specialcollections@tulane.edu / The biological embedding of maternal adversity, both preconception and prenatal, can alter health trajectories of the next generation. Alterations in biological processes, including inflammation and accelerated aging, are proposed mechanisms through which adverse environmental and experiential exposures alter disease risk over the life-course. To identify biological pathways of transgenerational risk, we describe how maternal preconception adversity, assessed by adverse childhood experience score (ACEs), influences the development of her infant’s psychopathology risk and autonomic nervous system (ANS) by examining genomic and epigenomic alterations in both the infant and the placenta. Maternal ACEs elevated her infant’s externalizing behaviors at 18-months of age. Cellular aging, indexed by telomere length (TL) erosion, modified this relation; in infants with greater TL erosion from 4- to 18-months of age, higher maternal ACEs predicted higher externalizing behaviors. At 4-months of age, we examined infant ANS stress physiology and found that higher maternal ACEs predicted lower ANS stress response. Next, we examined TL in the placenta as a pathway conferring transgenerational risk. Higher maternal ACEs predicted shorter placental TL and placental TL modified the impact of maternal ACEs on her infant’s ANS; in placentas with shorter placental TL, higher maternal ACEs predicted greater ANS stress responsivity. To understand the molecular pathways impacted by maternal ACEs and related to TL, we examined placental mRNA expression of an inflammatory gene (CCL2), a gene linked to apoptosis (BCL2), and a gene tied to cellular senescence (GLB1). CCL2 expression modified the relation between higher maternal ACEs and shorter placental TL and CCL2 expression also contributed to the relation between shorter placental TL and decreased BCL2 expression. Lastly, shorter TL moderated the relation between CCL2 expression and both BCL2 and GLB1. The demonstration of the effects of maternal ACE exposure across generations highlights the need to further define the underlying mechanisms contributing to disease risk in the next generation. Maternal ACE exposure effects the placenta, the infant’s ANS, and the infant’s behavior through the first 18-months of life, which highlights the powerful impact of maternal early life adversity across generations and compliments the known lasting health risks found within the individual. / 1 / Christopher Jones

No description available.

Marital disruption (i.e., marital separation, divorce) is associated with a wide range of poor mental and physical health outcomes, including increased risk for all-cause mortality. One biological intermediary that may help explain the association between marital disruption and poor health is accelerated cellular aging.

Life-history trade-offs have been well-documented within the literature through correlational and experimental studies. However, the physiological mechanisms underlying these trade-offs are less understood. Currently, there is great interest in shared mechanisms, specifically endocrine mechanisms, that might underlie the variation in life-history traits. Insulin-like growth factor-1 (IGF-1) may be one shared mechanism that is particularly important. IGF-1 is a metabolic hormone that is part of a highly conserved insulin-signaling pathway known to influence multiple life-history traits including growth and longevity across taxa, however, little is known about these trade-offs outside of laboratory populations. This dissertation focuses on the role of IGF-1 as a hormonal mechanism underlying the life-history trade-off between growth and aging in wild birds. While the causes of aging are not fully understood, telomere dynamics (length and change in length) are a potentially important mechanism underlying lifespan. To investigate the role of IGF-1 as a hormonal mechanism underlying the life-history trade-off between growth and aging in Franklin’s gulls (Leucophaeus pipixcan) and house sparrows (Passer domesticus). In Franklin’s gulls, dietary restriction reduced growth rate and IGF-1 levels but did not impact telomere dynamics. However, there was a significant negative correlation between IGF-1 levels and telomere length at the end of the post-natal growth period. In house sparrows, we found that nestling growth rates varied with respect to year, but IGF-1 levels did not. Telomere dynamics were not related to growth rates or IGF-1 levels, suggesting that during post-natal growth nestlings may be able to mitigate or even delay costs to later life stages. Finally, when exogenous IGF-1 was administered to house sparrow nestlings during the post-natal growth period, nestling growth was impacted but only in some years. Exogenous IGF-1 increased growth and final mass in 2016 and final mass in 2018. There was a trend suggesting experimental birds had shorter telomeres in 2016. Similarly, in 2018, experimental birds had significantly shorter telomeres than control birds. These effects were not observed in 2017, suggesting that trade-offs between growth an aging might only be visible under certain environmental conditions, which may vary with respect to year.

Este trabalho enfatiza o estabelecimento de parâmetros relacionados ao estado de estresse oxidativo em uma população de idosos, avaliando-se: níveis de antioxidantes de baixo peso molecular no plasma, vitC, αTC e βCT assim como a sua ingestão alimentar diária; atividade das enzimas antioxidantes eritrocitárias (CuZn-SOD, CAT e GPX) níveis de produtos derivados da oxidação de lipídios, mais especificamente as substâncias reativas ao ácido tiobarbitúrico (SRAT) e a atividade do burst oxidativo em neutrófilos sanguíneos. Foram estudados 90 idosos, residentes na comunidade, com idade igual ou superior a 65 anos, selecionados a partir de uma sub-amostra do projeto EPIDOSO sob acompanhamento regular no Centro de Estudos do Envelhecimento da Universidade Federal de São Paulo. Os parâmetros acima foram comparados aos de uma população adulta jovem saudável (40-49 anos). A ingestão alimentar diária de vitC, vitE e βCT, na população idosa é bastante superior em relação ao grupo de adultos jovens e, também, superior às RDA (recomendações dietéticas diárias). Isto, provavelmente, se deve à orientação clínica e nutricional a que esta população idosa vem sendo submetida, ao longo do tempo. Este dado reforça a importância de um acompanhamento clínico sistemático e diferenciado para o indivíduo idoso. Apesar da adequada ingestão diária de antioxidantes, pela dieta, as concentrações plasmáticas encontradas não se correlacionam com a ingestão, e são inferiores, às concentrações plasmáticas encontradas na população de adultos jovens. Estes resultados indicam que, uma dieta ainda que equilibrada e adequada, não proporciona, concentrações plasmáticas de antioxidantes em idosos, adequadas para controlar a atividade de espécies oxidantes. Estas baixas concentrações plasmáticas de vitC, αTC e βCT, encontradas nos idosos, podem ser atribuídas à diferenças na absorção, distribuição e biodisponibilidade destes antioxidantes, próprias do envelhecimento. A atividade específica das enzimas antioxidantes são superiores às da população de jovens. Além disso, os parâmetros oxidativos são maiores na população idosa, reforçando a idéia do estresse oxidativo presente no envelhecimento. Esses idosos (90) foram submetidos a uma suplementação vitamínico-mineral diária de 800mg de αTC, 15mg de βCT, 2g de vitC e 100 µg de selênio, para observarmos modificações nos parâmetros oxidantes. O estudo de suplementação, randomizado, duplo-cego e controlado por placebo, foi desenhado da seguinte forma: os idosos foram divididos em 2 grupos de tratamento, T1 e T2, onde T1 recebeu inicialmente a suplementação vitamínico-mineral (100 dias) e, depois do período de washout (período em que os parâmetros medidos retornam para os valores basais) recebeu suplementação com placebo (100 dias). O tratamento T2 apresentou desenho inverso (cross-over) ou seja, recebeu a suplementação placebo nos primeiros 90 dias e nos últimos 90 dias recebeu a suplementação vitamínico-mineral. A análise dos resultados após a suplementação vitamínico-mineral demonstra, para T1 e para T2, um aumento nas concentrações plasmáticas de antioxidantes acompanhado de uma diminuição na atividade das enzimas antioxidantes implicando, possivelmente, uma resposta adaptativa da célula. Os parâmetros oxidativos determinados (SRAT e burst oxidativo de neutrófilos) diminuíram com a suplementação. / This work emphasizes the setting of oxidative stress-related parameters in a population of aged individuals, evaluating: plasmatic levels of low molecular weight antioxidants, vitamin C, α-tocopherol (αTC) and β-carotene (βCT) as well as their daily intake; activity of erythrocyte antioxidant enzymes (CuZnSOD, CAT and GPX); lipid oxidation-derived products, more specifically thiobarbituric acid-reactant substances, and blood neutrophil oxidative burst activity. We studied 90 aged subjects living in the community, with ages 65 or more, selected from a subsample of EPIDOSO project under regular supervision by the Centro de Estudos do Envelhecimento of Universidade Federal de São Paulo. The parameters above mentioned were compared to those of a healthy young adult population. The daily intake of vitC, vitE and βCT of the aged population is well above that of young adults, and also above the RDA This is probably due to the clinical and nutritional orientation that has been offered to this aged group. This fact attests to the importance of systematic and specific clinical counseling to the elderly. Despite the proper daily intake of antioxidants, the plasmatic concentrations of these antioxidants do not correlate to their intake, being lower than the plasmatic concentrations in young adults. These results suggest that even a balanced and adequate diet is not enough, in the elderly, to promote the plasmatic antioxidant concentration needed to contral the activity of oxidant species. These low plasma levels of vitC, vitE and βCT in the elderly can be attributed to changes in absorption, distribution, and bioavailability of these antioxidants, which are common in the aging process. The specific activities of the antioxidant enzymes are higher than those of the younger population. Additionally, the oxidative parameters are higher in the aged group, supporting the idea that oxidative stress is involved in the aging process. These aged subjects received a vitamin-mineral supplementation (800 mg αTC, 15 mg βCT, 2g vitC and 100 µg selenium) aiming to modify the oxidative parameters. The randomized, double blind and placebo-controlled supplementation study was thus designed: the aged subjects were divided in 2 treatment groups, T1 and T2, where T1 received, first the vitamin-mineral supplementation (100 days) and then, after a washout period, a placebo treatment (100 days). The T2 group received the same treatment, but in inverse order (cross-over). The result analysis shows an increase in the plasmatic antioxidant concentrations in both treated groups, as well as a decrease in the activities of the antioxidant enzymes, hinting to an adaptive cellular response. The supplementation also decreased the assessed oxidative parameters (SRAT and neutrophil oxidative burst).

Este trabalho enfatiza o estabelecimento de parâmetros relacionados ao estado de estresse oxidativo em uma população de idosos, avaliando-se: níveis de antioxidantes de baixo peso molecular no plasma, vitC, αTC e βCT assim como a sua ingestão alimentar diária; atividade das enzimas antioxidantes eritrocitárias (CuZn-SOD, CAT e GPX) níveis de produtos derivados da oxidação de lipídios, mais especificamente as substâncias reativas ao ácido tiobarbitúrico (SRAT) e a atividade do burst oxidativo em neutrófilos sanguíneos. Foram estudados 90 idosos, residentes na comunidade, com idade igual ou superior a 65 anos, selecionados a partir de uma sub-amostra do projeto EPIDOSO sob acompanhamento regular no Centro de Estudos do Envelhecimento da Universidade Federal de São Paulo. Os parâmetros acima foram comparados aos de uma população adulta jovem saudável (40-49 anos). A ingestão alimentar diária de vitC, vitE e βCT, na população idosa é bastante superior em relação ao grupo de adultos jovens e, também, superior às RDA (recomendações dietéticas diárias). Isto, provavelmente, se deve à orientação clínica e nutricional a que esta população idosa vem sendo submetida, ao longo do tempo. Este dado reforça a importância de um acompanhamento clínico sistemático e diferenciado para o indivíduo idoso. Apesar da adequada ingestão diária de antioxidantes, pela dieta, as concentrações plasmáticas encontradas não se correlacionam com a ingestão, e são inferiores, às concentrações plasmáticas encontradas na população de adultos jovens. Estes resultados indicam que, uma dieta ainda que equilibrada e adequada, não proporciona, concentrações plasmáticas de antioxidantes em idosos, adequadas para controlar a atividade de espécies oxidantes. Estas baixas concentrações plasmáticas de vitC, αTC e βCT, encontradas nos idosos, podem ser atribuídas à diferenças na absorção, distribuição e biodisponibilidade destes antioxidantes, próprias do envelhecimento. A atividade específica das enzimas antioxidantes são superiores às da população de jovens. Além disso, os parâmetros oxidativos são maiores na população idosa, reforçando a idéia do estresse oxidativo presente no envelhecimento. Esses idosos (90) foram submetidos a uma suplementação vitamínico-mineral diária de 800mg de αTC, 15mg de βCT, 2g de vitC e 100 µg de selênio, para observarmos modificações nos parâmetros oxidantes. O estudo de suplementação, randomizado, duplo-cego e controlado por placebo, foi desenhado da seguinte forma: os idosos foram divididos em 2 grupos de tratamento, T1 e T2, onde T1 recebeu inicialmente a suplementação vitamínico-mineral (100 dias) e, depois do período de washout (período em que os parâmetros medidos retornam para os valores basais) recebeu suplementação com placebo (100 dias). O tratamento T2 apresentou desenho inverso (cross-over) ou seja, recebeu a suplementação placebo nos primeiros 90 dias e nos últimos 90 dias recebeu a suplementação vitamínico-mineral. A análise dos resultados após a suplementação vitamínico-mineral demonstra, para T1 e para T2, um aumento nas concentrações plasmáticas de antioxidantes acompanhado de uma diminuição na atividade das enzimas antioxidantes implicando, possivelmente, uma resposta adaptativa da célula. Os parâmetros oxidativos determinados (SRAT e burst oxidativo de neutrófilos) diminuíram com a suplementação. / This work emphasizes the setting of oxidative stress-related parameters in a population of aged individuals, evaluating: plasmatic levels of low molecular weight antioxidants, vitamin C, α-tocopherol (αTC) and β-carotene (βCT) as well as their daily intake; activity of erythrocyte antioxidant enzymes (CuZnSOD, CAT and GPX); lipid oxidation-derived products, more specifically thiobarbituric acid-reactant substances, and blood neutrophil oxidative burst activity. We studied 90 aged subjects living in the community, with ages 65 or more, selected from a subsample of EPIDOSO project under regular supervision by the Centro de Estudos do Envelhecimento of Universidade Federal de São Paulo. The parameters above mentioned were compared to those of a healthy young adult population. The daily intake of vitC, vitE and βCT of the aged population is well above that of young adults, and also above the RDA This is probably due to the clinical and nutritional orientation that has been offered to this aged group. This fact attests to the importance of systematic and specific clinical counseling to the elderly. Despite the proper daily intake of antioxidants, the plasmatic concentrations of these antioxidants do not correlate to their intake, being lower than the plasmatic concentrations in young adults. These results suggest that even a balanced and adequate diet is not enough, in the elderly, to promote the plasmatic antioxidant concentration needed to contral the activity of oxidant species. These low plasma levels of vitC, vitE and βCT in the elderly can be attributed to changes in absorption, distribution, and bioavailability of these antioxidants, which are common in the aging process. The specific activities of the antioxidant enzymes are higher than those of the younger population. Additionally, the oxidative parameters are higher in the aged group, supporting the idea that oxidative stress is involved in the aging process. These aged subjects received a vitamin-mineral supplementation (800 mg αTC, 15 mg βCT, 2g vitC and 100 µg selenium) aiming to modify the oxidative parameters. The randomized, double blind and placebo-controlled supplementation study was thus designed: the aged subjects were divided in 2 treatment groups, T1 and T2, where T1 received, first the vitamin-mineral supplementation (100 days) and then, after a washout period, a placebo treatment (100 days). The T2 group received the same treatment, but in inverse order (cross-over). The result analysis shows an increase in the plasmatic antioxidant concentrations in both treated groups, as well as a decrease in the activities of the antioxidant enzymes, hinting to an adaptive cellular response. The supplementation also decreased the assessed oxidative parameters (SRAT and neutrophil oxidative burst).

Le contrôle explicite de la convergence des sommes convenablement normalisées de variables aléatoires, ainsi que l'étude du principe de déviations modérées associé à ces sommes constituent les thèmes centraux de cette thèse. Nous étudions principalement deux types de processus. Premièrement, nous nous intéressons aux processus indexés par un arbre binaire, aléatoire ou non. Ces processus ont été introduits dans la littérature afin d'étudier le mécanisme de la division cellulaire. Au chapitre 2, nous étudions les chaînes de Markov bifurcantes. Ces chaînes peuvent être vues comme une adaptation des chaînes de Markov "usuelles'' dans le cas où l'ensemble des indices à une structure binaire. Sous des hypothèses d'ergodicité géométrique uniforme et non-uniforme d'une chaîne de Markov induite, nous fournissons des inégalités de déviations et un principe de déviations modérées pour les chaînes de Markov bifurcantes. Au chapitre 3, nous nous intéressons aux processus bifurcants autorégressifs d'ordre p (). Ces processus sont une adaptation des processus autorégressifs linéaires d'ordre p dans le cas où l'ensemble des indices à une structure binaire. Nous donnons des inégalités de déviations, ainsi qu'un principe de déviations modérées pour les estimateurs des moindres carrés des paramètres "d'autorégression'' de ce modèle. Au chapitre 4, nous traitons des inégalités de déviations pour des chaînes de Markov bifurcantes sur un arbre de Galton-Watson. Ces chaînes sont une généralisation de la notion de chaînes de Markov bifurcantes au cas où l'ensemble des indices est un arbre de Galton-Watson binaire. Elles permettent dans le cas de la division cellulaire de prendre en compte la mort des cellules. Les hypothèses principales que nous faisons dans ce chapitre sont : l'ergodicité géométrique uniforme d'une chaîne de Markov induite et la non-extinction du processus de Galton-Watson associé. Au chapitre 5, nous nous intéressons aux modèles autorégressifs linéaires d'ordre 1 ayant des résidus corrélés. Plus particulièrement, nous nous concentrons sur la statistique de Durbin-Watson. La statistique de Durbin-Watson est à la base des tests de Durbin-Watson, qui permettent de détecter l'autocorrélation résiduelle dans des modèles autorégressifs d'ordre 1. Nous fournissons un principe de déviations modérées pour cette statistique. Les preuves du principe de déviations modérées des chapitres 2, 3 et 4 reposent essentiellement sur le principe de déviations modérées des martingales. Les inégalités de déviations sont établies principalement grâce à l'inégalité d'Azuma-Bennet-Hoeffding et l'utilisation de la structure binaire des processus. Le chapitre 5 est né de l'importance qu'a l'ergodicité explicite des chaînes de Markov au chapitre 3. L'ergodicité géométrique explicite des processus de Markov à temps discret et continu ayant été très bien étudiée dans la littérature, nous nous sommes penchés sur l'ergodicité sous-exponentielle des processus de Markov à temps continu. Nous fournissons alors des taux explicites pour la convergence sous exponentielle d'un processus de Markov à temps continu vers sa mesure de probabilité d'équilibre. Les hypothèses principales que nous utilisons sont : l'existence d'une fonction de Lyapunov et d'une condition de minoration. Les preuves reposent en grande partie sur la construction du couplage et le contrôle explicite de la queue du temps de couplage. / The explicit control of the convergence of properly normalized sums of random variables, as well as the study of moderate deviation principle associated with these sums constitute the main subjects of this thesis. We mostly study two sort of processes. First, we are interested in processes labelled by binary tree, random or not. These processes have been introduced in the literature in order to study mechanism of the cell division. In Chapter 2, we study bifurcating Markov chains. These chains may be seen as an adaptation of "usual'' Markov chains in case the index set has a binary structure. Under uniform and non-uniform geometric ergodicity assumptions of an embedded Markov chain, we provide deviation inequalities and a moderate deviation principle for the bifurcating Markov chains. In chapter 3, we are interested in p-order bifurcating autoregressive processes (). These processes are an adaptation of $p$-order linear autoregressive processes in case the index set has a binary structure. We provide deviation inequalities, as well as an moderate deviation principle for the least squares estimators of autoregressive parameters of this model. In Chapter 4, we dealt with deviation deviation inequalities for bifurcating Markov chains on Galton-Watson tree. These chains are a generalization of the notion of bifurcating Markov chains in case the index set is a binary Galton-Watson tree. They allow, in case of cell division, to take into account cell's death. The main hypothesis that we do in this chapter are : uniform geometric ergodicity of an embedded Markov chain and the non-extinction of the associated Galton-Watson process. In Chapter 5, we are interested in first-order linear autoregressive models with correlated errors. More specifically, we focus on the Durbin-Watson statistic. The Durbin-Watson statistic is at the base of Durbin-Watson tests, which allow to detect serial correlation in the first-order autoregressive models. We provide a moderate deviation principle for this statistic. The proofs of moderate deviation principle of Chapter 2, 3 and 4 are essentially based on moderate deviation for martingales. To establish deviation inequalities, we use most the Azuma-Bennet-Hoeffding inequality and the binary structure of processes. Chapter 6 was born from the importance that explicit ergodicity of Markov chains has in Chapter 2. Since explicit geometric ergodicity of discrete and continuous time Markov processes has been well studied in the literature, we focused on the sub-exponential ergodicity of continuous time Markov Processes. We thus provide explicit rates for the sub-exponential convergence of a continuous time Markov process to its stationary distribution. The main hypothesis that we use are : existence of a Lyapunov fonction and of a minorization condition. The proofs are largely based on the coupling construction and the explicit control of the tail of the coupling time.