Calorie Restriction | The School of Biological Sciences

Calorie Restriction

Staff: Professor John Speakman, Sharon Mitchell, Jacques Togo
Student: Daniel Phillips MRes

Image: Calorie Restriction increases healthy lifespan in diverse range of animals from single cell, invertebrates and vertebrates. Reproduced from Fontana and Partridge 2015

Background

Calorie restriction (CR) is the only non-genetic manipulation of animals that reliably increases lifespan via an effect on the rate of ageing. CR animals also have improvements in the susceptibility to a wide range of pathological conditions including insulin resistance, type 2 diabetes and cancer. CR is therefore an important intervention modulating health span as well as lifespan. CR has been shown to be effective in a wide range of different species from yeast to non-human primates (Speakman, John R., Mitchell 2011). However, the CR effect is not universal. While a wealth of research on CR conducted in rodents report lifespan extension, a varying response to CR was found in 41 recombinant inbred mouse strains (ILSXISS) with a reduction in lifespan in a high proportion of the males and females on CR (Liao, Rikke et al. 2010). Of note CR also does not increase lifespan in house flies, something we plan to investigate further (Cooper, Mockett et al. 2004).

CR work on non-human primates raises the hope that CR may also be effective in humans.

Calorie restriction improves health, survival in rhesus monkeys - National Institute on Aging
Calorie restriction lets monkeys live long and prosper - University of Wisconsin-Madison

The effects of CR are so convincing in animal studies that some people have already started to voluntarily restrict their intake in the hope that they too will increase their lifespans. Known as CRONies (Caloric Restriction with Optimal Nutrition) their goal is to live longer and healthier by restricting their diet by 10 to 25% fewer calories.

Dr. Roy Walford was one of the first to advocate CR as means to extend lifespan. Dr. Walford was one of the researchers that entered the Biosphere 2 project in Arizona where he spent 2 years in involuntary restriction. After he emerged, he continued to restrict his intake and wrote several books on the power of CR to increase lifespan. Dr. Walford was an authority in gerontology and nutrition, publishing numerous papers and the book “The Retardation of Aging and Disease by Dietary Restriction” together with Dr. Richard Weindruch.

In addition to these volunteer organisations the NIA in the US have also sponsored a randomised clinical trial to evaluate the effectiveness of CR in humans. The trial is called CALERIE (Comprehensive Assessment of the Long-term Effects of Reduced Intake of Energy). The CALERIE study is run across three sites, the Pennington Biomedical Research center in Baton-Rouge (PI: Eric Ravussin), The Jean-Meyer Nutrition research center at Tufts in Boston (PI Susan Roberts), and the School of Medicine at the Washington University in St louis (PI John Holloszy). The study is coordinated from Duke University . John Speakman is a member of the data safety and monitoring board for CALERIE. Recent publications from CALERIE provided evidence that some of the metabolic responses to CR measured in humans are similar to those observed in animals.

A key problem with CR is that despite many years of intensive research effort it remains unclear what the defining mechanisms are that mediate the specific health and longevity effects. In rodents it has been established that the extension of lifespan is directly and linearly related to the extent of restriction (Speakman, John R., Hambly 2007, Speakman, JR, Mitchell et al. 2016). This led to the prediction that the mechanisms which lead to increased lifespan via CR must also be linear.

The relationship between level of calorie restriction (CR) and lifespan

Graph: The relationship between level of calorie restriction (CR) and lifespan

The relationship between % calorie restriction (CR) either with simultaneous protein restriction (PR) (grey points) or with no PR (black points), and the % increase in median lifespan relative to ad libitum fed animals. The data refer to various rat and mouse strains. The lines show the no intercept fitted regressions for the two data sets (dashed line for CR with no PR). (Speakman, JR, Mitchell et al. 2016)

Collaborators

From Graded CR project we gathered a team of experts from the CPA (China Partnership Award BBSRC BB/JO20028/1

Projects

The Graded Calorie Restriction Project Open Science Framework

UKRI logo

Funding from the UK BBSRC (Do neuropeptides mediate the link between caloric restriction and life span extension? BB/G009953/1) allowed us to explore the graded effect of CR. The project involved exposing male C57BL/6 mice to graded levels of CR from 0 to 40% restriction. All of the mice, including the control animals at 0% restriction, were only fed during the hours of darkness. We also included an additional 24hr ad libitum group. Adult mice (5 months) were exposed to the CR for a period of 12 weeks before their responses are characterised. We have published 17 papers to date with topics ranging from body composition, endocrine, metabolic, body temperature, physical activity, transcriptomics to metabolomics.

Graph

Graph: Daily body mass (BM) (g) recorded over 2 weeks of baseline (BL) (-14 to 0) and 12 weeks of treatment comprising 12 or 24h ad libitum (AL) feeding and graded levels of caloric restriction (CR) from 10 to 40% (10CR, 20CR, 30CR and 40CR respectively). Data are presented as daily mean ı SEM (g). (Mitchell, Tang et al. 2015)

Graph: Hormonal changes measured in male C57BL/6 mice following calorie restriction (CR). Mice were fed 12 or 24 hrs ad libitum (12AL or 24AL) or calorie restricted (CR) by 10, 20, 30 or 40% (10CR, 20CR, 30CR and 40CR) for 3 months. Circulating levels of a) leptin, c) tumor necrosis factor (TNF)-α, d) insulin-like growth factor (IGF-1) and f) insulin. Significant hormonal relationships are shown between b) fat mass and leptin, e) structural tissues and IGF-1, g) vital organs and insulin and h) liver and insulin. Results are expressed as mean ı sem. Different letters denote significant differences between treatment groups. (Mitchell, Delville et al. 2015)

Publications

The Graded CR Paper series

The effects of graded levels of calorie restriction XVII: multi-tissue metabolomics.

Garcia-Flores,L.A., Green,C.L., Mitchell,S.E., Promislow,D.E.L., Lusseau,D., Douglas,A. Speakman,J.R. PNAS (2021) (accepted)

The effects of graded levels of calorie restriction: XVI. Metabolomic changes in the cerebellum indicate activation of hypothalamocerebellar connections driven by hunger responses.

Green,C.L., Mitchell,S.E., Derous,D., García-Flores,L.A., Wang,Y., Chen,L Han,J.J.D., Promislow,D.E.L., Lusseau,D., Douglas,A. Speakman,J.R. Journals of Gerontology: Series A, 76(4), 2021, 601-610. https://doi.org/10.1093/gerona/glaa261

The Effects of Graded Levels of Calorie Restriction XV: Phase Space Attractors Reveal Distinct Behavioral Phenotypes.

Sun,D.*, Liu,F.*, Mitchell,S.E.*, Ma,H., Derous,D., Wang,Y., Han,J.J.D., Promislow,D.E.L., Lusseau,D., Douglas,A. Speakman,J.R. and Chen,L. Journals of Gerontology: Series A, 2020, 75(5), 858-866. https://doi.org/10.1093/gerona/glaa055

The effects of graded levels of calorie restriction: XIV. Global metabolomics screen reveals brown adipose tissue changes in amino acids, catecholamines, and antioxidants after short-term restriction in C57BL/6 mice.

Green,C.L.*, Mitchell,S.E.*, Derous,D., Wang,Y., Chen,L., Han,J.J.D., Promislow,D.E.L., Lusseau,D., Douglas,A. and Speakman,J.R. Journals of Gerontology: Biological Sciences, 75(2), 2020, 218-229.

The effects of graded levels of calorie restriction: XIII. Global metabolomics screen reveals graded changes in circulating amino acids, vitamins and bile acids in the plasma of C57BL/6 mice.

Green,C.L., Soltow,Q.A., Mitchell,S.E., Derous,D., Wang,Y., Chen,L., Han,J.J.D., Promislow,D.E.L., Lusseau,D., Douglas,A. and Speakman,J.R. Journal of Gerontology: Medical Sciences 74(1), 2018,16-26. https://doi.org/10.1093/gerona/gly058

The effects of graded calorie restriction: XII. Comparison of mouse to human impact on cellular senescence in the colon.

Fontana,L*., Mitchell,S.E.*, Wang,B, Tosti,V., van Vliet,T., Veronese,N., Bertozzi,B., Early,D.S., Maissan,P., Speakman,J.R., Demaria.M. Aging Cell 17(3), 2018, e12746. https://doi.org/10.1111/acel.12746

The effects of graded levels of calorie restriction: XI. Evaluation of the main hypotheses underpinning the life extension effects of CR using the hepatic transcriptome.

Derous,D., Mitchell,S.E., Wang,L., Green,C.L., Wang,Y., Chen,L., Han,J.D.J., Promislow,D.E., Lusseau,D., Douglas,A. and Speakman,J.R. Aging (Albany NY), 9(7), 2017, 1770-1804. doi: 10.18632/aging.101269

The effects of graded levels of calorie restriction: X. The transcriptomic responses of epididymal adipose tissue.

Derous,D., Mitchell,S.E., Green,C.L., Wang, Y., Han,J.D.J., Chen,L., Promislow,D.E.L., Lusseau,D., Douglas,A., Speakman,J.R. Journals of Gerontology Series A, 73(3), 2017, 279-288. https://doi.org/10.1093/gerona/glx101

The effects of graded levels of calorie restriction: IX. Global metabolomics screen reveals modulation of carnitines, sphingolipids and bile acids in the liver of C57BL/6 mice.

Green,C.L.*, Mitchell,S.E.*, Derous,D., Wang, Y., Chen,L., Han,J.D.J., Promislow,D.E.L., Lusseau,D., Douglas,A., Speakman,J.R. Aging Cell 16(3), 2017, 529-540. https://doi.org/10.1111/acel.12570

The effects of graded levels of calorie restriction: VIII. Impact of short term calorie and protein restriction on basal metabolic rate in the C57BL/6 mouse .

Mitchell,S.E., Tang,Z.H., Kerbois,C., Delville,C., Derous,D., Green,C.L., Wang,Y., Han,J.D.J., Chen,L., Douglas,A., Lusseau,D., Promislow,D.E.L., Speakman,J.R. Oncotarget 8(11), 2017, 17453-17474. doi: 10.18632/oncotarget.15294

The effects of graded levels of calorie restriction: VII. Topological rearrangement of hypothalamic aging networks.

Derous,D., Mitchell,S.E., Green,C.L., Wang,Y., Han,J.D.J., Chen,L., Promislow,D.E.L., Lusseau,D., Speakman,J.R. and Douglas,A., Aging 8(5), 2016, 917-931. doi: 10.18632/aging.100944

The effects of graded levels of calorie restriction: VI. Impact of short-term graded calorie restriction on transcriptomic responses of the hypothalamic hunger and circadian signaling pathways.

Derous,D., Mitchell,S.E., Green,C.L., Chen,L., Han,J.D.J., Wang,Y., Promislow,D.E.L., Lusseau,D., Speakman,J.R. and Douglas,A. Aging 8(4), 2016, 642-661. doi: 10.18632/aging.100895

The effects of graded levels of calorie restriction: V. Impact of short term calorie and protein restriction on physical activity in the C57BL/6 mouse.

Mitchell,S.E., Delville,C., Konstantopedos,P., Derous,D., Green,C.L., Wang,Y., Han,J.D.J., Promislow,D.E.L., Douglas,A., Chen,L., Lusseau,D. and Speakman,J.R. Oncotarget 7(15), 2016, 19147-19170. doi: 10.18632/oncotarget.8158

The effects of graded levels of calorie restriction: IV. Non-linear change in behavioural phenotype of male C57BL/6 mice in response to short-term graded caloric restriction. Lusseau,D.*, Mitchell,S.E.*, Barros,C., Derous,D., Green,C.L., Chen,L., Han,J.D.J., Wang,Y., Promislow,D.L., Douglas,A., Speakman,J.R. Scientific Reports 5, 13198, 2015. doi: 10.1038/srep13198

The effects of graded levels of calorie restriction: III. Impact of short term calorie and protein restriction on mean daily body temperature and torpor use in the C57BL/6 mouse.

Mitchell,S.E., Delville,C., Konstantopedos,P., Derous,D, Green,C., Chen,L., Han,J.D.J., Wang,Y., Promislow,D.L., Douglas,A., Lusseau,D., Speakman,J.R. Oncotarget 6(21), 2015, 18314-18337. doi: 10.18632/oncotarget.4506

The effects of graded levels of calorie restriction: II. Impact of short term calorie and protein restriction circulating hormones levels, glucose homeostasis and oxidative stress in male C57BL/6 mice.

Mitchell,S.E., Delville,C., Konstantopedos,P., Hurst,J., Derous,D, Green,C., Chen,L., Han,J.D.J., Wang,Y., Promislow,D.L., Lusseau,D., Douglas,A. and Speakman,J.R. Oncotarget 6(27), 2015, 23213-23237. doi: 10.18632/oncotarget.4003

The effects of graded levels of calorie restriction: I. Impact of short term calorie and protein restriction on body composition in the C57BL/6 mouse.

Mitchell,S.E., Tang,Z.H., Kerbois,C., Delville,C., Konstantopedos,P., Bruel,A., Derous,D, Green,C., Aspden,R.A., Goodyear,S.R., Chen,L., Han,J.D.J., Wang,Y., Promislow,D.L., Lusseau,D., Douglas,A., and Speakman,J.R. Oncotarget 6(18), 2015, 15902-15930. doi: 10.18632/oncotarget.4142

Other papers linked to CR from the group

Why does caloric restriction increase life and healthspan? The 'clean cupboards' hypothesis

Speakman, JR., National Science Review, 7(7), 2020, 1153-1156. https://doi.org/10.1093/nsr/nwaa078

Effect of calorie restriction or protein intake on circulating levels of insulin like growth factor I in humans: a systematic review and meta-analysis

Kazemi,A., Speakman,JR., Soltani,S., Djafarian,K. Clinical Nutrition, 39(6), 2020, 1705-1716. https://doi.org/10.1016/j.clnu.2019.07.030

Energy balance and the sphingosine‐1‐phosphate/ceramide axis

Green,C., Mitchell,S.E., Speakman,J.R. Aging, 9(12), 2017, 2463-2464. doi: 10.18632/aging.101347

Calories or protein? The effect of dietary restriction on lifespan in rodents is explained by calories alone.

Speakman,J.R., Mitchell,S.E. and Mazidi,M. Experimental Gerontology 86, 2016, 28-38. https://doi.org/10.1016/j.exger.2016.03.011

Mice that are resistant to diet-induced weight loss have greater food anticipatory activity and altered melanocortin-3 receptor (MC3R) and Dopamine receptor 2 (D2) gene expression.

Vaanholt,L.M., Mitchell,S.E., Sinclair,R.S., Speakman,J.R. Hormones and Behaviour 73, 2015, 83-93. https://doi.org/10.1016/j.yhbeh.2015.06.006

Update on human calorie restriction research

SB Roberts, J Speakman, Advances in Nutrition,4(5), 2013, 563-564. https://doi.org/10.3945/an.113.004317

Repletion of TNFα or leptin in calorically restricted mice suppresses post-restriction hyperphagia

Hambly,C. Duncan,JS., Archer,ZA., Moar,KM., Mercer,JG., Speakman,JR. Disease Models & Mechanisms, 5(1), 2012, 83-94. https://doi.org/10.1242/dmm.007781

Caloric Restriction

Speakman,J.R. and Mitchell,S.E. Molecular Aspects of Medicine 32 (3), 2011, 159-221. https://doi.org/10.1016/j.mam.2011.07.001

Gross energy metabolism in mice under late onset, short term caloric restriction

Cameron,KM., Golightly,A., Miwa,S. Speakman,JR., Boys,R.,von Zglinicki,T. Mechanisms of Ageing, 132(4), 2011, 202-209. https://doi.org/10.1016/j.mad.2011.04.004

The impact of acute caloric restriction on the metabolic phenotype in male C57BL/6 and DBA/2 mice.

Hempenstall,S, Picchio,L., Mitchell,SE., Speakman,JR and Selman,C. Mechanisms of Ageing and Development 131(2) ,2010, 111-118. https://doi.org/10.1016/j.mad.2009.12.008

Starving for life: what animal studies can and cannot tell us about the use of caloric restriction to prolong human lifespan

Speakman,JR., Hambly,C. The Journal of Nutrition, 137(4), 2007, 1078-1086. https://doi.org/10.1093/jn/137.4.1078

Hunger does not diminish over time in mice under protracted caloric restriction

C Hambly, JG Mercer, JR Speakman, Rejuvenation Research, 10(4), 2007, 533-541.

https://doi.org/10.1089/rej.2007.0555

Calorie-restricted mice that gorge show less ability to compensate for reduced energy intake

Hambly,C., Simpson,CA., McIntosh,S., Duncan,JS., Dalgleish,GD., Speakman,JR. Physiology & Behavior, 92(5), 2007, 985-992. https://doi.org/10.1016/j.physbeh.2007.07.005

Energy expenditure of calorically restricted rats is higher than predicted from their altered body composition

C Selman, T Phillips, JL Staib, JS Duncan, C Leeuwenburgh, JR Speakman, Mechanisms of Ageing, 126(7-7), 2005, 783-793. https://doi.org/10.1016/j.mad.2005.02.004

Contribution of different mechanisms to compensation for energy restriction in the mouse

Hambly,. Speakman,.Obesity Research, 13(9), 2005, 1548-1557. https://doi.org/10.1038/oby.2005.190

External links

CALERIE

Non-Human Primate Work

Calorie Restriction Society

Roy Walfords CR site

The Fly Story > Juliano