Chronic stress-associated accelerated ageing: inflammation and oxidative stress treatment

Petersen-Ross, Kelly Shirley (2020-12)

Thesis (PhD)--Stellenbosch University, 2020.

Thesis

ENGLISH ABSTRACT: In recent years, the incidence of non-communicable diseases (NCD) normally associated with advanced age has begun presenting in younger populations. This has resulted in a growing burden on global healthcare systems and decreasing quality of life in individuals. Cardiovascular diseases, cancers, chronic respiratory diseases, chronic inflammatory diseases and diabetes are some of the many NCD’s and all these have two maladaptive characteristics in common, namely chronic low-grade inflammation and increased oxidative stress. The aim of this research was to identify a threshold prior to maladaptation in both redox and inflammatory status which can be targeted with preventative medicine strategies; in this way, we may identify suitable models which are sensitive enough to identify this threshold as well as show small effect sizes so that they can be used for drug screening of preventative medicine treatments. In order to elucidate this threshold, two rodent models were employed to simulate a pre-onset and an early onset state. The pre-onset state was simulated by chronic D-galactose injections to mimic cumulative oxidative stress as is associated with chronological ageing. The early onset state was simulated with a collagen induced rheumatoid arthritis (RA) model. A grape seed polyphenol supplementation was employed to assess the sensitivity of the models. Comprehensive end-point analysis of the oxidative and inflammatory state of various compartments were performed. Analysis of parameters associated with ageing were also included as measure of relative ageing status in models. The results of both studies indicated that the threshold or point of onset of accelerated ageing was indeed identified. In the D-galactose model, a novel finding was the compromised antioxidant capacity in plasma, even in the absence of experimentally elevated oxidative damage, observed as decreases in plasma FRAP. However, oxidative damage was observed in tissue specific investigations, such a morphological changes in the mesenteric lymph nodes. In the RA model, decreases in antioxidant capacity was noted along with oxidative damage in plasma, but not in all tissue types investigated - particularly the brain. This novel finding of pre-damage oxidative changes in the brain was indicated by decreases in MDA and increases in FRAP. This combined with a switch to a pro-inflammatory state within the circulation, confirms the early disease state within the RA model. This investigation has elucidated the importance of monitoring the oxidative state within multiple compartments to identify the threshold at which disturbances to homeostasis turns into maladaptation and FRAP may be the most sensitive parameter to display this. The effect changes noted after supplementation with an antioxidant treatment also enhanced our knowledge of which parameters and tissue are susceptible to oxidative and inflammatory modulation to prevent maladaptations which may result in pathology.

AFRIKAANSE OPSOMMING: Die insidensie van nie-aanmeldbare siektes (NAS) wat normaalweg met gevorderde ouderdom verbind word, het meer onlangs ook begin presenter in jonger populasies. Hierdie tendens veroorsaak ‘n groeiende las op die gesondheidstelsels en verlaag lewenskwaliteit. Kardiovaskulêre siekte, kanker, kroniese respiratoriese siekte en diabetes is van die NAS en het almal twee kenmerke van wanaanpassing in gemeen, naamlik laegraad inflammasie en verhoogde oksidatiewe stres. Die doel van hierdie navorsing was om die drumpel voor wanaanpassing te identifiseer, waar beide redoks en inflammatoriese status geteiken kan word met voorkomende medisyne strategieë; sodoende kan ons geskikte modelle identifiseer wat sensitief genoeg is om hierdie drumpel uit te wys en ook klein effekte op te tel sodat hierdie modelle gebruik kan word vir middeltoetsing van voorkomende medisynes. Ten einde hierdie drumpel te belig, is twee knaagdiermodelle gebruik om wanaanpassingsgebeure voor siekte, asook vroeg in die proses, te simuleer. Die voor-siekte toestand is gesimuleer deur kroniese D-galaktose inspuitings om kumulatiewe oksidatiewe stress – en dus versnelde veroudering – te veroorsaak. Die vroeë siektetoestand is gesimuleer in ‘n kollageen-geïnduseerde model van rumatoïede artritis (RA). ‘n Druifpit-polifenool supplement is gebruik om die sensitiwiteit die model te toets. Omvattende eindpunt analise van oksidatiewe en inflammatoriese status in verskeie kompartemente is uitgevoer. ‘n Analise van parameters wat met veroudering verband hou, is ook ingesluit om die relatiewe toestand van veroudering te belig. Resultate dui aan dat die drumpel waar versnelde veroudering begin, suksesvol aangedui is. ‘n Nuwe bevinding in die D-galaktose model, is die verswakte anti-oksidant kapasiteit selfs in die afwesigheid van eksperimentele verhoogde oksidatiewe skade, soos aangedui deur die verlaagde plasma FRAP. Oksidatiewe skade is egter wel opgemerk in weefsel-spesifieke ondersoeke, bv. die morfologiese veranderinge in die mesenteriese limfnodes. In die artritis model is verlaagde anti-oksidant kapasiteit saam met oksidatiewe skade in plasma opgemerk, maar nie in alle weefsels nie – veral die brein. Hierdie nuwe bevinding van redoks veranderinge voordat skade opgemerk word in die brein, word ondersteun deur verlaagde MDA en verhoodge FRAP vlakke, en saam met die skuif na ‘n pro-inflammatoriese status in sirkulasie, bevestig huidige data die vroeg-siekte status in die RA model. Hierdie ondersoeke illustreer die belang van monitering van die oksidatiewe stress status in verskeie kompartemente, om die drumpel waar versteurings in homeostase na wanaanpassing verander, aan te dui. FRAP blyk die mees sensitiewe merker in hierdie verband te wees. Effekte van die supplement dra by tot ons kennis in terme van weefsel-verskille in terme van hul kwesbaarheid vir oksidatiewe en inflammatoriese modulasie, en waar terapie dus geteiken moet word om wanaanpassing te keer wat tot patologie kan lei.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/109148
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