Jane L. Tarry-Adkins

Poor maternal nutrition followed by accelerated postnatal growth leads to telomere shortening and increased markers of cell senescence in rat islets.

Low birth weight (LBW) followed by accelerated postnatal growth is associated with increased risk of developing age‐associated diseases such as type 2 diabetes. Gestational protein restriction in rats causes LBW, β‐cell dysfunction, and reduced longevity. These effects may be mediated by accelerated cellular aging. This study tested the hypothesis that LBW followed by rapid postnatal catch‐up growth leads to islet telomere shortening through alterations in antioxidant defense capacity, stress/senescence marker proteins, and DNA repair mechanisms at the gene expression level. We used our rat model of gestational protein restriction (recuperated offspring) and control offspring. Southern blotting revealed shorter (P<0.001) islet telomeres in recuperated animals compared to controls. This was associated with increased expression of peroxiredoxin 1 (P<0.05), peroxiredoxin 3 (P<0.01), and hemeoxygenase‐1 (HO‐1) (P<0.05), which are up‐regulated under stress conditions. MnSOD expression was significantly (P<0.05) decreased in recuperated offspring, suggesting partial impairment of mitochondrial antioxidant defenses. Markers of cellular senescence p21 and p16 were also increased (P<0.01 and P<0.05, respectively) in the recuperated group. We conclude that maternal diet influences expression of markers of cellular stress and telomere length in pancreatic islets. This may provide a mechanistic link between early nutrition and growth and type 2 diabetes.— Tarry‐ Adkins, J. L., Chen, J. H., Smith, N. S., Jones, R. H., Cherif, H., Ozanne, S. E. Poor maternal nutrition followed by accelerated postnatal growth leads to telomere shortening and increased markers of cell senescence in rat islets. FASEB J. 23, 1521–1528 (2009)

Maternal diet influences DNA damage, aortic telomere length, oxidative stress, and antioxidant defense capacity in rats

Low birth weight is associated with in creased cardiovascular disease (CVD) in humans. Detri mental effects of low birth weight are amplified by rapid catch–up growth. Conversely, slow growth during lactation reduces CVD risk. Gestational protein restriction causes low birth weight, vascular dysfunction, and accelerated aging in rats. Atherosclerotic aortic tissue has shortened telomeres, and oxidative stress accelerates telomere short ening through generation of DNA single–strand breaks (ssbs). This study tested the hypothesis that maternal diet influences aortic telomere length through changes in DNA ssbs, antioxidant capacity, and oxidative stress. We used our models of gestational protein restriction followed by rapid catch–up growth (the recuperated group) and pro tein restriction during lactation (the postnatal low–protein [PLP] group). Southern blotting revealed fewer aortic DNA ssbs and subsequently fewer short telomeres (P<0.05) in the PLP group. This result was associated with reduced (P<0.01) 8–hydroxy–2–deoxyguanosine, a marker of oxidative stress. PLP animals expressed in creased (P<0.01) manganese superoxide–dismutase, cop per–zinc superoxide–dismutase, catalase, and glutathione– reductase. Age–dependent changes in antioxidant defense enzymes indicated more protection to oxidative stress in the PLP animals;conversely, recuperated animals demon strated age–associated impairment of antioxidant de fenses. We conclude that maternal diet has a major influence on aortic telomere length. This finding may provide a mechanistic link between early growth patterns and CVD.— Tarry‐Adkins, J. L., Martin‐Gronert, M. S., Chen, J.‐H., Cripps, R. L., Ozanne, S. E. Maternal diet influences DNA damage, aortic telomere length, oxidative stress, and antioxidant defense capacity in rats. FASEB J. 22, 2037–2044 (2008)

Mechanisms of early life programming: current knowledge and future directions

It has been >20 y since epidemiologic studies showed a relation between patterns of early growth and subsequent risk of diseases, such as type 2 diabetes, cardiovascular disease, and the metabolic syndrome. Studies of identical twins, individuals who were in utero during periods of famine, and animal models have provided strong evidence that the early environment, including early nutrition, plays an important role in mediating these relations. The concept of early life programming is therefore widely accepted. However, the mechanisms by which a phenomenon that occurs in early life can have long-term effects on the function of a cell and therefore on the metabolism of an organism many years later are only starting to emerge. These mechanisms include 1) permanent structural changes in an organ resulting from suboptimal concentrations of an important factor during a critical period of development, eg, the permanent reduction in β cell mass in the endocrine pancreas; 2) persistent alterations in epigenetic modifications (eg, DNA methylation and histone modifications) that lead to changes in gene expression (eg, several transcription factors are susceptible to programmed changes in gene expression through such mechanisms); and 3) permanent effects on the regulation of cellular aging (eg, increases in oxidative stress that lead to macromolecular damage, including that to DNA and specifically to telomeres, can contribute to such effects). Further understanding of such processes will enable the development of preventive and intervention strategies to combat the burden of common diseases such as type 2 diabetes and cardiovascular disease.

Maternal Protein Restriction Affects Postnatal Growth and the Expression of Key Proteins Involved in Lifespan Regulation in Mice

We previously reported that maternal protein restriction in rodents influenced the rate of growth in early life and ultimately affected longevity. Low birth weight caused by maternal protein restriction followed by catch-up growth (recuperated animals) was associated with shortened lifespan whereas protein restriction and slow growth during lactation (postnatal low protein: PLP animals) increased lifespan. We aim to explore the mechanistic basis by which these differences arise. Here we investigated effects of maternal diet on organ growth, metabolic parameters and the expression of insulin/IGF1 signalling proteins and Sirt1 in muscle of male mice at weaning. PLP mice which experienced protein restriction during lactation had lower fasting glucose (P = 0.038) and insulin levels (P = 0.046) suggesting improved insulin sensitivity. PLP mice had higher relative weights (adjusted by body weight) of brain (P = 0.0002) and thymus (P = 0.031) compared to controls suggesting that enhanced functional capacity of these two tissues is beneficial to longevity. They also had increased expression of insulin receptor substrate 1 (P = 0.021) and protein kinase C zeta (P = 0.046). Recuperated animals expressed decreased levels of many insulin signalling proteins including PI3 kinase subunits p85α (P = 0.018), p110β (P = 0.048) and protein kinase C zeta (P = 0.006) which may predispose these animals to insulin resistance. Sirt1 protein expression was reduced in recuperated offspring. These observations suggest that maternal protein restriction can affect major metabolic pathways implicated in regulation of lifespan at a young age which may explain the impact of maternal diet on longevity.

Poor maternal nutrition leads to alterations in oxidative stress, antioxidant defense capacity, and markers of fibrosis in rat islets: potential underlying mechanisms for development of the diabetic phenotype in later life

Low birth weight is associated with glucose intolerance, insulin resistance, and type 2 diabetes (T2D) in later life. Good evidence indicates that the environment plays an important role in this relationship. However, the mechanisms underlying these relationships are defined poorly. Islets are particularly susceptible to oxidative stress, and this condition combined with fibrosis is thought to be instrumental in T2D pathogenesis. Here we use our maternal low‐protein (LP) rat model to determine the effect of early diet on oxidative stress and fibrosis in pancreatic islets of male offspring at 3 and 15 mo of age. Islet xanthine oxidase (XO) expression was increased in 15‐mo LP offspring, which suggests increased oxidative‐stress. Manganese superoxide‐dismutase (MnSOD), copper‐zinc superoxide dismutase (CuZnSOD), and heme oxygenase‐1 (HO‐1) (antioxidant enzymes) were reduced significantly in LP offspring, which indicated impairment of oxidative defense. Expression of fibrosis markers collagen I and collagen III also increased in 15‐mo LP offspring. Angiotensin II receptor type I (ATIIR1), induced by hyperglycemia and oxidative‐stress, was significantly up‐regulated in 15‐mo LP offspring. Lipid peroxidation was also increased in 15‐mo LP animals. We conclude that maternal protein restriction causes age‐associated increased oxidative stress, impairment of oxidative defense, and fibrosis. These findings provide mechanisms by which suboptimal early nutrition can lead to T2D development later in life.—Tarry‐Adkins, J. L., Chen, J.‐H., Jones, R. H., Smith, N. H., Ozanne, S. E. Poor maternal nutrition leads to alterations in oxidative stress, antioxidant defense capacity, and markers of fibrosis in rat islets: potential underlying mechanisms for development of the diabetic phenotype in later life. FASEB J. 24, 2762–2771 (2010). www.fasebj.org

Poor maternal nutrition followed by accelerated postnatal growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress, and oxidative defense capacity in rat heart

Low birth weight and accelerated postnatal growth lead to increased risk of cardiovascular disease. We reported previously that rats exposed to a low‐protein diet in utero and postnatal catch‐up growth (recuperated) develop metabolic dysfunction and have reduced life span. Here we explored the hypothesis that cardiac oxidative and nitrosative stress leading to DNA damage and accelerated cellular aging could contribute to these phenotypes. Recuperated animals had a low birth weight (P<0.001) but caught up in weight to controls during lactation. At weaning, recuperated cardiac tissue had increased (P<0.05) protein nitrotyrosination and DNA single‐stranded breaks. This condition was preceded by increased expression of DNA damage repair molecules 8‐oxoguanine‐DNA‐glycosylase‐1, nei‐endonuclease‐VIII‐like, X‐ray‐repair‐complementing‐defective‐repair‐1, and Nthl endonuclease III‐like‐1 on d 3. These differences were maintained on d 22 and became more pronounced in the case of 8‐oxoguanine‐DNA‐glycosylase‐1 and neiendonuclease‐VIII‐like. This was accompanied by increases in xanthine oxidase (P<0.001) and NADPH oxidase (P<0.05), major sources of reactive oxygen species (ROS). The detrimental effects of increased ROS in recuperated offspring may be exaggerated at 22 d by reductions (P<0.001) in the antioxidant enzymes perox‐iredoxin‐3 and CuZn‐superoxide‐dismutase. We conclude that poor fetal nutrition followed by accelerated postnatal growth results in increased cardiac nitrosative and oxidative‐stress and DNA damage, which could contribute to age‐associated disease risk.—TarryAdkins, J. L., Martin‐Gronert, M. S., Fernandez‐Twinn, D. S., Hargreaves, I., Alfaradhi, M. Z., Land, J. M., Aiken, C. E., Ozanne, S. E. Poor maternal nutrition followed by accelerated postnatal growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress and oxidative defense capacity in rat heart. FASEB J. 27, 379–390 (2013). www.fasebj.org

The impact of early nutrition on the ageing trajectory

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.

Maternal Diet-induced Obesity Programs Cardiovascular Dysfunction in Adult Male Mouse Offspring Independent of Current Body Weight

Obese pregnancies are not only associated with adverse consequences for the mother but also the long-term health of her child. Human studies have shown that individuals from obese mothers are at increased risk of premature death from cardiovascular disease (CVD), but are unable to define causality. This study aimed to determine causality using a mouse model of maternal diet–induced obesity. Obesity was induced in female C57BL/6 mice by feeding a diet rich in simple sugars and saturated fat 6 weeks prior to pregnancy and throughout pregnancy and lactation. Control females were fed laboratory chow. Male offspring from both groups were weaned onto chow and studied at 3, 5, 8, and 12 weeks of age for gross cardiac morphometry using stereology, cardiomyocyte cell area by histology, and cardiac fetal gene expression using qRT-PCR. Cardiac function was assessed by isolated Langendorff technology at 12 weeks of age and hearts were analyzed at the protein level for the expression of the β1 adrenergic receptor, muscarinic type-2 acetylcholine receptor, and proteins involved in cardiac contraction. Offspring from obese mothers develop pathologic cardiac hypertrophy associated with re-expression of cardiac fetal genes. By young adulthood these offspring developed severe systolic and diastolic dysfunction and cardiac sympathetic dominance. Importantly, cardiac dysfunction occurred in the absence of any change in corresponding body weight and despite the offspring eating a healthy low-fat diet. These findings provide a causal link to explain human observations relating maternal obesity with premature death from CVD in her offspring.

Coenzyme Q10 prevents accelerated cardiac aging in a rat model of poor maternal nutrition and accelerated postnatal growth

Studies in human and animals have demonstrated that nutritionally induced low birth-weight followed by rapid postnatal growth increases the risk of metabolic syndrome and cardiovascular disease. Although the mechanisms underlying such nutritional programming are not clearly defined, increased oxidative-stress leading to accelerated cellular aging has been proposed to play an important role. Using an established rodent model of low birth-weight and catch-up growth, we show here that post-weaning dietary supplementation with coenzyme Q10, a key component of the electron transport chain and a potent antioxidant rescued many of the detrimental effects of nutritional programming on cardiac aging. This included a reduction in nitrosative and oxidative-stress, telomere shortening, DNA damage, cellular senescence and apoptosis. These findings demonstrate the potential for postnatal antioxidant intervention to reverse deleterious phenotypes of developmental programming and therefore provide insight into a potential translatable therapy to prevent cardiovascular disease in at risk humans.

Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth

Background: It is well established that low birth weight and accelerated postnatal growth increase the risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental programming are not well characterized, and potential intervention strategies are poorly defined. Objectives: We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed phenotype. Design: A rat model of maternal protein restriction was used to generate low-birth-weight offspring that underwent accelerated postnatal growth (termed “recuperated”). These were compared with control rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress, and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase–polymerase chain reaction. Results: Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ± SEM: 12 ± 2 μm) than in controls (5 ± 0.5 μm) (P < 0.001). This was associated with greater inflammation (interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor α: 64% ± 24% increase; P < 0.05), lipid peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 μg/mL per μg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01) hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01). Conclusions: Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by downregulation of oxidative stress, inflammation, and hyperinsulinemia.