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The impact of early nutrition on the ageing trajectory

Published online by Cambridge University Press:  10 January 2014

Jane L. Tarry-Adkins*
University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Box 289 Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK
Susan E. Ozanne
University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Box 289 Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK
*Corresponding author: J. L. Tarry-Adkins, fax +(44) 1223 330598, email
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Epidemiological studies, including those in identical twins, and in individuals in utero during periods of famine have provided robust evidence of strong correlations between low birth-weight and subsequent risk of disease in later life, including type 2 diabetes (T2D), CVD, and metabolic syndrome. These and studies in animal models have suggested that the early environment, especially early nutrition, plays an important role in mediating these associations. The concept of early life programming is therefore widely accepted; however the molecular mechanisms by which early environmental insults can have long-term effects on a cell and consequently the metabolism of an organism in later life, are relatively unclear. So far, these mechanisms include permanent structural changes to the organ caused by suboptimal levels of an important factor during a critical developmental period, changes in gene expression caused by epigenetic modifications (including DNA methylation, histone modification and microRNA) and permanent changes in cellular ageing. Many of the conditions associated with early-life nutrition are also those which have an age-associated aetiology. Recently, a common molecular mechanism in animal models of developmental programming and epidemiological studies has been development of oxidative stress and macromolecule damage, specifically DNA damage and telomere shortening. These are phenotypes common to accelerated cellular ageing. Thus, this review will encompass epidemiological and animal models of developmental programming with specific emphasis on cellular ageing and how these could lead to potential therapeutic interventions and strategies which could combat the burden of common age-associated disease, such as T2D and CVD.

Conference on ‘Nutrition and Healthy Ageing’
Copyright © The Authors 2014 


caloric restriction


electron transport chain


in utero growth restricted


reactive oxygen species


superoxide dismutases


single-strand break


type 2 diabetes


target of rapamycin

The global burden of ageing

Globally, the population is steadily ageing with individuals aged 60 years and older doubling since 1980 and this is forecast to reach 2 billion by 2050. This can be construed as an indicator of improved global health; however, an ageing population also brings increases in the prevalence of age-associated diseases. About 75 % of all deaths in the USA and other developed countries now result from age-related conditions such as cancer, diabetes, heart disease, stroke, neurodegeneration and dementia. Environmental factors during any stage of the life course can influence risk of these conditions. However, this review will focus on the importance of the environment during very early life on modulating risk of age-associated metabolic diseases, such as type 2 diabetes (T2D) and CVD.

Ageing and the thrifty phenotype hypothesis

Over 20 years ago, Hales and Barker proposed the thrifty phenotype hypothesis( Reference Hales and Barker 1 ) in which it was postulated that under conditions of suboptimal in utero nutrition, the fetus permanently alters its organ structure and adapts its metabolism to ensure immediate survival of the organism. This can occur through the ‘sparing’ of certain vital organs, especially the brain, at the expense of other organs, including the heart, pancreas, kidney and skeletal muscle (Fig. 1). This hypothesis was the result of striking epidemiological studies in which Barker and colleagues( Reference Barker, Winter and Osmond 2 ) and Hales et al. ( Reference Hales, Barker and Clark 3 ) determined the prevalence of CVD and T2D in 64-year-old men. It was found that those individuals who were born smaller and weighed significantly less at age 1 year, compared with those with a normal birth-weight, had the highest mortality rates from IHD( Reference Barker, Winter and Osmond 2 ), a higher incidence of T2D and abnormal glucose tolerance( Reference Hales, Barker and Clark 3 ). These findings have been robustly reproduced in many populations worldwide( Reference Phipps, Barker and Hales 4 , Reference Lithell, McKeigue and Berglund 5 ). Furthermore, studies in monozygotic twins discordant for T2D have strongly implicated the environment playing a pivotal role in mediating the associations between low birth-weight and subsequent development of disease in later life. These studies demonstrated that the diabetic twin had the lower birth-weight( Reference Pouslen, Vaag and Kyvik 6 Reference Bo, Cavelli-Perin and Scaglione 8 ). Birth-weight has also been shown to be non-genetically linked with insulin sensitivity and glucose intolerance in elderly subjects( Reference Monrad, Grunnet and Rasmussen 9 , Reference Grunnett, Vielworth and Vaag 10 ), perhaps suggesting that the ageing process may be exacerbating the effects of low birth-weight. Studies of individuals exposed to famine while in utero, have also demonstrated very powerful direct evidence for the importance of maternal nutrition in early development. Ravelli et al. demonstrated that exposure to the Dutch famine of 1944–1945 significantly increased the risk of obesity( Reference Ravelli, Stein and Susser 11 ) and reduced glucose tolerance in later life( Reference Ravelli, van der Mullen and Michels 12 ).

Fig. 1. (colour online) The thrifty phenotype hypothesis.

Accelerated postnatal growth

Although sparing of vital organs such as the brain, at the expense of other organs, is beneficial in continued conditions of poor postnatal nutrition, several epidemiological studies have shown that this is detrimental in postnatal conditions of adequate or overnutrition. A study of a cohort of South African children demonstrated that those who were born small, but who underwent rapid postnatal weight gain had the worst glucose tolerance at age 7 years( Reference Crowther, Cameron and Trusler 13 ). Moreover, Indian children with a low birth-weight, who underwent rapid postnatal catch-up growth, were insulin resistant and had increased cardiovascular risk factors at age 8 years( Reference Yajnik 14 ). In a Finnish cohort, males who were born small, but had higher than average body mass in childhood, had higher mortality from CHD, compared with low birth-weight men with average body masses( Reference Eriksson, Forsen and Tuomilehto 15 ). Moreover, early development of adiposity and insulin resistance was observed in children who were small for gestational age but rapidly gained weight postnatally( Reference Ibanez, Ong and Dunger 16 ).

Utilisation of animal models in developmental programming

These observations from studies in human subjects have been supported by numerous studies in animal models. These have been carried out in a range of species including non-human primates, sheep and rodents. These have all been important in providing proof of principle that the early environment can influence long-term health and have provided insight into underlying mechanisms. For obvious practical reasons, the majority of studies that have addressed the impact of the early environment on ageing parameters have been carried out in rodents. Conditions that have been associated with early nutrition are also those with an ageing-associated aetiology; therefore, this review will focus upon models of developmental programming and their associations with the ageing process.

Maternal low-protein restriction

The maternal low-protein rat model is one of the most extensively studied of all programming models and was established by Snoeck et al. ( Reference Snoeck, Remacle and Reusens 17 ). This involved the administration of a low (8 % protein) or a ‘normal’ (20 %) protein diet to pregnant rats. These diets had similar fat content and were made isoenergetic by the addition of carbohydrates to the low-protein diet. The low-protein fed rat offspring were in utero growth restricted (IUGR) with significantly reduced birth-weights compared with control-fed offspring; however the placental weights were similar between groups( Reference Snoeck, Remacle and Reusens 17 ). The IUGR rat offspring had severe perturbations in pancreatic islets, including reduced pancreatic islet cell size and proliferation, diminished β-cell mass, and decreased islet vascularisation, and increased islet apoptosis( Reference Dahri, Snoeck and Reusens-Billen 18 , Reference Petrik, Reusens and Arany 19 ). These alterations were programmed in utero as they were irreversible after the islets were removed from the disturbed metabolic environment( Reference Dahri, Snoeck and Reusens-Billen 18 , Reference Cherif, Reusens and Dahri 20 ). Strong justification for the use of this model to accurately dissect the mechanistic changes in human studies has been demonstrated. Offspring of protein-restricted rat dams had alterations in key insulin signalling molecules in skeletal muscle and adipose tissue, which were strikingly similar in specificity and magnitude to those observed in skeletal muscle and adipose tissue from low birth-weight men( Reference Ozanne, Jensen and Tingey 21 , Reference Ozanne, Olsen and Hansen 22 ). Male rat offspring exposed to the low-protein diet in utero demonstrate an age-dependent loss of glucose tolerance from insulin-sensitive and glucose-tolerant phenotype in early life( Reference Petry, Ozanne and Wang 23 ), through insulin resistance during middle age( Reference Shepherd, Crowther and Desai 24 ) and to the development of frank diabetes in old age( Reference Petry, Dorling and Pawlak 25 ). This age-associated loss of insulin sensitivity and glucose tolerance is also observed in human populations( Reference Chen, Bergman and Pacini 26 ). Therefore, it is certainly feasible that accelerated cellular ageing may be a potential underlying mechanism of developmental programming. Maternal protein restriction has also been demonstrated to lead hypertension and age-associated deterioration of renal function in offspring( Reference Nwagwu, Cook and Langley-Evans 27 ). This was associated with reduced renal mitochondrial respiration rate( Reference Engeham, Mdaki and Jewell 28 ) and impairment of recovery of rat hearts subjected to ischaemia/reperfusion injury( Reference Elmes, Gardner and Langley-Evans 29 ).

Cellular senescence and developmental programming

In 1961, Hayflick first demonstrated that all somatic cells have a finite division potential (between 40 and 60 population doublings in normal human fetal cells) before they cease division and enter a cell senescent phase( Reference Hayflick and Moorhead 30 ). A potential explanation for this replicative senescent phenotype of somatic cells may be derived from ‘the free radical theory of ageing’ hypothesis; established by Harman in 1956( Reference Harman 31 ), which suggested that free radicals accumulate during the ageing process and cause damage to cellular macromolecules including DNA, proteins and lipids, mediating the development of various pathologies, which could result in cellular senescence and organismal ageing. This has been supported by several studies( Reference Stadtman 32 , Reference Sohal, Agarwal and Dubey 33 ). However, it is known that free radicals such as superoxide (O2 ) and reactive nitrogen species (ROS) including nitric oxide are formed in physiological as well as pathological processes (reviewed in ( Reference Bergendi, Benes and Durackova 34 , Reference Valko, Rhodes and Moncol 35 )); therefore it is only when excess O2 is produced, that damage to DNA, proteins and lipids through oxidation occurs (reviewed in( Reference Valko, Leibfritz and Moncol 36 )). Excess O2 can also combine with excess nitric oxide and form peroxynitrite, which can damage proteins through nitrotyrosination and increase DNA single-strand break (SSB) damage( Reference Salgo, Bermudez and Squadrito 37 ) and damage lipids via peroxidation. Therefore, unsurprisingly, oxidative and nitrosative stress have been implicated in various pathological diseases, all of which have an age-related aetiology, including CVD( Reference Kukreja and Hess 38 , Reference Csiszar, Pacher and Kaley 39 ), cancer( Reference Valko, Izakovic and Mazur 40 ), neurological disorders( Reference Jenner 41 , Reference Sayre, Smith and Perry 42 ) and diabetes( Reference Rosca, Mustata and Kinter 43 ). Consequently, organisms have evolved to develop cellular defence mechanisms in order to maintain redox homoeostasis; so that levels are sufficient for physiological, beneficial cell functions, but can prevent high pathophysiological levels, which are associated with age-associated pathology.

Antioxidant defence is a major mechanism by which cells can regulate redox homoeostasis. Cellular antioxidants can be either enzymatic or non-enzymatic. Enzymatic antioxidants include superoxide dismutases (SOD), which are the first line of cellular defence against excessive O2 and are responsible for the catalysis of the surfeit O2 into H2O2 and O2. There are three major isoforms of SOD known to exist in eukaryotic cells and are named according to their cell localisations. Copper–zinc SOD (SOD1) is localised to the cytoplasm, manganese SOD (SOD2) is expressed within mitochondria, and extracellular SOD (SOD3) is found within the extracellular matrix. Although H2O2 is less volatile than O2, it has the potential to react with transition metals (such as Fe2+ or Cu+) to generate the highly destructive hydroxyl radical (OH)( Reference Leonard, Harris and Shi 44 , Reference Valko, Morris and Cronin 45 ). Therefore, a further group of antioxidant enzymes, the peroxidases, including peroxiredoxins, catalase, glutathione peroxidases and glutathione reductase convert H2O2 into H2O and O2. Non-enzymatic endogenous antioxidants include ascorbate (vitamin C) and ubiquinol (coenzyme Q).

Studies utilising the maternal low-protein restriction of Snoeck et al. ( Reference Snoeck, Remacle and Reusens 17 ) have demonstrated that pancreatic islets from older rat offspring (age 15 months) had an accelerated cellular ageing phenotype, with evidence of decreased antioxidant defence capacity, increased fibrosis and oxidative stress, compared with age-matched control counterparts( Reference Tarry-Adkins, Chen and Jones 46 ). Moreover, a maternal protein restriction model in goats (40 % protein restriction) resulted in reductions of SOD in the offspring( Reference He, Sun and Tan 47 ).

Mechanisms of ageing and developmental programming

Telomeres are repeating guanine-rich nucleotide DNA sequences, which prevent chromosomal ends from being recognised as double-strand DNA breaks and prevent chromosomal deterioration or fusion with neighbouring chromosomes( Reference Blackburn 48 ). They are also particularly susceptible to oxidative damage due to their guanine–cytosine-rich sequences( Reference Oikawa and Kawanishi 49 , Reference Kawanishi and Oikawa 50 ). Telomeres shorten in eukaryotic somatic cells after each cellular division (between 20 and 200 base-pairs per division in human cells), due to the ‘end replication problem’( Reference Olivnikov 51 ) and this erosion is an integral part of the ageing process( Reference Armanios 52 , Reference Greider and Blackburn 53 ). Oxidative stress mediated damage to telomeric DNA is another major mechanism for telomere attrition( Reference Richter and von Zglinicki 54 , Reference von Zglinicki 55 ) and may contribute to the development of replicative senescence, as well as mediating oxidative damage induced by cellular senescence. DNA SSB damage has been reported to be a major mechanism of telomere shortening( Reference von Zglinicki, Pilger and Sitte 56 ) and oxidative stress can increase frequency of this damage( Reference Honda, Hjelmeland and Handa 57 ). Interestingly, telomeric DNA is deficient in the ability to repair DNA SSB, in contrast to the majority of genomic DNA( Reference Petersen, Saretzki and von Zglinicki 58 ). When telomeres reach a critically short length, they become dysfunctional and undergo a conformational change, resembling double-stranded breaks, which causes cells to enter irreversible G0/G1 growth arrest (senescence) or apoptosis( Reference Harley, Fuchter and Greider 59 ). This senescence is triggered by activation of the p53/p21/p19 and p16INK/retinoblastoma pathways( Reference Stein, Drullinger and Soulard 60 ).

Differences in the telomere length have been implicated in developmental programming. When low-protein-fed offspring were suckled by mothers fed a 20 % ‘normal’ protein diet, these ‘recuperated’ animals underwent rapid postnatal growth, had reduced longevity( Reference Jennings, Ozanne and Hales 61 ) and demonstrated accelerated telomere shortening in aorta( Reference Tarry-Adkins, Martin-Gronert and Chen 62 ), pancreatic islets( Reference Tarry-Adkins, Chen and Smith 63 ) and renal( Reference Jennings, Ozanne and Hales 61 ) tissues. This was accompanied by a reduction in SOD2 and increased p21 and p16INK in the pancreatic islets( Reference Tarry-Adkins, Chen and Smith 63 ). Moreover, evidence of accelerated cellular ageing is present in cardiac tissue from recuperated rats from weaning (age 22 d). This included evidence of increased oxidative stress, alterations in antioxidant defence capacity, increased DNA SSB damage, and increased DNA damage repair enzymes( Reference Tarry-Adkins, Martin-Gronert and Fernandez-Twinn 64 ). Increased frequency of DNA SSB damage was also observed in renal tissue from age 12-month recuperated animals compared with controls, which was associated with mitochondrial dysfunction( Reference Shelley, Tarry-Adkins and Martin-Gronert 65 ).

Ozanne and Hales have also demonstrated that offspring of control (20 %) protein-fed dams that were suckled by low (8 %) protein-fed dams, until weaning, had increased longevity in both rats( Reference Jennings, Ozanne and Hales 61 ) and mice( Reference Ozanne and Hales 66 ), compared with animals fed a control (20 %) protein diet during both gestation and lactation. These mice were also protected against longevity reduction when fed an obesogenic diet after weaning( Reference Ozanne and Hales 66 ). These data may suggest that the mild stress of reduced protein intake during the suckling postnatal period is eliciting a protective effect of lifespan extension, which is in keeping with a recent ageing theory; ‘the hormesis hypothesis of ageing’, first highlighted by Minius in 2000( Reference Minois 67 ). This suggests that the exposure of an organism to a mild stress (which in larger doses would be detrimental) can improve the functional ability of organisms. Much support for this theory has been gained from studies conducted in a variety of animal models including yeast, flies, worms and rodents, which have demonstrated that a mild stress, such as caloric restriction (CR) can increase longevity (reviewed in( Reference Le Bourg 68 )). Indeed, CR is the most potent and reproducible environmental variable capable of extending lifespan.

Uterine placental ligation

Uterine placental ligation( Reference Simmons, Gounis and Bangalore 69 , Reference Ogata, Bussey and Finley 70 ) is an elegant model of placental insufficiency which results in an IUGR phenotype. This model does not completely restrict blood supply to the fetus, but reduces it adequately to reflect human uteroplacental insufficiency, which can be caused by preeclampsia, maternal smoking and abnormalities in placental development. These neonatal IUGR rats demonstrated reduced glucose, insulin, insulin-like growth factor 1, amino acid and oxygen concentrations( Reference Simmons, Gounis and Bangalore 69 Reference Unterman, Lascon and Gotway 71 ). These IUGR animals later developed age-associated diabetes( Reference Simmons, Templeton and Gertz 72 ). Other studies demonstrated that bilateral uterine vessel ligation resulted in IUGR rat offspring with increased arterial vascular stiffness and selective endothelial uterine artery dysfunction( Reference Maccuza, Wlodek and Dragomir 73 ) and caused nephron deficits and modest renal insufficiency( Reference Moritz, Maccuza and Siebel 74 ).

Placental insufficiency in both animal models of uterine placental ligation( Reference Heltemes, Gingery and Soldner 75 ) and in human studies( Reference Karowicz-Bilinska, Suzin and Sieroszewski 76 Reference Wang and Walsh 79 ) is strongly associated with the development of oxidative stress, and it is thought that the mitochondria plays an important role in mediating this effect. Mitochondria are a major source of ROS generation in cells and are generated from the mitochondrial electron transport chain (ETC). This couples electron transfer from an electron donor (such as NADH) to an electron acceptor (O2), with consequential transfer of protons across the membrane and production of an electrochemical proton gradient, which can drive synthesis of ATP. However, during this process, electrons can leak out of the complexes of the ETC and can combine with O2 to form the free radical O2 . In 1980, Miquel proposed the ‘mitochondrial theory of free radicals in ageing’, in which he suggested that mitochondrially generated ROS can cause accumulation of somatic mutations to the mitochondrial genome and result in cellular senescence and apoptosis in post-mitotic cells( Reference Miquel, Economos and Fleming 80 ). This establishes a ‘vicious circle’ of mitochondrial DNA damage, altered oxidative phosphorylation and overproduction of ROS. Others have supported this theory, whereby mitochondria isolated from old animals produced more ROS compared with their younger counterparts( Reference Sohal and Sohal 81 ). Furthermore, accumulation of mitochondrial DNA damage( Reference Wei and Lee 82 , Reference Pang, Ma and Wei 83 ) and reduction of mitochondrial respiratory chain function in human tissue( Reference Yen, Chen and King 84 , Reference Trounce, Byrne and Marzuki 85 ) and that from rats and dogs( Reference Sugiyama, Takasawa and Hayakawa 86 ) have been demonstrated with increased age.

Simmons and colleagues have demonstrated an impairment of oxidative phosphorylation in both skeletal muscle( Reference Selak, Storey and Peterside 87 ) and liver mitochondria( Reference Peterside, Selak and Simmons 88 ) of IUGR rats, as well as a progressive accumulation of ROS generation and mitochondrial DNA mutations, and a progressive decline in activities of complex I and III of the ETC in the pancreatic islets of IUGR rats( Reference Simmons, Suponitsky-Kroyter and Selak 89 ). This may be associated with the low oxygen levels observed in IUGR fetuses, as it has been shown that hypoxia decreases the activity of ETC complexes and increases ROS production( Reference Esposti and McLennan 90 , Reference Chandel, Budinger and Schumaker 91 ). Taken together this may suggest that insulin-sensitive tissues of IUGR rats exhibit mitochondrial dysfunction, which may lead to accelerated cellular ageing of these tissues. Several studies have also utilised ovine models of placental insufficiency to induce IUGR in offspring. This model bears striking similarities to the human situation, with decreased fetal and placental weights, reduced fetal oxygen concentrations, decreased placental oxygen transfer rates, decreased fetal glucose and insulin concentrations, decreased glucose-stimulated insulin secretion and diminished β-cell mass (reviewed in( Reference Barry, Rozance and Anthony 92 )).

Maternal hypoxia

Maternal hypoxia has been studied in a number of human populations. It has been demonstrated that babies born to mothers living at high altitude are also significantly smaller than those born at normal altitude, and that this IUGR was associated with fetal hypoglycaemia and hypoinsulinaemia( Reference Zamudo, Torricos and Fik 93 , Reference Kingdom and Kaufman 94 ). Placental insufficiency is thought to contribute to this, through impaired placental invasion of maternal blood vessels or through poor placental vascular development( Reference Zamudo, Torricos and Fik 93 , Reference Kingdom and Kaufman 94 ). Animal models of maternal hypoxia recapitulate these findings, demonstrating that IUGR can result from maternal hypoxia( Reference De Grauw, Myers and Scott 95 , Reference Jacobs, Robinson and Owens 96 ). Giussani et al. initially, using a chick embryo model( Reference Giussani, Salinas and Villena 97 ) and subsequently a rat model( Reference Herrera, Camm and Cross 98 ) demonstrated that this IUGR was due to the hypoxia per se, and not maternal malnutrition, as severe hypoxia can result in reduced maternal food intake. Maternal hypoxia has also been shown to programme cardiac dysfunction in these rat and chick embryo models( Reference Giussani, Camm and Nui 99 , Reference Rouwet, Tintu and Schellings 100 ), including promotion of fetal cardiac overload, leading to ventricular and aortic wall thickening( Reference Camm, Hansell and Kane 101 ) and endothelial dysfunction( Reference Morton, Rueda-Clausen and Davidge 102 ). As observed in the model of protein restriction and placental insufficiency, evidence of oxidative stress has been demonstrated in this model. This has been reported in the placenta (increased levels of 4-hydroxynonenal and heat-shock protein 70)( Reference Richter, Camm and Modi 103 ), and in the heart (increased nitrotyrosine staining and heat-shock protein 70)( Reference Morton, Rueda-Clausen and Davidge 102 ) of rats and in sheep( Reference Thakor, Richer and Kane 104 ). Furthermore, the administration of the antioxidants allopurinol( Reference Thakor, Richer and Kane 104 ) and vitamin C( Reference Herrara, Kane and Hansell 105 ) reversed these phenotypes in sheep. Therefore, it is plausible that hypoxia accelerates ageing in the placenta and cardiovascular systems, potentially leading to eventual cellular senescence, apoptosis and organ dysfunction.

Maternal stress

Severe maternal stress can induce IUGR in offspring, through various pathways including transplacental transport of the stress hormone glucocorticoid, via activation of the hypothalamic–pituitary–adrenal axis. It has also been shown that babies with a low birth-weight have higher plasma cortisol levels throughout life, which also indicates hypothalamic–pituitary–adrenal-axis programming. Indeed, severe maternal stress can deleteriously affect placental physiology, including alterations in blood flow and changes in metabolism, which impact upon oxygen and glucose availability. This has been demonstrated in both human studies( Reference French, Hagan and Evans 106 Reference Reinisch, Simon and Karow 108 ), and animal models, including rats( Reference Nyirenda, Lindsay and Kenyon 109 ) and sheep( Reference Sloboda, Newnham and Challis 110 ), where these IUGR offspring demonstrated abnormal glucose tolerance( Reference Nyirenda, Lindsay and Kenyon 109 , Reference Sloboda, Newnham and Challis 110 ). Prenatal exposure to rats with glucocorticoids has also been shown to elevate plasma glucose, insulin and hepatic phosphoenolpyruvate carboxykinase in the next generation( Reference Drake, Walker and Seckl 111 ). Inhibition of 11β-hydroxysteroid (the fetoplacental barrier to maternal glucocorticoids) can also reduce birth-weight, increase the hypothalamic–pituitary–adrenal-axis activity and anxiety-related behaviours, and cause hyperglycaemia, hyperinsulinaemia and hypertension in the offspring (reviewed in( Reference Seckl and Holmes 112 )).

The mechanistic basis linking maternal stress to offspring metabolism is not clear; however oxidative stress is likely to be a major contributory factor. Entringer et al. demonstrated that severe stress in pregnant women was associated with shorter leucocyte telomere length in their children during young adulthood( Reference Entringer, Epel and Kumsta 113 ). Moreover, a recent study in chick embryos demonstrated that in utero exposure to glucocorticoids resulted in higher levels of ROS and increased leucocyte telomere shortening( Reference Haussmann, Longenecker and Marchetto 114 ). In addition, prenatal exposure to high levels of glucocorticoids in rats increased susceptibility of cerebellar granule cells to oxidative stress-induced cell death, increased mitochondrial dysfunction and reduced catalase expression( Reference Ahlbom, Goqvadze and Chen 115 ). These data suggest that severe maternal stress can accelerate cellular ageing. It is common clinical practice for pregnant women at risk of preterm labour to be prescribed with repeat courses of glucocorticoids to aid lung maturation of the premature baby, and indeed studies in sheep treated with glucocorticoids have reported reductions in oxidative stress in the lungs of pre-term lambs( Reference Walther, Jobe and Ikegami 116 , Reference Dani, Corsini and Burchielli 117 ).

Maternal caloric/nutrient restriction

Several models of maternal CR have been used in a variety of formats, ranging from models of moderate to severe restriction. Rat dams exposed to 50 % maternal CR from day 15 of pregnancy until weaning gave birth to offspring that were growth restricted, with a 50 % reduction in body and organ weights at weaning. These offspring also had a 70 % reduction in β-cell mass at age 21 d and decreased insulin content in adulthood( Reference Garofano, Czernichow and Breant 118 ). In this model, as in the model of maternal protein restriction, ageing plays a pivotal role in the development of glucose intolerance( Reference Garofano, Czernichow and Breant 119 ). Franco et al. also utilised a 50 % maternal CR model and demonstrated that both male and female offspring were hypertensive and had endothelial dysfunction( Reference Franco Mdo, Arruda and Fortes 120 ). They also demonstrated that enhanced oxidative stress was a potential mechanism for these observations( Reference Franco Mdo, Dantas and Akamine 121 ). Maternal dietary restriction, using a diet representative of that of Brazil, caused placental oxidative stress in rat dams, which later led to changes in kidney proximal tubule sodium ATPases in the offspring( Reference Vieira-Filho, Lara and Silva 122 ). In another rat model, 50 % maternal CR resulted in offspring that were growth restricted, however when suckled by ad libitum fed rat dams, these offspring underwent rapid postnatal growth, becoming heavier than the control offspring( Reference Desia, Gayle and Babu 123 ). A non-human primate model of maternal nutrient restriction (70 % of control food consumption) resulted in alterations in the renal transcriptome and kidney morphology of the offspring of nutrient restricted primates( Reference Cox, Nijland and Gilbert 124 ). Furthermore, the mammalian target of rapamycin (TOR) signalling pathway was found to be central to this phenotype( Reference Nijland, Schlabritz-Loutsevitch and Hubbard 125 ). Mammalian TOR is a serine/threonine kinase that regulates cell growth, cell proliferation and cell survival and it has recently been suggested that ageing can result from overactivation of TOR or mammalian TOR signalling pathways.

Maternal obesity and gestational diabetes

The deleterious effects of low birth-weight on long-term metabolic health are well established; however, it has become apparent that high birth-weight is also a clear indicator of increased risk of disease in later life. This relationship was initially found in epidemiological studies of Pima Indians( Reference Pettitt, Moll and Knowler 126 ) in which there is a very high prevalence of both T2D and maternal obesity, demonstrating that risk of developing T2D in later life is increased by both low and high birth-weight. This suggests that a U-shaped curve exists between birth-weight and risk of T2D development. A possible mechanism for the elevated risk of T2D in a high birth-weight population is the increased prevalence of gestational diabetes. Glucose can cross the placental barrier but maternal insulin cannot; therefore the fetus must regulate its own glucose homoeostasis by insulin production from fetal β-cells of pancreatic islets. In situations of maternal hyperglycaemia (which occurs in gestational diabetes), higher levels of fetal insulin are produced. Insulin is a potent growth factor in fetal life; therefore this results in gestational diabetic mothers giving birth to macrosomic offspring. Boney et al. demonstrated that macrosomic offspring of mothers with gestational diabetes were at increased risk of developing metabolic syndrome in childhood( Reference Boney, Verma and Tucker 127 ). Human studies have further characterised phenotypes of offspring born to gestationally diabetic mothers. These individuals were more obese and were hyperglycaemic compared with offspring of women who developed diabetes after pregnancy. They also had an increased propensity to develop diabetes in adulthood( Reference Boerschmann, Pfluger and Henneberger 128 ). More recently, studies of children exposed to maternal obesity and gestational diabetes in utero have shown higher incidence of insulin resistance( Reference Zielinsky and Piccoli 129 ), heart hypertrophy( Reference Zielinsky and Piccoli 129 ) and CVD in later life( Reference Krishnaveni, Venna and Hill 130 , Reference Lee, Jang and Park 131 ).

The detrimental effects of overnutrition during fetal and early postnatal life have also been observed in animal models. Offspring of mice fed a highly palatable obesogenic diet before mating and during pregnancy and lactation were hyperphagic in early postnatal life, had increased adiposity, were hypertensive and insulin resistant, and were heavier in later life( Reference Samuelsson, Matthews and Argenton 132 , Reference Nivoit, Morens and Van Assche 133 ). In addition, evidence of mitochondrial dysfunction was observed in this model, with reductions in complex II–III linked activity of the ETC in skeletal muscle of male offspring exposed to maternal obesity( Reference Shelley, Martin-Gronert and Rowlerson 134 ). Our laboratory has demonstrated that maternal obesity in the mouse programmes cardiac hypertrophy in the offspring which was associated with hyperinsulinaemia, protein kinase B, extracellular signal-related kinase and mammalian TOR activation, which was independent of obesity in the offspring. These animals demonstrated evidence of increased oxidative stress with elevation in 4-hydroxynonenal levels and reduction in SOD2 protein expression( Reference Fernandez-Twinn, Blackmore and Siggens 135 ). It has also been shown that maternal obesity prior to conception is associated with altered mitochondria in mouse oocytes and zygotes, including increases in mitochondrial potential, mitochondrial DNA content and biogenesis; moreover ROS generation was also increased, again suggestive of increased oxidative stress and an increased ageing phenotype( Reference Igosheva, Abramov and Poston 136 ). In addition, rat offspring fed a ‘junk food’ diet during pregnancy and lactation have a greater preference for ‘junk food’ and increased obesity in adulthood( Reference Bayol, Farrington and Stickland 137 ). This adiposity was more pronounced in females( Reference Bayol, Simbi and Bertrand 138 ) and this diet has recently been shown to promote non-alcoholic fatty liver disease in the offspring( Reference Bayol, Simbi and Fowkes 139 ).

Maternal iron restriction

Iron deficiency is very common with 2 billion people affected globally and causes many abnormalities including long-term cognitive impairment (reviewed in ( Reference Beard 140 )). Epidemiological studies have shown that maternal iron deficiency is associated with increased incidence of IUGR( Reference Singla, Tyagi and Kumar 141 , Reference Lee, Kim and Kim 142 ). Large placental weights and a high ratio of placental weight to birth-weight are observed( Reference Godfrey, Redman and Barker 143 ). A potential mechanism for these altered whole body and organ growth trajectories may be the alterations of placental cytokine expression, which was observed in rat offspring born to iron-restricted mothers( Reference Gambling, Charinia and Hannah 144 ). Other laboratories have shown that maternal iron restriction causes long-term problems for the offspring, including hypertension( Reference Lewis, Forhead and Petry 145 , Reference Gambling, Dunford and Wallace 146 ), changes in renal morphology( Reference Lisle, Lewis and Petry 147 ) and changes in placental vascularisation( Reference Lewis, Doherty and James 148 ). So far, models of maternal iron restriction have not addressed the potential role of oxidative stress.

Developmental programming, epigenetics and oxidative stress

Epigenetics can be defined as any change in phenotype or gene expression caused by modifications (including DNA methylation or histone methylation, acetylation, phosphorylation and ubiquination), which is independent of changes in genotype. It is known that environmental cues can be ‘remembered’ during the lifespan and changes to the epigenetic landscape are associated with the ageing process. It is now emerging that epigenetic modification of transcription factors is a common underlying mechanism in many models of developmental programming. This includes epigenetic silencing of the pancreatic development gene Pdx1 in offspring of mothers with placental insufficiency( Reference Park, Stoffers and Nicholls 149 ). Moreover, rat offspring of a maternal low-protein diet have demonstrated epigenetic alterations in the PPAR-α( Reference Lillycrop, Phillips and Jackson 150 ). In addition, we have also demonstrated that in utero exposure to a low-protein diet can alter the dynamics of age-associated epigenetic changes at the hepatocyte nuclear factor 4-α locus( Reference Sandovici, Smith and Dekker-Nitert 151 ). Oxidative stress can induce epigenetic modifications, including DNA methylation and histone modification. DNA breaks caused by oxidant damage can provide access sites to DNA methyltransferases, which promote DNA methylation; moreover ROS can directly interact with histones resulting in disruption of normal gene expression. During oxidative stress, guanine residues are replaced with the oxygen radical adduct 8-hydroxyguanine and this can profoundly alter methylation status of adjacent cytosines and cause alteration of gene expression( Reference Cerda and Weitzman 152 ). Therefore, it is feasible that a molecular mechanism for the observed changes in epigenetic modification in several models of developmental programming may well be the development of oxidative stress.

The potential of antioxidant therapy in models of developmental programming

A common mechanism for the observed phenotypic outcomes in most of these animal models of developmental programming is oxidative stress and this finding fully recapitulates epidemiological studies in which IUGR children demonstrate increased lipid peroxidation( Reference Franco Mdo, Dantas and Akamine 153 Reference Hracsko, Orvos and Norvak 155 ), increased DNA damage( Reference Hracsko, Orvos and Norvak 155 ) and reduced antioxidant enzyme capacity( Reference Hracsko, Orvos and Norvak 155 ) compared with children of a normal birth-weight. Therefore, several animal models of developmental programming have focused upon using antioxidants as a therapeutic intervention in order to reverse the observed phenotypic changes. These included the reduction of adiposity and improvement of glucose tolerance resulting from the exposure to a high-fat diet, by maternal supplementation with high concentrations of vitamins A, C, E and selenium( Reference Sen and Simmons 156 ). Moreover, cardiac dysfunction in both rat( Reference Camm, Hansell and Kane 101 ) and sheep( Reference Thakor, Richer and Kane 104 ) models of acute hypoxia has been demonstrated to be improved by maternal supplementation with vitamin C. In addition, prevention of hypoxia-induced placental oxidative stress with vitamin C has also been observed in rats( Reference Richter, Camm and Modi 103 ). In a model of maternal protein restriction, hypertension, vascular dysfunction and microvascular rarefaction were prevented by antenatal treatment with the antioxidant Lazaroid( Reference Cambonie, Comte and Yzdorczyk 157 ) however, the physiological relevance of this antioxidant dose for translation into human studies is not known. Prenatal exposure to hypoxia in sheep also increased oxidative stress in the offspring, and maternal administration of an antioxidant; allopurinol reversed this phenotype( Reference Herrara, Kane and Hansell 105 , Reference Derks, Oudijk and Torrence 158 ). These studies show proof of principle that maternal antioxidants can prevent detrimental programming effects; however, the doses used to achieve these effects may not be able to be used safely in pregnant women. In addition, they focus on interventions to the mother.

Future perspectives

Many epidemiological studies and animal studies have demonstrated that growth and nutrition during early life development can influence the long-term physiology and health and as a result, the lifespan of the individual. However, the molecular mechanisms that underpin this phenomenon are only starting to be dissected. Studies in human populations, animal models and cell systems all seem to be pointing to the accumulation of oxidative stress and consequently accelerated cellular ageing, as an important underlying molecular mechanism (Fig. 2). Several developmental programming studies have demonstrated proof of principle that maternal antioxidant therapy may reverse some of deleterious effects of a suboptimal early life exposure. However, both animal( Reference Petry, Dorling and Pawlak 25 , Reference Nwagwu, Cook and Langley-Evans 27 ) and human studies( Reference Curhan, Willet and Rimm 159 , Reference Mi, Law and Zhang 160 ) demonstrate that evaluation of suboptimal in utero exposure may only be possible until later postnatal life and therefore further studies are required to address the potential beneficial effects of targeted postnatal antioxidant supplementation. This targeted intervention has the potential to combat the burden of common age-related diseases such as T2D, CVD and the metabolic syndrome that represent the major health-care issues of the 21st century.

Fig. 2. (colour online) Oxidative stress (Ox stress) as an underlying mechanism of developmental programming and ageing.


The authors would like to thank James Adkins for IT support in the preparation and submission of this manuscript.

Financial support

This work was supported by The British Heart Foundation. S. E. O is a British Heart Foundation Senior Fellow and a member of the MRC Metabolic Diseases Unit.

Conflicts of interest



Both authors contributed equally to the writing of this manuscript.


1. Hales, CN & Barker, DJ (2001) The thrifty phenotype hypothesis. Br Med Bull 60, 520.CrossRefGoogle ScholarPubMed
2. Barker, DJ, Winter, PD, Osmond, C et al. (1989) Weight in infancy and death from ischaemic heart disease. Lancet 2, 577580.CrossRefGoogle ScholarPubMed
3. Hales, CN, Barker, DJ, Clark, PMS et al. (1991) Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303, 10191022.CrossRefGoogle ScholarPubMed
4. Phipps, K, Barker, DJ, Hales, CN et al. (1993) Fetal growth and impaired glucose tolerance in men and women. Diabetologia 36, 973974.CrossRefGoogle ScholarPubMed
5. Lithell, HO, McKeigue, PM, Berglund, L et al. (1996) Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50–60 years. BMJ 312, 406410.CrossRefGoogle ScholarPubMed
6. Pouslen, P, Vaag, AA, Kyvik, KK et al. (1997) Low birth weight is associated with NIDDM in discordant monozygotic and dizygotic twin pairs. Diabetolgia 40, 439446.Google Scholar
7. Pouslen, P, Kyvik, KO, Vaag, A et al. (1999) Heritability of type 2 (non-insulin dependent) diabetes mellitus and abnormal glucose tolerance – a population twin study. Diabetolgia 42, 139145.Google Scholar
8. Bo, S, Cavelli-Perin, P, Scaglione, L et al. (2000) Low birthweight and metabolic abnormalities in twins with increased susceptibility of Type 2 diabetes mellitus. Diabet Med 5, 365370.CrossRefGoogle Scholar
9. Monrad, RN, Grunnet, LG, Rasmussen, EL et al. (2009) Age-dependent nongenetic influences of birth weight and adult body fat on insulin sensitivity in twins. J Clin Endocrinol Metab 94, 23942399.CrossRefGoogle ScholarPubMed
10. Grunnett, L, Vielworth, S, Vaag, AA et al. (2007) Birth weight is non-genetically associated with glucose intolerance in elderly twins, independent of obesity. J Intern Med 262, 96103.CrossRefGoogle Scholar
11. Ravelli, GP, Stein, ZA & Susser, MW (1976) Obesity in young men after famine exposure in utero and early infancy. J Med 295, 349353.Google ScholarPubMed
12. Ravelli, AC, van der Mullen, JH, Michels, RP et al. (1998) Glucose intolerance in elderly twins, independent of adults after pre-natal exposure to famine. Lancet 351, 173177.CrossRefGoogle Scholar
13. Crowther, NJ, Cameron, N, Trusler, J et al. (1998) Association between poor glucose tolerance and rapid postnatal weight gain in seven year-old children. Diabetologia 41, 11631167.CrossRefGoogle Scholar
14. Yajnik, C (2000) Interactions of perturbations in intrauterine growth and growth during childhood on the risk of adult-onset disease. Proc Nat Soc 59, 257265.CrossRefGoogle ScholarPubMed
15. Eriksson, JG, Forsen, T, Tuomilehto, J et al. (1999) Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ 318, 427431.CrossRefGoogle ScholarPubMed
16. Ibanez, L, Ong, K, Dunger, DB et al. (2006) Early development of adiposity and insulin resistance after catch-up weight gain in small-for-gestational-age children. J Clin Endocrinol Metab 91, 21532158.CrossRefGoogle ScholarPubMed
17. Snoeck, A, Remacle, C, Reusens, B et al. (1990) Effects of low protein during pregnancy on the fetal pancreas. Biol Neonate 57, 107118.CrossRefGoogle Scholar
18. Dahri, S, Snoeck, A, Reusens-Billen, B et al. (1991) Islet function in offspring of mothers on low protein diet during gestation. Diabetes 40, 115120.CrossRefGoogle ScholarPubMed
19. Petrik, J, Reusens, B, Arany, E et al. (1999) A low protein diet alters the balance of islet cell replication and apoptosis in the fetal and neonatal rat and is associated with insulin-like growth factor-II. Endocrinology 140, 48614873.CrossRefGoogle ScholarPubMed
20. Cherif, H, Reusens, B, Dahri, S et al. (2001) A protein restricted diet during pregnancy alters in-vitro insulin secretion from islets of fetal Wistar rats. J Nutr 131, 15551559.CrossRefGoogle ScholarPubMed
21. Ozanne, SE, Jensen, CB, Tingey, KT et al. (2005) Low birth weight is associated with specific changes in muscle insulin signalling protein expression. Diabetologia 48, 547552.CrossRefGoogle ScholarPubMed
22. Ozanne, SE, Olsen, GE, Hansen, LL et al. (2003) Early growth restriction leads to down regulation of protein kinase C zeta and insulin resistance in skeletal muscle. J Endocrinol 177, 235242.CrossRefGoogle ScholarPubMed
23. Petry, CJ, Ozanne, SE, Wang, CL et al. (2000) Effects of early low protein restriction and adult obesity on rat pancreatic hormone content and glucose tolerance. Horm Metab Res 32, 233239.CrossRefGoogle Scholar
24. Shepherd, PR, Crowther, NJ, Desai, M et al. (1997) Altered adipocyte properties in the offspring of protein-restricted rats. Br J Nutr 78, 121129.CrossRefGoogle Scholar
25. Petry, CJ, Dorling, MW, Pawlak, DB et al. (2001) Diabetes in old male offspring of rat dams fed a reduced protein diet. Int J Exp Diabet Res 2, 139143.CrossRefGoogle ScholarPubMed
26. Chen, M, Bergman, RN, Pacini, G et al. (1985) Pathogenesis of age-related glucose tolerance in man: insulin resistance and decreased β-cell function. J Clin Endocrinol Metab 60, 1320.CrossRefGoogle ScholarPubMed
27. Nwagwu, MO, Cook, A & Langley-Evans, SC (2000) Evidence of progressive deterioration of renal function of renal function in rats exposed to maternal low-protein diet in utero. Br J Nutr 83, 7985.Google ScholarPubMed
28. Engeham, S, Mdaki, K, Jewell, K et al. (2012) Mitochondrial respiration is decreased in rat kidney following fetal exposure to a maternal low-protein diet. J Nutr Metab (Epublication ahead of print version).CrossRefGoogle Scholar
29. Elmes, MJ, Gardner, DS & Langley-Evans, SC (2007) Fetal exposure to a maternal low protein diet is associated with altered left ventricular pressure response to ischaemia-reperfusion injury. Br J Nutr 98, 93100.CrossRefGoogle ScholarPubMed
30. Hayflick, L & Moorhead, PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25, 585621.CrossRefGoogle ScholarPubMed
31. Harman, D (1956) Aging: a theory based on free-radical and radiation chemistry. J Gerontol 3, 298300.CrossRefGoogle Scholar
32. Stadtman, ER (1992) Protein oxidation and aging. Science 257, 12201224.CrossRefGoogle ScholarPubMed
33. Sohal, RS, Agarwal, S, Dubey, A et al. (1993) Protein oxidative damage is associated with life expectancy of houseflies. Proc Natl Acad Sci USA 90, 72557259.CrossRefGoogle ScholarPubMed
34. Bergendi, L, Benes, L, Durackova, Z et al. (1999) Chemistry, physiology and pathology of free radicals. Life Sci 65, 18651874.CrossRefGoogle ScholarPubMed
35. Valko, M, Rhodes, CJ, Moncol, J et al. (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160, 140.CrossRefGoogle ScholarPubMed
36. Valko, M, Leibfritz, D, Moncol, J et al. (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39, 4484.CrossRefGoogle ScholarPubMed
37. Salgo, MG, Bermudez, E, Squadrito, GL et al. (1995) Peroxynitrite causes DNA-damage and oxidation of thiols peroxynitrite causes in rat thymocytes (corrected) Arch . Biochem Biophys 322, 500505.CrossRefGoogle Scholar
38. Kukreja, RC & Hess, ML (1992) The oxygen free-radical system – From equations through membrane-protein interactions to cardiovascular injury and protection. Cardiovasc Res 26, 641655.CrossRefGoogle ScholarPubMed
39. Csiszar, A, Pacher, P, Kaley, G et al. (2005) Role of nitrosative and oxidative stress, longevity genes, and Poly(ADP-ribose) polymerase in cardiovascular dysfunction associated with aging. Curr Vasc Pharmacol 3, 285291.CrossRefGoogle ScholarPubMed
40. Valko, M, Izakovic, M, Mazur, M et al. (2004) Role of oxidative stress in DNA damage and cancer incidence. Mol Cell Biochem 266, 3756.CrossRefGoogle ScholarPubMed
41. Jenner, P (2003) Oxidative stress in Parkinson's disease. Ann Neurol 53, S26S36.CrossRefGoogle ScholarPubMed
42. Sayre, LM, Smith, MA & Perry, G (2001) Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Curr Med Chem 8, 721738.CrossRefGoogle ScholarPubMed
43. Rosca, MG, Mustata, TG, Kinter, MT et al. (2005) Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am J Renal Physiol 289, F420F430.CrossRefGoogle ScholarPubMed
44. Leonard, SS, Harris, GK & Shi, X (2004) Metal-induced oxidative stress and signal transduction. Free Radic Biol Med 37, 19211942.CrossRefGoogle ScholarPubMed
45. Valko, M, Morris, H & Cronin, MTD (2005) Metals, toxicity and oxidative stress. Curr Med Chem 12, 11611208.CrossRefGoogle ScholarPubMed
46. Tarry-Adkins, JL, Chen, JH, Jones, RH et al. (2009) Poor maternal nutrition leads to alterations in oxidative stress, antioxidant defense capacity, and markers of fibrosis in rat islets. FASEB J 24, 27622771.CrossRefGoogle Scholar
47. He, ZX, Sun, ZH, Tan, ZL et al. (2012) Effects of protein or energy restriction during late gestation on antioxidant status of plasma and immune tissues in postnatal goats. J Anim Sci 90, 43194326.CrossRefGoogle ScholarPubMed
48. Blackburn, EH (1991) Structure and function of telomeres. Nature 350, 569573.CrossRefGoogle Scholar
49. Oikawa, S & Kawanishi, S (1999) Site-specific DNA damage at GGG sequence by oxidative stress may accelerate telomere shortening. FEBS Lett 453, 365368.CrossRefGoogle ScholarPubMed
50. Kawanishi, S & Oikawa, S (2004) Mechanism of telomere shortening by oxidative stress. Ann NY Acad Sci 1019, 278284.CrossRefGoogle ScholarPubMed
51. Olivnikov, AM (1971) Principle of marginotomy in template synthesis of polynucleotides. Dokl Akad Nauk SSSR 201, 14691499.Google Scholar
52. Armanios, M (2013) Telomeres and age-related disease: how telomere biology informs clinical paradigms. J Clin Inv 123, 9961002.CrossRefGoogle ScholarPubMed
53. Greider, CW & Blackburn, EH (1996) Telomeres, telomerase and cancer. Sci Am 274, 9297.CrossRefGoogle ScholarPubMed
54. Richter, T & von Zglinicki, T (2007) A continuous correlation between oxidative stress and telomere length in fibroblasts. Exp Gerontol 11, 10391042.CrossRefGoogle Scholar
55. von Zglinicki, T (2002) Oxidative stress shortens telomeres. Trends Biochem Sci 7, 339344.CrossRefGoogle Scholar
56. von Zglinicki, T, Pilger, R & Sitte, N (2000) Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic Biol Med 28, 6474.CrossRefGoogle ScholarPubMed
57. Honda, S, Hjelmeland, LM & Handa, JT (2001) Oxidative stress-induced single-strand breaks in chromosomal telomeres of human retinal pigment epithelial cells in vitro . Invest Opthalmol Vis Sci 42, 21392144.Google ScholarPubMed
58. Petersen, S, Saretzki, G & von Zglinicki, T (1998) Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. Exp Cell Res 239, 152160.CrossRefGoogle ScholarPubMed
59. Harley, CB, Fuchter, AB & Greider, CW (1990) Telomeres shorten during ageing of fibroblasts. Nature 345, 448460.CrossRefGoogle ScholarPubMed
60. Stein, GH, Drullinger, LF, Soulard, A et al. (1999) Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol 19, 21092117.CrossRefGoogle ScholarPubMed
61. Jennings, BJ, Ozanne, SE & Hales, CN (1999) Early growth determines longevity in male rats and may be related to telomere shortening. FEBS Lett 488, 48.CrossRefGoogle Scholar
62. Tarry-Adkins, JL, Martin-Gronert, MS, Chen, JH et al. (2008) Maternal diet influences DNA damage, aortic telomere length oxidative stress and antioxidant defense capacity in rats. FASEB J 6, 20372044.CrossRefGoogle Scholar
63. Tarry-Adkins, JL, Chen, JH, Smith, NS et al. (2009) Poor maternal nutrition followed by accelerated postnatal growth leads to telomere shortening and increased markers of cell senescence in rat islets. FASEB J 5, 15211528.CrossRefGoogle Scholar
64. Tarry-Adkins, JL, Martin-Gronert, MS, Fernandez-Twinn, DS et al. (2013) Poor maternal nutrition followed by accelerated postnatal catch up growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress and oxidative defense capacity in rat heart. FASEB J 1, 379390.CrossRefGoogle Scholar
65. Shelley, P, Tarry-Adkins, J, Martin-Gronert, M et al. (2007) Rapid neonatal weight gain results in a ubiquinone (CoQ) deficiency associated with premature death. Mech Age Dev 128, 681687.CrossRefGoogle Scholar
66. Ozanne, SE & Hales, CN (2004) Lifespan: catch-up growth and obesity in male mice. Nature 427, 411412.CrossRefGoogle ScholarPubMed
67. Minois, N (2000) Longevity and aging: beneficial effects of exposure to mild stress. Biogerontology 1, 1529.CrossRefGoogle ScholarPubMed
68. Le Bourg, E (2009) Hormesis, aging and longevity. Biochim Biophys Acta 1790, 10301039.CrossRefGoogle ScholarPubMed
69. Simmons, RA, Gounis, AS, Bangalore, SA et al. (1992) Intrauterine growth retardation: fetal glucose transport is diminished in the lung but spared in the brain. Pediatr Res 31, 5963.CrossRefGoogle Scholar
70. Ogata, ES, Bussey, M & Finley, S (1986) Altered gas exchange, limited glucose, branched amino acids and hypoinsulinism retard fetal growth in the rat. Metabolism 35, 970977.CrossRefGoogle ScholarPubMed
71. Unterman, T, Lascon, R, Gotway, M et al. (1990) Circulating levels of insulin-like growth factor binding protein-1 (IGFBP-1) and hepatic mRNA are increased in the small for gestational age fetal rat. Endocrinology 127, 20352037.CrossRefGoogle Scholar
72. Simmons, RA, Templeton, LJ & Gertz, SJ (2001) Intrauterine growth retardation leads to the development of type 2 diabetes in the rat. Diabetes 10, 22792286.CrossRefGoogle Scholar
73. Maccuza, MQ, Wlodek, ME, Dragomir, NM et al. (2010) Uteroplacental insufficiency programs regional vascular dysfunction and alters arterial stiffness in female offspring. J Physiol 588, 19972010.Google Scholar
74. Moritz, KM, Maccuza, MQ, Siebel, AL et al. (2009) Uteroplacental insufficiency causes a nephron deficit, modest renal insufficiency but no hypertension in with ageing in female rats. J Physiol 587, 26352646.CrossRefGoogle ScholarPubMed
75. Heltemes, A, Gingery, A, Soldner, ELB et al. (2010) Chronic placental ischemia alters amniotic milieu and results in impaired glucose tolerance, insulin resistance and hyperleptinemia in young rats. Exp Biol Med (Maywood) 235, 892899.CrossRefGoogle ScholarPubMed
76. Karowicz-Bilinska, A, Suzin, J & Sieroszewski, P (2002) Evaluation of oxidative stress indices during treatment in pregnant women with intrauterine growth retardation. Med Sci Monit 8, CR211CR216.Google ScholarPubMed
77. Kato, H, Yoneyama, Y & Araki, T (1997) Fetal plasma lipid peroxidase levels in pregnancies complicated with preeclampsia. Gynecol Obstet Invest 43, 158161.CrossRefGoogle Scholar
78. Bowen, RS, Moodley, J, Dutton, MF et al. (2001) Oxidative stress in pre-eclampsia. Acta Obstet Gynecol Scand 80, 719725.CrossRefGoogle ScholarPubMed
79. Wang, Y & Walsh, SW (2001) Increased superoxide generation is associated with decreased superoxide dismutase activity and mRNA expression in placental trophoblast cells in pre-eclampsia. Placenta 22, 206212.CrossRefGoogle ScholarPubMed
80. Miquel, J, Economos, AC, Fleming, J et al. (1980) Mitochondrial role in cell aging. Exp Gerontol 15, 575591.CrossRefGoogle ScholarPubMed
81. Sohal, RS, Sohal, BH (1991) Hydrogen peroxide release by mitochondria increases during aging. Mech Ageing Dev 57, 187202.CrossRefGoogle ScholarPubMed
82. Wei, YH & Lee, HC (2002) Oxidative stress, mitochondrial DNA mutation and impairment of antioxidant enzymes in aging. Exp Biol Med 227, 671682.CrossRefGoogle Scholar
83. Pang, CY, Ma, YS & Wei, YH (2008) MtDNA mutations, functional decline and turnover of mitochondria in aging. Front Biosci 13, 36613675.CrossRefGoogle Scholar
84. Yen, TC, Chen, YS, King, KL et al. (1989) Liver mitochondrial respiratory function declines with age. Biochem Biophys Res Commun 165, 9441003.CrossRefGoogle Scholar
85. Trounce, I, Byrne, E & Marzuki, S (1989) Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in aging. Lancet i, 637639.CrossRefGoogle Scholar
86. Sugiyama, S, Takasawa, M, Hayakawa, M et al. (1993) Changes in skeletal muscle, heart and liver of rats and dogs of various ages Biochem Mol Biol Int 30, 937944.Google ScholarPubMed
87. Selak, M, Storey, BT, Peterside, IE et al. (2003) Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats. Am J Physiol Endocrinol Metab 285, E130E137.CrossRefGoogle ScholarPubMed
88. Peterside, IE, Selak, M & Simmons, RA (2003) Impaired oxidative phosphorylation in hepatic mitochondria in growth-retarded rats. Am J Physiol Endocrinol Metab 285, E1258E1266.CrossRefGoogle ScholarPubMed
89. Simmons, RA, Suponitsky-Kroyter, I & Selak, MA (2005) Progressive decline of mitochondrial DNA mutations and decline in mitochondrial function lead to β-cell failure. J Biol Chem 31, 2878528791.CrossRefGoogle Scholar
90. Esposti, MD & McLennan, H (1998) Mitochondria and cells produce reactive oxygen species in virtual anaerobiosis: relevance to ceramide induced apoptosis. FEBS Lett 430, 338342.CrossRefGoogle ScholarPubMed
91. Chandel, NS, Budinger, GRS & Schumaker, PT (1996) Molecular oxygen modulates cytochrome C oxidase function. J Biol Chem 271, 86728677.CrossRefGoogle ScholarPubMed
92. Barry, JS, Rozance, PJ & Anthony, RV (2008) An animal model of placental insufficiency-induced intrauterine growth restriction. Semin Perinatol 32, 225230.CrossRefGoogle ScholarPubMed
93. Zamudo, S, Torricos, T, Fik, E et al. (2010) Hypoglycemia and the origin of hypoxia-induced reduction of fetal growth. PLoS ONE 5, e8851.Google Scholar
94. Kingdom, JC & Kaufman, P (1997) Oxygen and placental villous development: origins of fetal hypoxia. Placenta 18, 613621.CrossRefGoogle ScholarPubMed
95. De Grauw, TJ, Myers, R & Scott, WJ (1986) Fetal growth in rats from different levels of hypoxia. Biol Neonate 49, 8589.CrossRefGoogle ScholarPubMed
96. Jacobs, R, Robinson, JS, Owens, JA et al. (1988) The effect of prolonged hypobaric hypoxia on growth of fetal sheep. J Dev Physiol 10, 97112.Google ScholarPubMed
97. Giussani, DA, Salinas, CE, Villena, M et al. (2007) The role of oxygen in prenatal growth: studies in the chick embryo. J Physiol 583, 911917.CrossRefGoogle Scholar
98. Herrera, EA, Camm, EJ, Cross, CM et al. (2011) Morphological and functional alterations in the aorta of the chronically hypoxic fetal rat. J Vasc Res 49, 5058.CrossRefGoogle ScholarPubMed
99. Giussani, DA, Camm, EJ, Nui, Y et al. (2012) Developmental programming of cardiovascular dysfunction by prenatal hypoxia and oxidative stress. PLoS ONE 7, e31017.CrossRefGoogle ScholarPubMed
100. Rouwet, EV, Tintu, AN, Schellings, MW et al. (2002) Hypoxia induces aortic hypertrophic growth, left ventricular dysfunction, and sympathetic hyperinnervation of peripheral arteries in the chick embryo. Circulation 105, 27912796.CrossRefGoogle ScholarPubMed
101. Camm, EJ, Hansell, JA, Kane, AD et al. (2010) Partial contributions of developmental hypoxia and undernutrition to prenatal alterations in somatic growth and cardiovascular structure and function. Am J Obstet Gynecol 5, e24e34.Google Scholar
102. Morton, JS, Rueda-Clausen, CF & Davidge, ST (2011) Flow-mediated vasodilation is impaired in adult rat offspring exposed to prenatal exposure. J Appl Physiol 4, 10731082.CrossRefGoogle Scholar
103. Richter, HG, Camm, EJ, Modi, BN et al. (2012) Ascorbate prevents placental oxidative stress and enhances birth weight in hypoxic pregnancy in rats. J Physiol 590, 13771387.CrossRefGoogle ScholarPubMed
104. Thakor, AS, Richer, HG, Kane, AD et al. (2010) Redox modulation of the fetal cardiovascular defence to hypoxia. J Physiol 588, 42354247.CrossRefGoogle Scholar
105. Herrara, EA, Kane, AD, Hansell, JA et al. (2012) A role for xanthine oxidase in the control of fetal cardiovascular function in late gestation sheep. J Physiol 15, 18251837.CrossRefGoogle Scholar
106. French, NP, Hagan, R, Evans, SF et al. (1999) Repeated antenatal glucocorticoids: size at birth and subsequent development. Am J Obest Gynecol 180, 114121.CrossRefGoogle Scholar
107. Newnham, JP & Moss, TJ (2001) Antenatal glucocorticoids and growth: single versus multiple doses in animal and human studies. Sem Neonatal 6, 285292.CrossRefGoogle ScholarPubMed
108. Reinisch, JM, Simon, NG, Karow, WG et al. (1978) Prenatal exposure to prednisone in humans and animals retards intra-uterine growth. Science 202, 436438.CrossRefGoogle Scholar
109. Nyirenda, MJ, Lindsay, RS, Kenyon, CJ et al. (1998) Glucocorticoid exposure in late gestation permanently programmes rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose tolerance in adult offspring. J Clin Invest 101, 21742181.CrossRefGoogle Scholar
110. Sloboda, DM, Newnham, JP & Challis, JRG (2002) Repeated maternal glucocorticoid administration and the developing liver in fetal sheep. J Endocrinol 175, 535543.CrossRefGoogle ScholarPubMed
111. Drake, AJ, Walker, BR & Seckl, JR (2005) Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats. Am J Physiol Regul Integr Comp Physiol 288, R34R38.CrossRefGoogle ScholarPubMed
112. Seckl, JR & Holmes, MC (2007) Mechanisms of disease: glucocorticoids, their placental metabolism and fetal ‘programming’ of adult pathophysiology. Nat Clin Pract Endocrinol Metab 3, 479488.CrossRefGoogle ScholarPubMed
113. Entringer, S, Epel, ES, Kumsta, R et al. (2011) Stress exposure in intrauterine life is associated with shorter telomere length in young adulthood. Proc Natl Acad Sci USA 108, E513E518.CrossRefGoogle ScholarPubMed
114. Haussmann, MF, Longenecker, AS, Marchetto, NM et al. (2012) Embryonic exposure of corticosterone modifies the juvenile stress response, oxidative stress response and telomere length. Proc Biol Sci 279, 14471456.CrossRefGoogle ScholarPubMed
115. Ahlbom, E, Goqvadze, V, Chen, M et al. (2000) Prenatal exposure to high levels of glucocorticoids increases the susceptibility of cerebellar granule cells to oxidative-stress induced cell death. Proc Natl Acad Sci USA 97, 1472614730.CrossRefGoogle ScholarPubMed
116. Walther, FJ, Jobe, AH & Ikegami, M (1998) Repetitive prenatal glucocorticoid exposure reduces oxidative stress in the lungs of pre-term lambs. J Appl Physiol 85, 273278.Google Scholar
117. Dani, C, Corsini, I, Burchielli, S et al. (2009) Natural surfactant combined with beclomethasone decreases oxidative lung-injury in the pre-term lamb. Pediatr Pulmonol 44, 11591167.CrossRefGoogle Scholar
118. Garofano, A, Czernichow, P & Breant, B (1998) Postnatal somatic growth and insulin contents in moderate or severe growth retardation in the rat. Biol Neonate 73, 8998.CrossRefGoogle ScholarPubMed
119. Garofano, A, Czernichow, P & Breant, B (1999) Effect of aging on beta-cell mass and function in rats malnourished during the perinatal period. Diabetologia 45, 711718.CrossRefGoogle Scholar
120. Franco Mdo, C, Arruda, RM, Fortes, ZB et al. (2002) Severe nutritional restriction in pregnant rats aggravates hypertension, altered vascular reactivity, and renal development in spontaneously hypertensive rats offspring. J Cardiovasc Pharmacol 39, 369377.CrossRefGoogle ScholarPubMed
121. Franco Mdo, C, Dantas, AP, Akamine, EH et al. (2002) Enhanced oxidative stress as a potential mechanism underlying the programming of hypertension in utero. J Cardiovasc Pharmacol 40, 501509.CrossRefGoogle ScholarPubMed
122. Vieira-Filho, LD, Lara, LS, Silva, PA et al. (2009) Placental oxidative stress in malnourished rats and changes in kidney proximal tubule sodium ATPases in offspring. Clin Exp Pharmacol Physiol 36, 1157–116.CrossRefGoogle ScholarPubMed
123. Desia, M, Gayle, D, Babu, J et al. (2005) Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. Am J Physiol Regul Interg Comp Physiol 288, R91R96.CrossRefGoogle Scholar
124. Cox, LA, Nijland, MJ, Gilbert, JS et al. (2006) Effect of 30 percent maternal nutrient restriction from 0·16 to 0·5 gestation on fetal baboon kidney gene expression. J Physiol 572, 6785.CrossRefGoogle Scholar
125. Nijland, MJ, Schlabritz-Loutsevitch, NE, Hubbard, GB et al. (2007) Non-human primate fetal kidney transciptome analysis indicates mammalian target of rapamycin (mTOR) is a central nutrient-responsive pathway. J Physiol 579, 643656.CrossRefGoogle Scholar
126. Pettitt, DJ, Moll, PP, Knowler, WC et al. (1993) Insulinemia in children at low and high risk of NIDDM. Diabet Care 16, 608615.CrossRefGoogle ScholarPubMed
127. Boney, CM, Verma, A, Tucker, R et al. (2005) Metabolic syndrome in childhood: association with birth weight, maternal obesity and gestational diabetes mellitus. Pediatrics 1153, e290e296.CrossRefGoogle Scholar
128. Boerschmann, H, Pfluger, M, Henneberger, M et al. (2010) Prevalence and predictors of overweight and insulin resistance in offspring of mothers with gestational diabetes mellitus. Diabet Care 33, 18451849.CrossRefGoogle ScholarPubMed
129. Zielinsky, P & Piccoli, AL Jr (2012) Myocardial hypertrophy and dysfunction in maternal diabetes. Early Hum Dev 88, 273278.CrossRefGoogle ScholarPubMed
130. Krishnaveni, GV, Venna, SR, Hill, JC et al. (2010) Intrauterine exposure to maternal diabetes is associated with higher adiposity and insulin resistance and clustering of cardiovascular risk markers in Indian children. Diabet Care 33, 402404.CrossRefGoogle ScholarPubMed
131. Lee, H, Jang, HC, Park, HK et al. (2007) Early manifestation of cardiovascular disease risk factors in offspring of mothers with previous history of gestational diabetes mellitus. Diabet Res Clin Pract 78, 238245.CrossRefGoogle ScholarPubMed
132. Samuelsson, AM, Matthews, PA, Argenton, M et al. (2008) Diet-induced obesity in female mice leads to hyperphagia, adiposity, hypertension and insulin resistance in a novel murine model of developmental programming. Hypertension 51, 383392.CrossRefGoogle Scholar
133. Nivoit, P, Morens, C, Van Assche, FA et al. (2009) Established diet-induced obesity in female rats leads to offspring hyperphagia, adiposity and insulin resistance. Diabetologia 52, 11331142.CrossRefGoogle ScholarPubMed
134. Shelley, P, Martin-Gronert, MS, Rowlerson, A et al. (2009) Altered skeletal muscle insulin signaling and mitochondrial complex II-III linked activity in adult offspring of obese mice. Am J Physiol Regul Integr Comp Physiol 293, R675R681.CrossRefGoogle Scholar
135. Fernandez-Twinn, DS, Blackmore, HL, Siggens, L et al. (2012) The programming of cardiac hypertrophy in the offspring by maternal obesity is associated with hyperinsulinaemia, AKT, ERK and mTOR activation. Endocrinology 153, 59615971.CrossRefGoogle ScholarPubMed
136. Igosheva, N, Abramov, AY, Poston, L et al. (2010) Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes. PLoS ONE 5, e10074.CrossRefGoogle ScholarPubMed
137. Bayol, SA, Farrington, SJ & Stickland, NC (2007) A maternal ‘junk food’ diet in pregnancy and lactation promotes an exacerbated taste for ‘junk food’ and a greater propensity for obesity in rat offspring. Br J Nutr 98, 843851.CrossRefGoogle Scholar
138. Bayol, SA, Simbi, BH, Bertrand, JA et al. (2008) Offspring from mothers fed a ‘junk food’ diet in pregnancy and lactation exhibit exacerbated adiposity that is more pronounced in females. J Physiol 586, 32193230.CrossRefGoogle ScholarPubMed
139. Bayol, SA, Simbi, BH, Fowkes, RC et al. (2010) A maternal ‘junk food’ diet in pregnancy and lactation promotes non-alcoholic fatty liver disease in rat offspring. Endocrinology 151, 14511461.CrossRefGoogle Scholar
140. Beard, J (2007) Recent evidence from human and animal studies regarding iron status and infant development. J Nutr 137, 524S530S.CrossRefGoogle ScholarPubMed
141. Singla, PN, Tyagi, M, Kumar, A et al. (1997) Fetal growth in maternal anaemia. J Trop Pediatr 43, 8992.CrossRefGoogle ScholarPubMed
142. Lee, HS, Kim, MS, Kim, MH et al. (2006) Iron status and its association with pregnancy outcome in Korean pregnant women. Eur J Clin Nutr 60, 11301135.CrossRefGoogle ScholarPubMed
143. Godfrey, KM, Redman, CW, Barker, DJ et al. (1991) The effect of maternal anaemia and iron deficiency on the ratio of fetal weight to placental weight. Br J Obstet Gynaecol 98, 886891.CrossRefGoogle ScholarPubMed
144. Gambling, L, Charinia, Z, Hannah, L et al. (2002) Effect of iron deficiency on placental cytokine expression and fetal growth in the pregnant rat. Biol Reprod 66, 516532.CrossRefGoogle ScholarPubMed
145. Lewis, RM, Forhead, AJ, Petry, CJ et al. (2002) Long term programming of blood pressure by maternal dietary iron restriction in the rat. Br J Nutr 88, 283290.CrossRefGoogle ScholarPubMed
146. Gambling, L, Dunford, S, Wallace, DI et al. (2003) Iron deficiency during pregnancy affects post-natal blood pressure in the rat. J Physiol 552, 603610.CrossRefGoogle Scholar
147. Lisle, SJ, Lewis, RM, Petry, CJ et al. (2003) Effect of iron restriction during pregnancy on renal morphology in the adult rat offspring. Br J Nutr 90, 3339.CrossRefGoogle ScholarPubMed
148. Lewis, RM, Doherty, CB, James, LA et al. (2001) Effects of maternal iron restriction on placental vascularization in the rat. Placenta 22, 534539.CrossRefGoogle ScholarPubMed
149. Park, JH, Stoffers, DA, Nicholls, RD et al. (2008) Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 118, 23162324.Google ScholarPubMed
150. Lillycrop, KA, Phillips, ES, Jackson, AA et al. (2005) Dietary protein restriction of pregnant rats induces and folic supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135, 13821386.CrossRefGoogle ScholarPubMed
151. Sandovici, I, Smith, NH, Dekker-Nitert, M et al. (2011) Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci USA 108, 54495454.CrossRefGoogle ScholarPubMed
152. Cerda, S & Weitzman, SA (1997) Influence of oxygen radical injury on DNA methylation. Mutat Res 386, 141152.CrossRefGoogle ScholarPubMed
153. Franco Mdo, C, Dantas, AP, Akamine, EH et al. (2007) Biomarkers of oxidative stress and antioxidant status in children born small for gestational age. Pediatr Res 62, 204208.CrossRefGoogle Scholar
154. Chiavaroli, V, Giannini, C, D'Adamo, T et al. (2009) Insulin resistance and oxidative stress in children born small and large for gestational age. Pediatrics 124, 695702.CrossRefGoogle ScholarPubMed
155. Hracsko, Z, Orvos, H, Norvak, Z et al. (2008) Evaluation of oxidative stress markers in neonates with intra-uterine growth retardation. Redox Rep 13, 1116.CrossRefGoogle ScholarPubMed
156. Sen, S & Simmons, RA (2010) Maternal antioxidant supplementation prevents adiposity in Western diet fed rats. Diabetes 59, 30583065.CrossRefGoogle ScholarPubMed
157. Cambonie, G, Comte, B, Yzdorczyk, C et al. (2007) Antenatal oxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet. Am J Regul Interg Comp Physiol 292, R1236R1245.CrossRefGoogle ScholarPubMed
158. Derks, JB, Oudijk, HL, Torrence, HL et al. (2010) Allopurinol reduces oxidative stress in the ovine fetal cardiovascular system after repeated episodes of ischemia-reperfusion. Pediatr Res 68, 374380.Google ScholarPubMed
159. Curhan, GC, Willet, WC, Rimm, EB et al. (1996) Birth weight and adult hypertension, diabetes mellitus and obesity in US men. Circulation 15, 32463250.CrossRefGoogle Scholar
160. Mi, J, Law, C, Zhang, KL et al. (2000) Effects of infant birthweight and maternal body mass index in pregnancy on components of the insulin resistance syndrome in China. Ann Intern Med 15, 253260.CrossRefGoogle Scholar
Figure 0

Fig. 1. (colour online) The thrifty phenotype hypothesis.

Figure 1

Fig. 2. (colour online) Oxidative stress (Ox stress) as an underlying mechanism of developmental programming and ageing.

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