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Implication of the receptor for advanced glycation end-products (RAGE) during inflammation and ageing

Abstract : Ageing is defined by the accumulation of events leading to a reduction in the efficacy of organ functions and an increased probability of death with time. This process affects all the animal kingdom and while the pace of ageing varies significantly among species, greatly affecting longevity, the mechanisms of ageing itself are widely conserved. In humans, as life expectancy at birth has been steadily increasing for over a century, the amount of people with age-related diseases and dependency has greatly increased and is becoming a major concern.Glycation is a non-enzymatic process leading to the irreversible interaction of carbonyl compounds, such as sugars, with nucleophiles, including lysine or arginine, forming advanced glycation end-products (AGEs). This process is thought to be involved in ageing as AGEs accumulate in the body with age. However, the role in ageing of consuming AGEs produced during cooking processes is much less understood. Digestion vastly modifies their structure and they can only have indirect an impact. Our group has shown that the long-term consumption of a diet enriched with carboxymethyllysine (CML), one of the most abundant AGEs, induced an accelerated vascular ageing in middle-aged mice. However, this effect was entirely dependent on the expression of the receptor for AGEs, RAGE.RAGE is a multiligand receptor and its activation is primarily characterised by a self-sustaining pro-inflammatory response which has been implicated in both age-related and age-independent disorders including complications of diabetes, cardiovascular diseases, Alzheimer’s disease or cancers. Given the relationship between AGEs and RAGE and their respective role in ageing or age-related disorders, it was hypothesized that RAGE has an important role in both physiological and AGE-accelerated ageing. In addition, our group has demonstrated that dietary CML mostly accumulates in mice kidneys, which age slower than vessels. Therefore, a key aim of this thesis was to investigate whether dietary CML also induces accelerated kidney ageing in older mice and whether the deletion of RAGE prevents this effect and has an impact on normal ageing.Two-month-old wild-type (WT) and RAGE-/- mice were fed a control or a CML-enriched diet (200μg CML/gfood) for 18 months. CML distribution was assessed by immunohistochemistry (IHC) and HPLC-MS/MS. Kidney ageing was assessed by measuring markers of its function, lesions and amyloidosis, as well as of inflammation, oxidation and ageing. In addition, motor function in old (~22 month-old) mice was also assessed using locomotion tests.Firstly, it was demonstrated that although CML accumulated in the kidneys of mice fed the CML-enriched diet, this diet had little effect upon the studied parameters while mice deprived of RAGE were largely protected against age-related renal lesions, renal senile amyloidosis and exhibited decreased inflammation and improved pro-longevity pathways. Thereafter, it was shown that some of old RAGE-/- mice motor functions might be better preserved than in old WT animals, suggesting a reduced sarcopenia in RAGE-/- mice.The significant impact of RAGE on ageing and on low-grade and chronic inflammation, associated with its intrinsic characteristic, strongly suggest that RAGE is a pattern recognition receptor and is a proof of principle that inflammaging is an important motor of ageing which may be modulated through genetic or possibly pharmacologic interventions.
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Thibault Teissier. Implication of the receptor for advanced glycation end-products (RAGE) during inflammation and ageing. Human health and pathology. Université de Lille, 2019. English. ⟨NNT : 2019LILUS017⟩. ⟨tel-03349928⟩

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