Orientador: Rita Cássia Menegati Dornelles / Banca: Willian Fernando Zambuzzi / Banca: Márcio Mateus Beloti / Resumo: Ocitocina (OT) é hormônio peptídico sintetizado no hipotálamo e armazenado na neurohipófise. A literatura evidencia atuação anabólica da OT no esqueleto de animais jovens. Em nosso laboratório estamos realizando pesquisas para estudar a ação da OT no metabolismo ósseo, durante o envelhecimento. Analisamos inicialmente o processo de remodelação óssea alveolar em ratas com 24 meses e detectamos ação importante da OT na maior formação óssea nesses animais, o que não foi observado em animais com 12 meses. Esses resultados evidenciaram a necessidade de investigação da ação da OT, visando à compreensão dos mecanismos envolvidos na maior formação óssea em organismos senis, no período caracterizado pela aciclicidade estral (estropausa - 24 meses) comparado com organismos adultos com ciclo estral regular (12 meses). Nesse estudo foi avaliada a influência da idade (12 e 24 meses) e a ação da OT associada a indutores osteogênicos clássicos durante a diferenciação em linhagem osteogênica de células-tronco mesenquimais (CTMs) a partir do estroma da medula óssea de fêmures de ratas Wistar, com 12 e 24 meses. Quatro grupos de cada idade foram formados, sendo: MC (meio de crescimento); MO (meio de crescimento suplementado com indutores osteogênicos); MCO (meio de crescimento + OT); MOO (meio de crescimento suplementado com indutores osteogênicos + OT). O ensaio com vermelho de alizarina demonstrou mineralização biológica a partir do 17º dia no grupo com 12 meses em ambos os grupos osteogênicos (MO e MOO), porém a adição de OT (MOO) promoveu a mineralização a partir do 14º dia. No grupo de 24 meses não foi detectada mineralização em nenhum dia experimental no grupo MO, porém a adição de OT no meio (MOO) promoveu a mineralização a partir do 17º dia. As escalas de expressão... / Abstract: Peripheral oxytocin (OT) has been shown to have direct effects on the skeleton, and to provide stimulus for the activity of osteoblasts, as an anabolic factor affecting bone mass. The effects of OT can vary with age. Here we evaluated the effects of OT on the differentiation of bone marrow mesenchymal stem cells, in 12- and 24-months-old Wistar female rats. Four treatment groups were formed for each age group: control (C) (growth medium); osteogenic medium (OM); control + oxytocin (C+OT) (growth medium + oxytocin) and osteogenic medium + oxytocin (OM+OT). Alizarin Red assay was performed and in cells from 12-month-old rats mineralization was detected on day 17 in OM. However, the addition of OT to osteogenic medium (OM+OT) provided biological mineralization on day 14. In cells from 24-month-old acyclic rats, the OM subgroup showed no mineralization; in the OM+OT subgroup mineralization was detected on day 17. Osterix, matrix protein (bone sialoprotein, osteopontin and osteocalcin) and oxytocin gene expression was lower in the 24-month-old than the 12-month-old group; these proteins were increased by OT. The oxytocin receptor was up-regulated only in the 12-month-old group and PGE2 showed an increase in the OM group than in the OM + OT group in both age groups. These findings suggest that OT shows different, differentiation-dependent actions, and is important in the biological mineralization performed by osteoblasts, mainly in cells of bone marrow mesenchymal stem cells from acyclic 24-month-old rats highlighting oxytocin as a potential therapy for control of osteoporosis. / Mestre

Wild-type transthyretin amyloidosis (ATTRwt) is a rare, sporadic protein misfolding disorder with no validated biomarkers or specific treatments. The disease is characterized by deposition of amyloid fibrils composed of wild-type transthyretin (TTR) in cardiac tissue, which leads to cardiomyopathy, heart failure, and death within 5 years. The hypothesis for the studies detailed in this dissertation was non-coding variants in the TTR gene regulatory regions impact expression and serum levels of the protein, thereby contributing to ATTRwt pathogenesis. Investigations included examination of 2 enhancer regions and the proximal promoter of the TTR gene for risk factors which could contribute to pathogenesis of ATTRwt amyloidosis. In total, 11 common and 20 rare variants were identified. The analyses demonstrated significant associations of 3 variants with increased disease risk and 4 variants with age at disease onset and/or survival. Functional studies using GFP and luciferase reporter assays in HepG2 cells were performed to examine the impact of nucleotide alterations in the TTR proximal promoter on reporter expression. Three ATTRwt-risk factors (rs3764479, rs72922940, rs3794885), caused significantly decreased reporter expression in both GFP and luciferase assays (p < 0.02). Moreover, serum TTR levels, measured by immunoturbidity and analyzed along with ATTRwt clinical data, demonstrated that lower serum TTR concentrations were associated with worse survival (hazard ratio = 0.89, p = 0.003). Follow-up analysis of an ATTRwt subset treated with diflunisal, a TTR stabilizer, showed increased serum TTR (p = 0.002) and organ improvement as assessed by cardiac biomarkers (p = 0.043). Unexpectedly, our genetic sequencing data suggested that the TTR G6S variant was disease-protective. Analysis of the TTR G6S protein using circular dichroism and aggregation assay corroborated these findings by demonstrating a higher structural stability and a lower aggregation propensity compared to L55P and V122I, two unstable amyloidogenic TTR variants. In summary, the major findings of this work were: 1) identification of genetic variants that confer risk for ATTRwt amyloidosis through changes in expression, 2) evidence in support of serum TTR as a candidate for monitoring disease progression and response to treatment, and 3) evidence suggesting that TTR G6S may confer protection from ATTRwt by slowing the amyloid cascade. / 2017-09-08T00:00:00Z

This study addressed the political participation of Older Americans. Political participation was defined as all behavior through which people directly expressed their political opinions and ideologies. This definition was broad enough to cover all expressions of political opinions--from discussing politics to contacting public officials. The main concern of this study was to distinguish between the social roles and status of the 'Young Old' (ages 55-74) and the 'Old Old' (ages 75 and over) and their effect on political participation. Little is known about the precise political behavior of these two age groups. This research examined the level of their political activity through multiple regression and factor analysis. A secondary analysis of University of Michigan 1984 pre- and post- National Election Study data provided the evidence for this study. The principal findings of this study were the social characteristics that differentiate those 'Young Old' and 'Old Old' who were more likely to participate in political activities. For the 'Young Old' they were: being married, educated, paying attention to the political campaign of 1984, community residence, "feeling closest" to blacks, belonging to interest groups, and having a strong feeling of political efficacy. For the 'Old Old' also being married, educated, belonging to interest groups, "feeling closest" to environmentalists were significant. Identification with the elderly as a group, was not a significant predictor of participation for the 'Young Old' and the 'Old Old'. This relationship held for all types of participation. No evidence existed to indicate that strictly age-based interests were prevalent among the 1984 elderly respondents.

Population projections indicate that China will be the most rapidly aging country in the world in the near future. To meet the challenge of providing eldercare in a context of shrinking family sizes––where children are no longer able to care for their aging parents–-the Chinese government has selected community eldercare as its major solution. Despite the increasing popularity of community eldercare facilities, little is known about how they operate, their impact on the aging population, and their workforce. Drawing on qualitative date collected during six months of fieldwork in Beijing and Shanghai, this dissertation investigates how community eldercare facilities are established and operated, how they promote the Chinese government’s “healthy aging” agenda, how and to what extent they replace home care, and what kinds of working conditions they create for their caregivers. Findings reveal that (1) The local government collaborates with NGOs to set up community eldercare programs. Instead of striving for autonomy, these NGOs enjoy positive and collaborative relationships with their local governments, which allows them to have access to more eldercare projects and to occupy (and build) the eldercare market to earn future profits. (2) The community eldercare programs support the government’s “healthy aging” agenda, which promotes a lifestyle intended to facilitate independence and mobility. The eldercare programs’ support of this agenda allows the Chinese government to govern at a distance. (3) Community eldercare centers aim to provide a homely feeling for older adults in order to replace home care and facilitate aging in place; at the same time, they constitute a space of control. (4) Caregivers working to create homely feelings at community eldercare centers are required to work in accordance with care ethics, which places them in a “prison of love.” / 2021-04-30

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Age is associated with alterations in sensation and cognition, but little is known of how sensory-cognitive interactions change over time, especially during late middle age. This project examined the change in relations between sensation and cognition and their consistency with established models of neurocognitive aging. Three studies examined associations between visual contrast sensitivity (CS), auditory pure tone acuity (PTA), and cognition among male twins from the Vietnam Era Twin Study of Aging (VETSA), who were assessed twice (VETSA 1, x̅𝑎𝑔𝑒 = 56, n =1,237, VETSA 2, x̅𝑎𝑔𝑒 = 62, n =1,016). Study 1 examined sensory relations, with the hypothesis of more and stronger correlations between CS and PTA at VETSA 2 than at VETSA 1 and a larger genetic correlation at VETSA 2 than at VETSA 1. Heritability at VETSA 1 and VETSA 2 was significant for multiple CS and PTA frequencies, and heritability increased with age. At VETSA 2, there were more shared genes between CS and PTA than at VETSA 1. Studies 2 and 3 examined sensory-cognitive associations. The Study 2 hypotheses of more and stronger associations between CS and cognition at VETSA 2 than VETSA 1 were not supported. Performance in five of nine cognitive domains was correlated with low frequency CS at VETSA 1. Four of these five correlations were significant at VETSA 2. The Study 3 hypotheses of increasing associations between PTA and cognition also were not supported. Low frequency PTA correlated with performance in six cognitive domains at VETSA 1 and in four at VETSA 2. High frequency PTA and episodic memory significantly interacted with age. Neither CS nor PTA was associated with cognition dependent on the sensory modality in which the cognitive tests were presented. The hypothesis that correlations between CS and PTA would increase with age was partially supported, and the hypothesis that correlations between sensory function (vision, audition) and cognition would increase with age was not supported, in both cases because these correlations were independent of age. The results did not follow a single established model of cognitive aging, supporting a model-agnostic approach to future aging research.

archives@tulane.edu / Models that mimic angiogenesis are extremely valuable for elucidating underlining mechanisms and pre-clinical development of therapies. Angiogenesis, defined as the growth of new blood vessels from preexisting vessels, is a multi-cellular process that involves the temporal and spatial coordination between endothelial cells, pericytes, nerves, growth factors, and macrophages. A need exists for biomimetic models that bridge the gap between the mechanistic control of in vitro constructs and the multi-system physiological environment of in vivo models. To meet this need our lab has introduced the rat mesentery culture model as top down approach with intact microvascular networks and a nearly two-dimensional view. Previous development of the model has proven its time-lapse, angiogenic, and lymphangiogenic capabilities. The goal of this work is to advance the model to include the maintenance of peripheral nerves in culture and develop it as a platform for aging and cell therapy studies. The first aim of this study was to expand the rat mesentery culture model to maintain nerves and the spatiotemporal relationship between nerves and blood vessels in culture. We developed a nerve culture media to prevent regression of nerves. Nerve alignment was maintained at the network feeding arteriole and capillary plexus levels. We further demonstrated the presence of neurotransmitter precursors was preserved. We demonstrate for the first time the ability to maintain adult peripheral nerves in an ex vivo model. For the second aim of this study, we developed an aging rat mesentery culture model as a basis for investigating differences in angiogenesis across age groups. We demonstrated that impaired angiogenesis associated with advanced age could be recovered to adult-like levels with serum and individual growth factor stimulation. The discovery of increased vascular island frequency in aged tissues reveals that the method of angiogenesis for older networks can differ. These results establish the rat mesentery culture model as a method for studying aging effect on angiogenesis. The objective of the third aim was to demonstrate the capability of the rat mesentery culture model to study stromal vascular fraction therapy. We developed a protocol to isolate the SVF from adipose tissue and transplant onto the mesentery. We identified unique patterns of vasculogenesis and increased vascular coverage. We confirmed that this increase in vascular area was a combination of the vasculogenesis of SVF, proangiogenic effect on host vessels, and incorporation of SVF into the growing host vessels. We used the aging model in developed in the second aim to show that adult SVF on adult tissue has the greatest therapeutic potential. These results display the investigative potential of the rat mesentery culture model in cell therapy research. This work establishes for the first time, to the best of our knowledge, an ex vivo model capable of maintaining adult peripheral nerves. We demonstrate that angiogenesis can be rescued in aging scenarios. The results, for the first time, reveal the effect that SVF therapy has on preexisting networks as well as how it integrates during microvascular remodeling. / 1 / Nicholas Hodges

Older adults (OAs) typically experience memory failures as they age. However, with some exceptions, studies of OAs’ ability to assess their own memory functions– Metamemory (MM)– find little evidence that this function is susceptible to age-related decline. Our study examines OAs’ and young adults’ (YAs) MM performance and strategy use. Groups of YAs (N = 138) and OAs (N = 79) performed a MM task that required participants to place bets on how likely they were to remember words in a list. Our analytical approach includes hierarchical clustering, and we introduce a new measure of MM—the modified Brier—in order to adjust for di↵erences in scale usage between participants. Our data indicate that OAs and YAs di↵er in the strategies they use to assess their memory and in how well their MM matches with memory performance. However, there was no evidence that the chosen strategies were associated with di↵erences in MM match, indicating that there are multiple strategies that might be e↵ective (i.e. lead to similar match) in this MM task.

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