Understanding the molecular mechanisms by which maternal diet influences longevity

Lead Research Organisation: University of Cambridge
Department Name: Clinical Biochemistry

Abstract

The diet of an individual has an important influence on the health of an individual at any stage of life. However there is evidence to suggest that the diet of a pregnant woman is particularly important as it has major long-term consequences on the health of her baby many years later when they themselves are adult. Babies that are not well nourished during pregnancy often have a low birth weight. It has been shown that individuals with a low birth weight are not only less likely to survive delivery but are also at substantially increased risk of developing various common diseases such as diabetes, high blood pressure and heart disease and are more likely to die at a younger age. The detrimental effect of having a low birth weight is exaggerated if rapid growth occurs during the postnatal period and the individual becomes fat. The molecular mechanisms linking poor fetal growth, long-term health and lifespan are not known. Many of our attempts to decipher mechanisms of human diseases both rely on and have benefited from studying animal models. We have shown that in a mouse model that if pregnant animals have too little protein during pregnancy their babies are small at birth. These animals growth very quickly during the lactation period if suckled by a normally fed mother and reach an apparently normal weight by weaning. However these patterns of growth have detrimental consequences for the animal and we have shown results in over a 25 % reduction in lifespan. We now plan to study these animals further to understand how a modest reduction in protein intake of the mother can have such a large effect on the lifespan of her offspring. We are particularly interested in proteins involved in insulin signalling as it is know that insulin has effects on growth and metabolism in mammals and more recently has been implicated in regulation of lifespan in simple organisms such as fruit flies. Once the underlying mechanisms linking maternal diet to the health and longevity of the offspring are understood, intervention strategies can then be developed to help improve the health of both pregnant women and their offspring.

Technical Summary

A fetus responds to the nutrients it receives in a variety of ways including metabolic and endocrine changes that may lead to life-long changes in the function and structure of the body / a concept termed fetal programming. It is proposed that the baby receives from its mother a forecast of the nutritional environment it will receive after birth and modifies it metabolism to maximise chances of survival postnatally. These adaptations become detrimental if conditions after birth are not the same as those during fetal life. This Developmental Origins of Health and Disease hypothesis proposes that disorders such as heart disease and type 2 diabetes result from an imbalance between the environment experienced in utero and that experienced postnatally. This has been supported by human and animal studies. Furthermore human studies and our studies in rodents have shown that reduced fetal growth followed by rapid postnatal catch-up growth can lead to early death. There is emerging evidence to suggest that nutrition during early postnatal life also has long-term consequences on health. We showed that rodents that are suckled by low protein fed mums grow slowly during lactation, remain smaller and live longer than controls. Prior to these observations, the only known non-genetic way to increase life span in mammals was by permanent calorie restriction. Reducing the food intake of rodents can increase their life span by 40 %. A reproducible finding in such studies is that animals maintained on dietary restriction regimes exhibit reduced plasma insulin, enhanced glucose tolerance and reduced production of reactive oxygen species. This thus provides a direct association between food intake, plasma insulin concentrations and longevity. Our recent data suggests that nutritional restriction during critical periods of development is sufficient to influence longevity. This proposal addresses the possibility that this occurs through similar mechanisms as permanent calorie restriction.

Publications

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Barnes SK (2011) Pathways linking the early environment to long-term health and lifespan. in Progress in biophysics and molecular biology

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Carr SK (2014) Maternal diet amplifies the hepatic aging trajectory of Cidea in male mice and leads to the development of fatty liver. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

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Chen JH (2007) Methods of cellular senescence induction using oxidative stress. in Methods in molecular biology (Clifton, N.J.)

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Chen JH (2010) Early growth and ageing. in Nestle Nutrition workshop series. Paediatric programme

 
Description The diet of an individual has an important influence on the health of an individual at any stage of life. However there is evidence to suggest that the diet of a pregnant woman is particularly important as it has major long-term consequences on the health of her baby many years later when they themselves are an adult. Babies that are not well nourished during pregnancy often have a low birth weight. It has been shown that individuals with a low birth weight are not only less likely to survive delivery but are also at substantially increased risk of developing various common diseases such as diabetes, high blood pressure and heart disease and are more likely to die at a younger age. The detrimental effect of having a low birth weight is exaggerated if rapid growth occurs during the postnatal period and the individual becomes fat. In contrast growing slowly during the lactation period appears to confer protection against diabetes, high blood pressure and heart disease. The molecular mechanisms linking patterns of early growth, long-term health and lifespan are not known. Many of our attempts to decipher mechanisms of human diseases both rely on and have benefited from studying animal models. We have shown using a rodent model that if pregnant animals have too little protein during pregnancy their babies are small at birth. These animals (termed recuperated animals) grow very quickly during the lactation period if suckled by a normally fed mother and reach an apparently normal weight by weaning. However these patterns of growth have detrimental consequences for the animal and we have shown results in over a 25 % reduction in lifespan. In contrast, pups born to normally fed mothers when suckled by a mother who is fed a low protein diet (termed postnatal low protein animals) grow slowly during lactation and remain small even after being weaned onto a diet containing an adequate amount of protein. These offspring also have a longer lifespan. We studied these animals in order to understand how a modest reduction in protein intake of the mother during critical periods can have such a large effect on the lifespan of her offspring. We observed that the long lived postnatal low protein offspring have higher relative weights of brain and thymus and are leaner compared to control animals. The thymus and spleen, which play a critical role in immune function, showed delayed tissue atrophy and enhanced immune capacity respectively in young adult PLP animals. This was accompanied by reduced expression of an ageing biomarker, p16. These PLP animals also had increased expression of some key insulin signaling proteins which could lead to increased insulin sensitivity - a common feature of increased longevity in mammals. In contrast to PLP animals, recuperated animals gained more weight that controls when fed a control diet from weaning and had an increased percentage fat mass. This was associated with reduced expression of key insulin signaling molecules which could result in the development of insulin resistance. These animals also demonstrated accelerated aging at the cellular level, including more rapid telomere shortening (regions of DNA associated with life span), reduced expression of the longevity promoting molecule SIRT1 and increased expression of the aging biomarker p16. Global gene expression analysis identified novel markers of aging that were modified in response to maternal diet including heme oxygenase 1 which was overexpressed in PLP kidneys and NAUK2 was increased in recuperated tissue. Therefore these studies have identified a number of molecules and pathways that are influenced by maternal diet which could mediate its effects on longevity. Understanding these mechanisms linking maternal diet to the health and longevity of the offspring will contribute to the development of intervention strategies to help improve the health of both pregnant women and their offspring.
Exploitation Route We were the first group to show that maternal diet during pregnancy impacted on the life span of the offspring. Accelerated ageing at the cellular level is now a commonly observed mechanism underlying nutritional programming and therefore can be used as a target for intervention strategies.
Sectors Other

 
Description NIH meeting on Body Weight, Adiposity, Energetics and Longevity, St Simons Island, Georgia, USA, 2007 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation paper presentation
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk given: The role of rapid catch-up growth or intense positive energy balance in early life



no actual impacts realised to date
Year(s) Of Engagement Activity 2007
 
Description 13th Insulin receptor and insulin action meeting. Programming by maternal over-nutrition: a developing obesity crisis. Nice France 20-22nd April 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited speaker. 13th Insulin receptor and insulin action meeting. Programming by maternal over-nutrition: a developing obesity crisis. Nice France 20-22nd April 2017
Year(s) Of Engagement Activity 2017
 
Description 65th Nestle Workshop, Malaysia 
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 65th Nestle Nutrition Institution Workshop on the Importance of Growth for Health and Development, 29 March - 2nd April 2009, Kuala Lumpur, Malaysia
"Early growth and ageing"

NA
Year(s) Of Engagement Activity 2009
 
Description Annual meeting of the European Society for Pediatric Endocrinology, Istanbul, Turkey, 2008 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation paper presentation
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk given: Long-term consequences of early nutrition



no actual impacts realised to date
Year(s) Of Engagement Activity 2008
 
Description Biocenter Oulu Day 'Fifty Shades of Fat' conference, Oulu, Finland 23rd March 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited speaker, Biocenter Oulu Day 'Fifty Shades of Fat' conference, 23rd March 2017, Oulu, Finland.
Year(s) Of Engagement Activity 2017
 
Description CUDOS conference on understanding molecular mechanisms underlying cardiovascular disease, diabetes, obesity and stroke, Doha, Qatar 10-12 April 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited speaker. CUDOS conference on understanding molecular mechanisms underlying cardiovascular disease, diabetes, obesity and stroke. Nutritional programming of health and disease: are we ready to intervene? Doha, Qatar 10-12 April 2017
Year(s) Of Engagement Activity 2017
 
Description Consequences of maternal over-nutrition: mechanisms of hyperphagia and insulin resistance 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk given at the ILSI Europe roundtable Workshop on the effects of pre- and postnatal nutrition of infants of obese mothers: metabolic imprinting and later health outcomes, Brussels, Belgium

no actual impacts realised to date
Year(s) Of Engagement Activity 2009
 
Description DNA damage, repair and lifespan: the influence of the early environment 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk given at the biennial colloquium series, nutrition, metabolism and the brain on " Energy regulation from conception to old age", Groningen, The Netherlands

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description Dept of Women's Health, Kings College London. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Department of Women's Health, KCL, 11 March 2010, Kings College London
"You are what your mother ate: the developmental origins of type 2 diabetes and the metabolic syndrome"

NA
Year(s) Of Engagement Activity 2010
 
Description Developmental programming of metabolism-from global diabetes epidemiology to molecular mechanisms in animals and humans. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Taught PhD course in Copenhagen ;Programming of metabolism in rodents;

no actual impacts realised to date
Year(s) Of Engagement Activity 2009
 
Description Early growth and ageing 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk given at teh 65th Nestle Nutrition Institute Workshop on the importance of growth for the health and development, Kuala Lumpur, Malaysia

no actual impacts realised to date
Year(s) Of Engagement Activity 2009
 
Description Early nutrition and long term health - the role of epigenetic programming 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk given at the ESRC International Symposium on social science and epigenetics: opportunities and challenges, Edinburgh, Scotland

no actual impacts realised to date
Year(s) Of Engagement Activity 2012
 
Description Epigenetics, neonatal environment and nutrition 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk given a the 10th Agricultural Biotechnology International Conference, Saskatoon, Canada

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
 
Description Experimental Biology conference 2017, Chicago, USA 22nd - 26th April 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited speaker. Experimental Biology 2017 Epigenetics and the developmental origins of obesity, type 2 diabetes and cardiovascular disease: knowns, unknowns and possibilities. Chicago USA 22nd-26th April 2017
Year(s) Of Engagement Activity 2017
 
Description Human Nutrition Research Center (CRNH) Mtg, Clermont Ferrand, France 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Human Nutrition Research Center (CRNH), 28-29 May 2009, Clermont Ferrand, France
"Nutritional programming of type 2 diabetes, obesity and longevity"

NA
Year(s) Of Engagement Activity 2009
 
Description MSD Merck Diabetes Mtg, Seattle, USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact MSD Merck Meeting, 17-19 April 2010, Seattle, USA
"Type 2 diabetes: Emerging Science"

NA
Year(s) Of Engagement Activity 2010
 
Description Mechanisms of early life programming 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk given at the Gordon Research Conference on Ageing, Ventura, USA

no actual impacts realised to date
Year(s) Of Engagement Activity 2012
 
Description Nutricia Research Scientific Symposium Mechanisms of metabolic programming: what can we learn from translational research? Groningen, The Netherlands. 31st January 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited speaker.
Year(s) Of Engagement Activity 2017
 
Description Nutritionally programmed influences on gene expression - a mechanism underlying the developmental origins of health and disease. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk given at the 6th Congress of the International Society of Nutrigenetics and Nutrigenomics (ISNN), Sao Paulo, Brazil

no actual impacts realised to date
Year(s) Of Engagement Activity 2012
 
Description OHSU Heart Research Center's Annual Lecture, Portland, Oregon, USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact OHSU Heart Research Center's Annual Lecture, 1 April 2012, Portland, Oregon, USA
You are what your mother ate: The developmental origins of type 2 diabetes and obesity"

NA
Year(s) Of Engagement Activity 2010
 
Description Pathways linking the early environment to long-term health and lifespan 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk given at the NIH Longevity Consortium Symposium on Environment, Developmental and Genetic factors in ageing and longevity. San Francisco, USA

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
URL http://www.bbsrc.ac.uk/news/food-security/2010/101109-f-new-disease-pigs.aspx
 
Description Seminar Series MRI, Cambridge, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Seminar Series 2010 MRI, 12 May 2010, Cambridge
"Developmental programming and ageing"

NA
Year(s) Of Engagement Activity 2010
 
Description Summer School, University of Angers. What is fetal programming? Angers, France 29th June 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact University of Angers summer school. What is fetal programming? Angers, France 26th June - 7th July 2017
Year(s) Of Engagement Activity 2017
 
Description Tea Talk Series, Dept of Zoology, Cambridge, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Tea Talk Series, Dept of Zoology, 21 January 2010, Cambridge
"The developmental origins of type 2 diabetes and the metabolic syndrome"

NA
Year(s) Of Engagement Activity 2010
 
Description The influence of early diet on the ageing trajectory 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk given at the China/UK Joint Workshop on Healthy Ageing - Diet and nutrition across the life course, Beijing, China

no actual impacts realised to date
Year(s) Of Engagement Activity 2010