Do hunger neuropeptides mediate the link between caloric restriction and lifespan extension?

Lead Research Organisation: University of Aberdeen
Department Name: Inst of Biological and Environmental Sci

Abstract

Seventy years ago it was discovered that if rats are fed less than their normal ration of food they live longer. This treatment has since been found to extend the lives of many different species, including non-human primates. It is known that this process of restricting calorie intake (called caloric restriction - or CR) reduces the risk of developing age related diseases like cancer and it improves levels of many markers that alter with age - such as damage to DNA, fats and proteins, and circulating glucose and insulin levels. Exactly how CR exerts its effects remains uncertain. As a method for extending human life it is recognised that it would be extraordinarily difficult for people in modern society to restrict their intake of food voluntarily. A search has started therefore for drugs that will mimic the effects of CR, but without the need to eat less food. Another uncertainty concerns the mechanism that translates eating less food into switching on the cellular responses that ultimately lead to extended lifespan. There are two ideas about how this might work. When animals and people undergo CR they tend to lose body fat. The response to CR might be switched on by eating less food, alternatively it might be switched on by the reduction in body fatness. Normally these two things change together so it is difficult to separate which is of most importance. I have previously shown that when animals are taken off CR they over-eat until their fat stores are repleted. This suggests that it is probably signals from the fat that are important in signalling to the brain to switch on the 'CR programme' that ultimately extends life. The first part of this proposal aims to explore the roles of reduced fatness and fat signals (called adipokines) as opposed to simply eating less food in initiating the CR programme. To do this I will perform an experiment which dissociates the changes in food intake from the changes in body fatness using mice as a model organism. This can be achieved by exposing mice to different temperatures. For example if the temperature is made warm mice eat less food because their energy demands decrease, but they don't lose body fat because they remain in energy balance. Perhaps mice kept in the warm switch on the CR programme and live longer because they are eating less food. Alternatively if it is fat loss that is important as I suspect from my previous work I predict this manipulation will not switch on the CR programme. To further test the role of adipokines in switching on the CR programme I will perform another experiment where I place animals at normal room temperature under CR so that they lose weight and switch the programme on. I will then implant them with small devices that continuously deliver some of the compounds produced by fat so see if the CR programme can be switched off. Clearly whether reduced body fat, or eating less food switches, on the CR programme it is controlled by events in the animal's brains. My recent work has suggested that some neuropeptides in the hypothalamus are an important part of this process. These neuropeptides are known to interact with some of the signals generated by fat tissue. To experimentally test if they are indeed important I will place animals under CR and then interfere with these pathways by introducing compounds into their brains which disrupt the signalling. These compounds are commercially available and have very specific effects on receptor populations that the neuropeptides of interest interact with. If the neuropeptides that I suspect are important really do switch on the CR programme then interfering with them should switch the CR programme off. If this experiment works the final experiment I will perform is to do the opposite. Introduce compounds that have the opposite effects into the same brain regions. These should in theory turn on the CR programme but without the need for the animals concerned to eat less food.

Technical Summary

The mechanism by which caloric restriction (CR) induces cellular and molecular level events that lead to life extension remains obscure. One possibility is that eating less food generates signals directly to activate the CR programme. Alternatively reduced adiposity during CR may alter the adipokine profile, triggering the response. Normally reduced food intake and adiposity occur in parallel so separating between them is difficult. I will expose mice to altered ambient temperatures to dissociate changes in food intake from adiposity. I will monitor the extent to which the CR programme is initiated in animals that eat the same levels of food, but differ in their energy balance and body fatness. To further test the role of adipokines in switching on the CR programme I will place animals under CR so that they lose weight and switch the programme on. I will then replete levels of key adipokines (leptin and TNFalpha) using mini-osmotic pumps to their pre-restriction levels, to see if the CR programme can be switched off. Clearly whatever the peripheral trigger is, the CR programme is probably controlled by events in the brain. My recent work has implicated several neuropeptides in the hypothalamus (notably the hunger neuropeptides AgRP, NPY, POMC and CART) which are the immediate downstream targets of leptin in the hypothalamus. To experimentally confirm their role in CR, I will place animals under CR and then antagonise Y1 and Y5, or agonise MC4 and MC3 receptors which are the primary receptors of the relevant neuropeptides. If the neuropeptide profiles switch on the CR programme then these manipulations switch the CR programme off. If this experiment works the final experiment I will perform is to do the opposite. I will agonise Y1 and Y5 and antagonise MC4 and MC3 receptors while clamping intake. This should in theory turn on the CR programme without the animals eating less food.

Publications

10 25 50

publication icon
Derous D (2018) The Effects of Graded Levels of Calorie Restriction: X. Transcriptomic Responses of Epididymal Adipose Tissue. in The journals of gerontology. Series A, Biological sciences and medical sciences

 
Description Caloric restriction (CR) involves eating less food. It leads to weight loss and changes in body composition in particular reductions in body fat. It has been known for almost 100 years that it also increases lifespan and reduces age related diseases. We have shown that graded levels of caloric restriction have a complex impact on many different processes. However, the effects seem to be mediated in the brain by a limited number of brain chemicals (called neuropeptides) that can switch on the protective effects of CR. This lends hope to the possibility that it may be possible to switch on the CR effects without the need to eat less food.
Exploitation Route We have found that the benefits of Caloric restriction seem to be mediated via a particular set of neuropeptides in the brain. These neuropeptides provide a viable target for pharmaceutical intervention that may enable to the Caloric restriction program to be initiated without eating less food. This may have important benefits in terms of healthspan.
Sectors Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://www.abdn.ac.uk/energetics-research
 
Description Developing a network model of caloric restriction in the mouse, China Partnering Award (CPA)
Amount £22 (GBP)
Funding ID BB/J020028/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 06/2012 
End 12/2014
 
Description The impact of short term CR and various drugs on weight loss 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution During the course of the grant we established a research collaboration with Astrazeneca based in the UK in Cheshire, who acted as CASE partner on a BBSRC funded PhD studentship
Collaborator Contribution Astrazeneca provided CASE support for the student and since we wished to employ a non-UK citizen they topped up the fees payment to cover these costs. They hosted the student at Astra for a period of about 3 months and provided us with financial and in-kind support for various parts of the project. Finally they helped with the student training and supported the resultant publications.
Impact we have published the following papers from this collaboration Zhang, L.N., Morgan, D., Sinclair, R., Selman, C., Mitchell, S.E., Clapham, J.C. and SPEAKMAN, J.R. (2013) Effects of chronic oral administration of a melanin-concentrating hormone receptor 1 (MCHR1) antagonist (GW803430) on energy budgets and glucose homeostasis in diet-induced obese C57BL/6J mice Obesity Zhang, L.N., Gamo, Y., Sinclair, R., Mitchell, S.E., Morgan, D., Clapham, J.C. and SPEAKMAN, J.R. (2012) Effects of chronic oral rimonabant administration on energy budgets of diet-induced obese C57BL/6J mice Obesity 20: 954-962 Zhang, L.N., Mitchell, S.E., Hambly, C., Morgan, D., Clapham J.C., and SPEAKMAN, J.R. (2012) Physiological and behavioral responses to intermittent starvation in C57BL/6J mice Physiology and Behaviour 105: 376-387 Zhang, L.N., Morgan, D., Clapham, J.C. and SPEAKMAN, J.R. (2012) Factors predicting non-genetic variability in body weight gain induced by a high fat diet in inbred C57BL/6J mice. Obesity 20: 1179-88
Start Year 2009
 
Description Body composition and ageing in the dog. Effects of body size. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keck conference, Dallas, Texas, USA

no actual impacts realised to date
Year(s) Of Engagement Activity 2009
 
Description Caloric restriction and life extension - will it work in humans 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Experimental Biology Annual Meeting, Los Angeles, USA

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
 
Description Caloric restriction to retard ageing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Scottish Ecological Ageing group, Edinburgh, Scotland

no actual impacts realised to date
Year(s) Of Engagement Activity 2013
 
Description Do hunger neuropeptides mediate the link between caloric restriction and lifespan extension? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact China partnering workshop, Beijing, China, Sept 2012

no actual impacts realised to date
Year(s) Of Engagement Activity 2012
 
Description Energetics in the context of ageing and obesity 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Clive McCay endowment lecture, Cornell University, Ithaca, NY, USA, 2011;

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description John Speakman Calorie restriction Society Conference (Tuscan, Arizona) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact presentation entitled "Is the Effect of Dietary Restriction Due to Calorie Restriction or Protein Restriction?". The meeting was organised by CR Society members. The key aim was to interact directly with scientists and fellow practitioners about how to optimise the practice of calorie restriction. A number of key researchers in the fields of CR, metabolism, and the retardation of aging presented.
Year(s) Of Engagement Activity 2016
URL http://www.crsociety.org/conferences/cr_009a
 
Description John Speakman Participation in workshop organised by Royal Society of Edinburgh 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Participation in workshop organised by Royal society of Edinburgh 9th Feb 2018, held at Royal Botanic Gardens. Scoping out the Future of UK Science activity.
Year(s) Of Engagement Activity 2018
 
Description John Speakman Talk at the University of Wageningen, Netherlands "Calorie Restriction: does eating fewer calories lead to a longer life?" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact Invited talk at the University of Wageningen, Netherlands on Calorie Restriction: does eating fewer calories lead to a longer life?
Year(s) Of Engagement Activity 2011,2018
 
Description John Speakman ACSM Conference on Integrative Physiology of Exercise 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact John Speakman gave an invited talk on the " Interactions between calorie restriction and physical activity" to the American College of Sports Medicine (ACSM) Conference on Integrative Physiology of Exercise, San Diego, Sept 2018
Year(s) Of Engagement Activity 2018
URL https://www.emedevents.com/c/medical-conferences-2018/acsm-conference-on-integrative-physiology-of-e...
 
Description John Speakman Chaired and spoke at World Economic Forum, Tianjin, People's Republic of China 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact John Speakman attended the World Economic forum summer meeting in Tianjin, China as a representative of the Royal Society. Chaired and spoke at a workshop meeting on Ethics of Research, Sept 2018
Year(s) Of Engagement Activity 2018
URL https://www.weforum.org/events/annual-meeting-of-the-new-champions/programme
 
Description John Speakman IAEA Dec 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact John Speakman invited talk "Physical activity and weight regulation". International Symposium on Understanding the Double Burden of Malnutrition for Effective Interventions, international Atomic Energy Agency, Vienna Dec 2018
Year(s) Of Engagement Activity 2018
URL https://www.iaea.org/newscenter/news/toward-a-healthier-future-iaea-symposium-on-the-double-burden-o...
 
Description John Speakman Invited lenary address at LipidALL meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The LipidALL International Conference on Lipid Metabolism was founded by the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and the Lipid Metabolism Conference organized by the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences. It is currently a major influence in the field of lipid metabolism science in China. John Speakman was invited to give a plenary address " Metabolomics signatures of caloric restriction: a multi-tissue perspective" Beijing Nov 2018
Year(s) Of Engagement Activity 2018
 
Description John Speakman Invited presentation on energy balance. Amway company, Shanghai, China 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact John Speakman invited to give a presentation on energy balance to Amway company, Shanghai, China, Nov 2018
Year(s) Of Engagement Activity 2018
 
Description John Speakman Invited talk University of Leeds, Feb 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact John Speakman Invited seminar presentation "Why do we get fat?" University of Leeds UK, Feb 2018
Year(s) Of Engagement Activity 2019
 
Description John Speakman Invited talk University of Reading. UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact John Speakman invited talk to evolutionary medicine students, University of Aberdeen, "The evolution of Obesity" Feb 2019
Year(s) Of Engagement Activity 2019
 
Description John Speakman Royal Academy of the Netherlands conference on Energy Balance 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact John Speakman inited to talk on Calorie Restriction at the Royal Academy of the Netherlands conference on Energy Balance, Oct 2018
Year(s) Of Engagement Activity 2018
 
Description John Speakman School of Biological Sciences Research Seminar Series 2019 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact John Speakman invited speaker at School of Biological Sciences Research Seminar Series 2019. "Pandas and Pikas- Studies of Energy Balance in some Enigmatic Chinese Mammals" Feb 2019
Year(s) Of Engagement Activity 2019
 
Description John Speakman Talk European Congress of Obesity, Vienna 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk given "Macronutrients, fast food and regulation of body weight" EASO Vienna, May 2018
Year(s) Of Engagement Activity 2018
URL https://eco2018.easo.org/
 
Description John Speakman Talk at International Conference on Obesity and Cardiovascular Diseases 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk on Body weight regulation at the International Conference on Obesity and Cardiovascular Diseases, Copenhagen June 2019
Year(s) Of Engagement Activity 2018
URL https://waset.org/conference/2018/06/copenhagen/ICOCD
 
Description John Speakman Talk at keystone meeting in Hannover, Germany - Pushing the Limits of Healthspan and Longevity 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact This conference addresses factors that may contribute to healthier lifestyles and outcomes, thereby delaying the onset of age-associated diseases and extending longevity. The focus is to highlight cutting-edge advances in aging research, novel technologies and potential therapeutic interventions. The conference will focus on topics not covered at previous Keystone Symposia meetings on aging biology and will specifically examine both the fundamental mechanisms involved in the aging process as well as interventions and potential therapeutics that may delay aging and the onset of age-associated diseases to forge a deeper understanding of the complex, multifactorial aging process. The discussions of novel interventions and/or therapeutics that appear to slow aging processes will, in turn, guide the field toward facilitating extended periods of good health and prolonging lifespan in humans
Year(s) Of Engagement Activity 2018
URL http://www.keystonesymposia.org/18D3
 
Description John Speakman Workshop meeting on Science Advisory Board for CALERIE 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact CALERIE (Comprehensive Assessment of Long term Effects of Reducing Intake of Energy) was a study designed to determine the biological effects of two years of prolonged caloric restriction in humans.
As part of the Science Advisory Board for CALERIE John Speakman attended Workshop meeting, Chicago August 2018
Year(s) Of Engagement Activity 2018
URL https://calerie.duke.edu/
 
Description John Speakman invited presentation at Novo-Nordisk forum meeting, Copenhagen 2018 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact John Speakman "invited presentation on 'The Regulation of Body Weight' at the Novo-Nordisk forum meeting, Copenhagen 6th Dec 2018.
Year(s) Of Engagement Activity 2018
 
Description Jojn Speakman Invited talk at the General Assembly of the Alliance of International Science organisations (ANSO) Belt and Road conference 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The General Assembly of the Alliance of International Science organisations (ANSO) Belt and Road conference, Beijing, China 4th Nov 2018. John Speakman invited to talk, International liaison with the University of Aberdeen
The Declaration is committed to establish an official governing body with legal independence to promote cooperation of science, technology and innovation in the Belt and Road regions.
Policy makers, scientist, public health experts will share their knowledge and experience in cutting-edge research and innovation, in working with local authorities to implement policies and promoting education and training.
Year(s) Of Engagement Activity 2018
 
Description Metabolism and Ageing in mice: Assessing the link between free-radical damage theory and rate of living theory. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact We found that, in a large sample of MF-1 mice strain, Lifespan was not significantly related to Daily Energy Expenditure, Resting Metabolic Rate (RMR) and body mass, but significantly negatively related to RMR. However after measuring body composition and statistically removing the effect of fat mass on RMR the significant association between RMR and lifespan disappeared. We conclude that the negative association between RMR and lifespan is primarily due to the effect of FM, with FM positively related to both RMR and mortality and hence RMR negatively to lifespan. In 40 additional screened mice, greater FM was also associated with greater oxidative damage to DNA. Although recent studies, including ours, do not support the strong version of the "free-radical damage theory", the positive relationship between fatness and DNA damage give some endurance to the use of 8OHdG method as an ageing marker. Abstract Book

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description Metabolism and personality 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach international
Primary Audience Participants in your research or patient groups
Results and Impact Poster: SEB annual meeting, Salzburg, Austria

no actual impacts realised to date
Year(s) Of Engagement Activity 2012
 
Description The contribution of doubly-labelled water studies to our understanding of human nutrition: comparative aspects. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Society for Integrative and Comparative Biology, SanFrancsiso, California, USA

no actual impacts realised to date
Year(s) Of Engagement Activity 2013
 
Description The effects of graded caloric restriction on the metabolomic profiles of mice 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keystone conference, "Adaptations to extreme conditions", Big sky, Montana, April 2011

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description The response of mice to graded CR 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact MitoFOOD conference, Wageningen, Netherlands, April 2011

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description The role of physical activity in the aetiology of obesity 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact FIMS meeting, Barcelona

no actual impacts realised to date
Year(s) Of Engagement Activity 2008
URL http://iec2013.com/downloads/abstractbook.pdf
 
Description What contribution have metabolic chamber studies made to our understanding of energy balance? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact RACMEM meeting, Maastricht, Netherlands

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description Why do we get fat? Increased food intake or reduced physical activity? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Stock conference, Budapest, Hungary

no actual impacts realised to date
Year(s) Of Engagement Activity 2011