longevity advantage.


How exactly that works is not entirely clear. The mechanism of action of metformin, which is derived from an ancient herbal remedy called French lilac or goat’s rue, has been debated among scientists for decades. One thing it is known to do is activate the AMPK pathway and its favorable metabolic changes. It also seems to affect insulin through other paths and even to inhibit mTOR somewhat.


The possibility that metformin might enhance longevity caught the attention of Albert Einstein’s Barzilai, among others. As head of a major study of Ashkenazi Jewish centenarians, Barzilai knew that longlived people rarely have problems with high blood glucose or diabetes; ultraefficient processing of blood glucose in fact is a marker for longevity. Metformin, he thinks, might alter our metabolism to more closely resemble that of a centenarian. “A lot of its antidiabetic activity is also antiaging, just improving cellular function and insulin sensitivity,” Barzilai says. He actually takes the drug himself as a preventive because his parents both had diabetes. He stops just short of saying that everyone older than 50 should think about getting a prescription (he is 60). “It looks like a superdrug,” Barzilai says. “It looks like it’s involved in many things related to aging.”


“There are 60 years of data in humans showing that it targets a whole lot of conditions that, in aggregate, would have you believe that it’s targeting fundamental aging processes,” agrees James L. Kirkland, director of the Robert and Arlene Kogod Center for Aging Research at the Mayo Clinic and a collaborator on the metformin studies.


Yet to test suspected antiaging drugs in people, researchers have to deal with another obstacle: time. A conventional life span study would require decades to complete—literally, a lifetime. The trial approved in 2015, called TAME, for Targeting Aging with Metformin, takes a different approach. Rather than simply comparing longevity in healthy subjects who get the drug with those who do not, the scientists will instead look at the progression of aging-related diseases in each subject.


One of the hallmarks of aging is the way that older people often develop more than one chronic condition, such as high blood pressure and diabetes or heart disease and cognitive impairment. These socalled comorbidities, one disease on top of another, are a major cause of misery in the elderly (not to mention a driver of increased health care spending). In the TAME trial, scientists plan to give metformin to elderly patients who already have one aging-related condition, such as diabetes or high blood pressure. The subjects will be monitored for five to seven years and compared against a control group that has agreed not to take the drug to see whether or not they go on to develop other age-related diseases at a faster or slower rate. If metformin is really slowing the aging process, then it should be able to stave off the progression of comorbidities.


The TAME trial, then, will really be measuring metformin’s effect on health span—evaluating it as, in essence, preventive medicine. “The same kind of process occurred with, for example, giving antihypertensives to people who haven’t had a heart attack,” says Kirkland.


If the TAME study is successful, and the drug agency shows an openness to test new medications that target aging, Barzilai thinks, pharmaceutical companies will begin to move into the space—and not just traditional pharma, but ventures like the Googlebacked Calico project, where none other than Cynthia Kenyon, who discovered the D AF-2 a ging gene two decades ago, is vice president of aging research. Calico, some reports have speculated, may be investing more than $1 billion in a search for drugs that will extend health span, an amount close to to the entire budget of the National Institute on Aging.


“If longevity is a side effect” of extending health span, Barzilai says half-jokingly, “we’ll apologize for that.”




THE PIPELINE of potential antiaging medications is already beginning to fill. Another antidiabetic agent called acarbose has extended life span significantly in male mice, for example. Like metformin, acarbose is already approved for human use, so it, too, could be a candidate for a clinical trial against aging. Still another drug, the hormone alpha-estradiol, has also had good results, in the same kinds of trials that discovered the antiaging effect of rapamycin.


A newer and perhaps even more promising group of antiaging drug candidates does not work on metabolic pathways but by clearing out so-called senescent cells, which have stopped dividing but have not actually died. Like cellular zombies, they sit there and secrete small proteins known as cytokines that can damage the cells around them. Kirkland believes that their true function is as a cancer defense mechanism—a way for the body to kill neighboring cells that may be malignant. Senescent cells also play a role in wound healing because the cytokines they secrete help to marshal the immune system. Unfortunately, their toxic effects reach far beyond the immediate neighborhood, contributing to the low-grade inflammation that characterizes aging bodies—and, paradoxically, increasing cancer risk in surrounding tissues. Kirkland and others see them as a key driver of the aging process.


Even worse, the older we get, the more senescent cells we harbor in our bodies. What if we could get rid of them? Kirkland and his colleagues, including molecular biologist Jan van Deursen of the Mayo Clinic, have shown that eliminating senescent cells from genetically modified mice seems to increase their health span. The problem is that senescent cells are very hard to isolate—they are dispersed among healthy cells—and even harder to kill. “They’re very resistant to dying,” Kirkland says. “They’re hardy as all get-out.”


A team of researchers at Mayo, the Scripps Research Institute and other institutions looked for drugs that could kill senescent cells by inducing apoptosis, or cell suicide. In 2015 they reported in a paper that they found three, including two cancer drugs, dasatinib and navitoclax, as well as quercetin, a naturally occurring flavonoid. This is an antioxidant and pigment-carrying compound that is found in, among other things, the peel of apples and in capers (among many other foods).


In one experiment, animals had one leg disabled by irradiation, which caused muscle atrophy that was similar to the loss of muscle caused by aging. The radiation also created lots of senescent cells in the muscle, a condition that has also been observed in cancer patients after radiation or chemotherapy. After a short treatment with the drugs, the animals’ leg function was restored almost completely. The dramatic effect, Kirkland believes, was because the drugs killed more senescent cells than other types. “We only gave a single dose, and treadmill endurance improved considerably—and stayed improved for seven months,” Kirkland says. “That gives us reassurance that it’s actually clearing senescent cells. And once they’re dead, they’re dead.”


They have to die, perhaps, so that we might live.

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Journal of Gerontology: BIOLOGICAL SCIENCES

Special Issue: Moving Geroscience Into Uncharted Waters


Moving Geroscience Into Uncharted Waters.

Sierra F.

J Gerontol A Biol Sci Med Sci. 2016 Aug 16. pii: glw087. [Epub ahead of print] No abstract available.

PMID: 27535965


"Research into the basic biology of aging has undergone a seismic shift in the last 10–20 years, moving rapidly from the very descriptive approach focused on the aged that was the predominant focus by the end of the last century, to a more mechanistic (and primarily genetics-driven) phase, focused less on describing the aging phenotype in different models, and more on a definition of the molecular and cellular drivers of the process. This progression was accompanied by an evolution in the concepts and ideas that have dominated the field in the past, namely free radicals, cell senescence, and caloric restriction ..."


Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms.

Burd CE, Gill MS, Niedernhofer LJ, Robbins PD, Austad SN, Barzilai N, Kirkland JL.

J Gerontol A Biol Sci Med Sci. 2016 Aug 16. pii: glw112. [Epub ahead of print]

PMID: 27535964



Evaluating Health Span in Preclinical Models of Aging and Disease: Guidelines, Challenges, and Opportunities for Geroscience.

Huffman DM, Justice JN, Stout MB, Kirkland JL, Barzilai N, Austad SN.

J Gerontol A Biol Sci Med Sci. 2016 Aug 16. pii: glw106. [Epub ahead of print]

PMID: 27535967



Resilience in Aging Mice.

Kirkland JL, Stout MB, Sierra F.

J Gerontol A Biol Sci Med Sci. 2016 Aug 16. pii: glw086. [Epub ahead of print]

PMID: 27535963



Frameworks for Proof-of-Concept Clinical Trials of Interventions That Target Fundamental Aging Processes.

Justice J, Miller JD, Newman JC, Hashmi SK, Halter J, Austad SN, Barzilai N, Kirkland JL.

J Gerontol A Biol Sci Med Sci. 2016 Aug 16. pii: glw126. [Epub ahead of print]

PMID: 27535966



Strategies and Challenges in Clinical Trials Targeting Human Aging.

Newman JC, Milman S, Hashmi SK, Austad SN, Kirkland JL, Halter JB, Barzilai N.

J Gerontol A Biol Sci Med Sci. 2016 Aug 16. pii: glw149. [Epub ahead of print]

PMID: 27535968



[it did not look like the exercise only group benefitted more than those losing weight by diet alone to me.]

Relationship of Objectively-Measured Habitual Physical Activity to Chronic Inflammation and Fatigue in Middle-Aged and Older Adults.

Nicklas BJ, Beavers DP, Mihalko SL, Miller GD, Loeser RF, Messier SP.

J Gerontol A Biol Sci Med Sci. 2016 Jul 5. pii: glw131. [Epub ahead of print]

PMID: 27382039



... (non-exercise) physical activity (PA) ... at baseline and 18 months after a diet-induced weight loss, exercise, or diet-induced weight loss plus exercise intervention in 167 overweight/obese, middle-aged, and older adults. ... At baseline, individuals with higher plasma interleukin-6, as well as those who reported feeling less energetic (more fatigued), took less steps per day and had lower PA energy expenditure and minutes of light and moderate–vigorous PA (p < .05 for all). At the 18-month follow-up, inflammation was lower in both weight loss groups, fatigue was reduced in all three groups with larger decreases in the combined group, and mean levels of habitual PA were not changed in any group. In longitudinal analyses with all groups combined, we found that participants reporting larger increases in vitality (eg, declines in fatigue) had greater increases in PA (p < .05 for all). Also, changes in steps/d and physical activity energy expenditure were indirectly associated with changes in interleukin-6 (β [sEM] for steps/d = −565 [253]; β [sEM] for physical activity energy expenditure = −22.4 [10.17]; p < .05).


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High-Protein Intake during Weight Loss Therapy Eliminates the Weight-Loss-Induced Improvement in Insulin Action in Obese Postmenopausal Women.

Smith GI, Yoshino J, Kelly SC, Reeds DN, Okunade A, Patterson BW, Klein S, Mittendorfer B.

Cell Rep. 2016 Oct 11;17(3):849-861. doi: 10.1016/j.celrep.2016.09.047.

PMID: 27732859


... High-protein (HP) intake during weight loss (WL) ... 10% WL with a hypocaloric diet containing 0.8 g protein/kg/day and a hypocaloric diet containing 1.2 g protein/kg/day ... HP intake reduced the WL-induced decline in lean tissue mass by 45%. However, HP intake also prevented the WL-induced improvements in muscle insulin signaling and insulin-stimulated glucose uptake, as well as the WL-induced adaptations in oxidative stress and cell structural biology pathways. ...

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Improvement of serum adiponectin and leptin concentrations: effects of a low-calorie or isocaloric diet combined with metformin or orlistat - a prospective randomized open-label trial.

Kargulewicz A, Szulińska M, Kujawska-Łuczak M, Swora-Cwynar E, Musialik K, Grzymisławska M, Kręgielska-Narożna M, Bogdański P.

Eur Rev Med Pharmacol Sci. 2016 Sep;20(18):3868-3876.

PMID: 27735028


... 114 obese Caucasian women were randomized into three groups receiving a low-calorie diet (LC; n = 39), an isocaloric diet with 500 mg of metformin twice a day (IM; n = 38), and an isocaloric diet with 120 mg of orlistat three times a day (IO; n = 37), for three months. ... Both IO and LC, but not IM, caused an increase in serum adiponectin concentration (p < 0.01, p < 0.05 respectively). A decrease in serum leptin level was documented in the LC (p < 0.001), IM (p < 0.01), and IO group (p < 0.01). Beneficial changes in anthropometric and body composition values were observed following all interventions with the greatest advantage seen in the IO group. The strongest correlations, of Δadiponectin with Δbody weight (r = -0.54), ΔBMI (r = -0.49), ΔFAT [%] (r = -0.48), ΔFAT [kg] (r = -0.48), and Δlean [%] (r = 0.48); and of Δleptin with Δbody weight, ΔBMI, Δwaist, Δfat, and Δlean, were documented in the IO group.


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Calorie restriction protects against experimental abdominal aortic aneurysms in mice.

Liu Y, Wang TT, Zhang R, Fu WY, Wang X, Wang F, Gao P, Ding YN, Xie Y, Hao DL, Chen HZ, Liu DP.

J Exp Med. 2016 Sep 26. pii: jem.20151794. [Epub ahead of print]

PMID: 27670594


Abdominal aortic aneurysm (AAA) ... CR markedly reduced the incidence of AAA formation and attenuated aortic elastin degradation in Apoe-/- mice. The expression and activity of Sirtuin 1 (SIRT1), a key metabolism/energy sensor, were up-regulated in vascular smooth muscle cells (VSMCs) upon CR. Importantly, the specific ablation of SIRT1 in smooth muscle cells abolished the preventive effect of CR on AAA formation in Apoe-/- mice. ...

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Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males.

Moro T, Tinsley G, Bianco A, Marcolin G, Pacelli QF, Battaglia G, Palma A, Gentil P, Neri M, Paoli A.

J Transl Med. 2016 Oct 13;14(1):290.

PMID: 27737674



... Intermittent fasting (IF) ... time-restricted feeding (TRF) or normal diet group (ND). TRF subjects consumed 100 % of their energy needs in an 8-h period of time each day, with their caloric intake divided into three meals consumed at 1 p.m., 4 p.m., and 8 p.m. The remaining 16 h per 24-h period made up the fasting period. Subjects in the ND group consumed 100 % of their energy needs divided into three meals consumed at 8 a.m., 1 p.m., and 8 p.m. Groups were matched for kilocalories consumed and macronutrient distribution (TRF 2826 ± 412.3 kcal/day, carbohydrates 53.2 ± 1.4 %, fat 24.7 ± 3.1 %, protein 22.1 ± 2.6 %, ND 3007 ± 444.7 kcal/day, carbohydrates 54.7 ± 2.2 %, fat 23.9 ± 3.5 %, protein 21.4 ± 1.8). ... After 8 weeks, the 2 Way ANOVA (Time * Diet interaction) showed a decrease in fat mass in TRF compared to ND (p = 0.0448), while fat-free mass, muscle area of the arm and thigh, and maximal strength were maintained in both groups. Testosterone and insulin-like growth factor 1 decreased significantly in TRF, with no changes in ND (p = 0.0476; p = 0.0397). Adiponectin increased (p = 0.0000) in TRF while total leptin decreased (p = 0.0001), although not when adjusted for fat mass. Triiodothyronine decreased in TRF, but no significant changes were detected in thyroid-stimulating hormone, total cholesterol, high-density lipoprotein, low-density lipoprotein, or triglycerides. Resting energy expenditure was unchanged, but a significant decrease in respiratory ratio was observed in the TRF group.



[The below paper is pdf-availed.  The only things that significantly happened for the resistance exercise alone treatment were increased blood glucose and decreased fasting insulin levels.]

Effect of Resistance Training and Caloric Restriction on the Metabolic Syndrome.

Normandin E, Chmelo E, Lyles MF, Marsh AP, Nicklas BJ.

Med Sci Sports Exerc. 2016 Oct 13.

PMID: 27741216

... resistance training (RT) on metabolic syndrome (MetS) ...

... We performed a 5-month randomized controlled trial in 126 older (65-79 yrs) overweight and obese (Body Mass Index: 27-35 kg/m) men and women who were assigned to progressive 3-d/wk, moderate-intensity RT with (RT+CR) or without caloric restriction (RT). ...

... Body mass decreased in RT+CR (-5.67% loss of initial mass) but was unchanged in RT (-0.15%). Compared to RT, RT+CR resulted in reduced very low-density lipoprotein cholesterol (VLDL-chol), triglycerides (TG), and systolic and diastolic blood pressures (p between 0.000 and 0.013). The RT group showed no significant within group changes in MetS criteria. Abdominal obesity, hypertension, the number of metabolic abnormalities and the presence of MetS significantly decreased with RT+CR. There were significant group differences for abdominal obesity, hypertension, and number of metabolic abnormalities.

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Unraveling the metabolic health benefits of fasting related to beliefs of religion: A narrative review

Angeliki Persynaki, Spyridon Karras, Claude Pichard

Nutrition DOI: http://dx.doi.org/10.1016/j.nut.2016.10.005

Publication stage: In Press Accepted Manuscript

Published online: October 14, 2016


Review Highlights

    •Religious fasting (RF) reflects dietary habits of million of believers.

    •Health impact of RF has been documented among Buddhists, Christians and Muslims.

    •Energy and/or food item restrictions are key components of RF.

    •RF has potential benefits on energy balance, dyslipidemia and oxidative stress.

    •RF could be integrated into health management for diseases prevention.

... Caloric restriction, with or without eviction of certain type of food, is a key component of most religious dietary patterns. Fasting varies significantly among different populations according to cultural habits and local climate condition. Religious fasting in terms of patterns (continuous vs. intermittent) and duration can vary from 1 to 200 days, thus their positive and negative impact on human health can be considerable.

Advantages of religious fasting on human health are claimed by many, but have been explored by a limited number of studies conducted in Buddhist, Christian or Muslim populations. These trials indicate that religious fasting has beneficial effects on body weight, glycaemia, cardiometabolic risk markers and oxidative stress parameters. Animals exposed to a mimicking fasting diet have demonstrated: weight loss, plasma levels of glucose, triglycerides and insulin growth factor-1, although their lean body mass remained stable. Diabetic mice on repeated intermittent fasting had less insulin resistance that mice fed ad libitum. The long term significance of such changes on global health remained to be explored.


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The Role of Exercise in a Weight-loss Program on Clinical Control in Obese Adults with Asthma: a RCT.

Freitas PD, Ferreira PG, Silva AG, Stelmach R, Carvalho-Pinto RM PhD, Fernandes FL, Mancini MC Prof, Sato MN, Martins MA, Carvalho CR.

Am J Respir Crit Care Med. 2016 Jul 19.

PMID: 27744739


... Fifty-five obese patients with asthma were randomly assigned to either a weight-loss program + exercise (WL+E group, n=28) or a weight-loss program + sham (WL+S group, n=27) group, where the weight-loss program included nutrition (caloric restriction) and psychological therapies. The WL+E group incorporated aerobic and resistance muscle training, whereas the WL+S group incorporated breathing and stretching exercises. ... Compared with the WL+S group, the WL+E group demonstrated improved clinical control scores (-0.7 [-1.3, -0.3] vs. -0.3 [-0.9, 0.4]; P=0.01) and greater weight-loss (-6.8%±3.5 vs. -3.1%±2.6; P<0.001) and aerobic capacities (3.0 [2.4, 4.0] vs. 0.9 [-0.3, 1.3] mL O2.kg.min-1; P<0.001). These improvements in the WL+E group were also accompanied by improvements in lung function, anti-inflammatory biomarkers and vitamin D levels, as well as reductions in airway and systemic inflammation.


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Preventive Effects of Long-Term Caloric Restriction on Aging Related In Vivo Bladder Dysfunction and Molecular Biological Changes in the Bladder and Dorsal Root Ganglia in Rats.

Ito H, Kamei J, Aizawa N, Fujita Y, Suzuki M, Fukuhara H, Fujimura T, Kojima T, Homma Y, Kubota Y, Ito M, Andersson KE, Igawa Y.

J Urol. 2016 Nov;196(5):1575-1583. doi: 10.1016/j.juro.2016.05.104.

PMID: 27259654


... The old group with free access to normal food showed higher threshold pressure, more nonvoiding contractions and lower bladder compliance than the young group with free access to food. Old rats with free access showed greater post-void residual volume and lower voiding efficiency than old rats with caloric restriction and young rats. ...


Caloric Restriction and Aging Bladder Dysfunction.

Chai TC.

J Urol. 2016 Nov;196(5):1339. doi: 10.1016/j.juro.2016.08.013. No abstract available.

PMID: 27520084




Sleep Duration Important in Weight Management

Aaron B. Holley

October 18, 2016



Authors of a recent study published in the journal Sleep tested the inverse of the sleep duration–weight gain relationship.[6] Twelve young-adult males of normal weight were studied in a lab for 5 days. On the second and third days of the experiment, their caloric intake was reduced to 10% of baseline. On the fourth and fifth days, they were able to eat freely without restriction. Sleep was measured each night with polysomnography.

During caloric restriction, the percentage of slow-wave sleep (SWS) increased. Although the researchers didn't measure "delta power," given that most SWS was stage IV, one can infer an increase. Additional relationships between caloric restriction and serum endocrine markers were found: reductions in leptin, thyrotropin, and orexin.

Sleep, Diet, and the Endocrine System

The authors of this study spend time discussing the complex interactions between eating, sleep, and the endocrine system. They also offer an evolutionary theory to explain their findings: Humans adapted to protect themselves from starvation conditions by spending more time with a lower metabolic rate, in SWS. We are not unlike animals who hibernate.[6]

During SWS, the metabolic rate hits its nadir, along with heart rate and blood pressure. Growth hormone is secreted during SWS, arousal threshold increases, breathing stabilizes, and sleep continuity is optimized. The greater the delta power within SWS, the more these changes are assumed to occur. SWS is critical when caloric intake is normal, and now we know that it is even more important when energy balance is negative. The conditions imposed on the study participants (energy intake reduced to 10% of baseline) were much more severe than in most diets. Still, for those trying to achieve a net negative energy balance through dieting, I would consider increasing total sleep time. You're likely to need more SWS than usual.


[The below paper is pdf-availed.

The Sleep/Wake Cycle is Directly Modulated by Changes in Energy Balance.

Collet TH, van der Klaauw AA, Henning E, Keogh JM, Suddaby D, Dachi SV, Dunbar S, Kelway S, Dickson SL, Farooqi IS, Schmid SM.

Sleep. 2016 Sep 1;39(9):1691-700. doi: 10.5665/sleep.6094.

PMID: 27306267

... Twelve healthy normal weight men ... 2 days of caloric restriction to 10% of energy requirements, and after energy balance was restored by 2 days of ad libitum/free feeding. ... Two days of caloric restriction significantly increased the duration of deep (stage 4) sleep (16.8% to 21.7% of total sleep time; P = 0.03); an effect which was entirely reversed upon free feeding (P = 0.01). Although the apnea-hypopnea index stayed within the reference range (< 5 events per hour), it decreased significantly from caloric restriction to free feeding (P = 0.03). Caloric restriction was associated with a marked fall in leptin (P < 0.001) and insulin levels (P = 0.002). The fall in orexin levels from baseline to caloric restriction correlated positively with duration of stage 4 sleep (Spearman rho = 0.83, P = 0.01) and negatively with the number of awakenings in caloric restriction (Spearman rho = -0.79, P = 0.01). ...


Energy restriction at young age, genetic variants in the insulin-like growth factor pathway and colorectal cancer risk in the Netherlands Cohort Study.

Simons CC, Schouten LJ, Godschalk RW, van Engeland M, van den Brandt PA, van Schooten FJ, Weijenberg MP.

Int J Cancer. 2016 Sep 20. doi: 10.1002/ijc.30439.

PMID: 27649841


... The energy restriction (ER)-colorectal cancer (CRC) ... Individuals living in a Western city during the Hunger Winter (1944-45) or Western rural versus non-Western area were exposed to (severe) ER at young age. ... Multiplicative and additive interactions were nonsignificant. Combined ER-genetic sum score categories showed increasing CRC risks in men, but confidence intervals were wide. Women carrying two variant IGF1 19-CA repeat alleles versus those carrying two wild type IGF1 19-CA repeat alleles were at an 50% decreased CRC risk, irrespective of ER exposure. In conclusion, data indicate that the IGF pathway might be involved in the ER-CRC association in men, but not women, although interactions were nonsignificant, hampering definite conclusions.


Food-restriction lowers the acoustic startle response in both male and female rats, and in combination with acute ghrelin injection, abolishes the expression of fear-potentiated startle in male rats.

Toufexis DJ, Lipatova O, Johnson AC, Abizaid A.

J Neuroendocrinol. 2016 Oct 18. doi: 10.1111/jne.12436.

PMID: 27754564


... moderate food restriction (80% of ad-libitum fed weight), with or without an acute application of a small dose of exogenous ghrelin intended to cause an immediate hunger response, on the expression of the acoustic startle reflex (ASR). This was done under basal conditions (baseline ASR to 90 and 95 dB noise bursts), and in the presence of a light cue associated with a mild foot-shock, as measured by fear-potentiated startle, which compares the proportional change in ASR in the presence of the conditioned stimulus. Results show that food-restriction reduces basal ASR in both male and female rats, apart from any concomitant change in motor activity, suggesting that food-restriction reduces anxiety levels in both sexes. In addition, data show that food-restriction reduces fear-potentiated startle in male, but not female, rats. Acute ghrelin injection, prior to fear-potentiated startle testing, eliminates the expression of fear-potentiated startle in food-restricted male rats alone, suggesting a role for ghrelin in the reduction of fear expression in food-restricted male rats. These data imply that while food-restriction decreases anxiety in both sexes, learned fear responses remain intact following food-restriction in female, but not male rats.

Edited by AlPater
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