Research Article: Erythrocyte Senescence in a Model of Rat Displaying Hutchinson-Gilford Progeria Syndrome

Date Published: May 29, 2018

Publisher: Hindawi

Author(s): Manoj Kumar Chaudhary, Syed Ibrahim Rizvi.

http://doi.org/10.1155/2018/5028925

Abstract

Increased oxidative stress is a major cause of aging and age-related diseases. Erythrocytes serve as good model for aging studies. Dihydrotachysterol is known to induce premature aging feature in rats mimicking Hutchinson-Gilford progeria syndrome.

In the present study, attempts have been made to explore the differential response of young and senescent erythrocytes separated by density gradient centrifugation from accelerated senescence model of rats mimicking Hutchinson-Gilford progeria syndrome and naturally aged rats.

The erythrocytes of naturally aged and progeroid rats were separated into distinct, young and old cells on the basis of their differential densities. The parameters of oxidative stress and membrane transport systems were studied.

Our study provides evidence that organismal aging negatively affects oxidative stress markers and membrane transport systems in both young and old erythrocytes. This study further substantiates that the changes in progeria model of rats resemble natural aging in terms of erythrocyte senescence.

Partial Text

Hutchinson-Gilford progeria syndrome (HGPS) is a sporadic disorder characterized by premature aging. The primary etiology of the disease is a genetic mutation wherein cytosine to thymine substitution at position 1824 of Lamin A (LMNA) gene located in exon 11 erroneously produces a mutant prelamin A with the deletion of 50 amino acids including proteolytic cleavage site required for its post translational maturation. This mutant prelamin A protein is called progerin which retains farnesyl group through which it remains anchored tightly to the nuclear envelope leading to their accumulation and consequent nucleo-skeleton defect resulting into features of aging [1, 2]. Progerin accumulation is not only confined to HGPS but also its progressive accumulation has been studied in relevance to normal aging [3, 4]. Importantly, progerin accumulation has been reported to promote oxidative stress [5].

A plethora of evidence is available linking oxidative stress to aging and age-related diseases [26]. Numerous studies suggest that the molecular mechanisms involved in accelerated aging phenomena of progeroid human subjects also occur in healthy cells of older individuals. The experimental reports from in vitro studies in human fibroblasts suggest that progeroid subjects experience higher oxidative stress compared to age-matched controls [5, 27]. It has been proposed that progerin sequesters NRF2 at nuclear periphery and prevents binding to ARE motifs. NRF2 is a major stress response factor which activates antioxidant and cytoprotective genes through binding to ARE motifs. Therefore, the reduced availability of NRF2 for transcriptional activation of antioxidant genes results in elevated oxidative damage and consequential HGPS defects [28]. To the best of our knowledge, this is the first report on oxidative damage caused by erythrocytes in HGPS rat model. Since erythrocytes interact with multiple organ systems in the circulation, they are exposed to significant oxidative challenges from several sources during their normal lifespan. Although erythrocytes have evolved robust antioxidant systems to mitigate these challenges, the increased oxidative stress incurred due to aging predisposes them towards significant oxidative damage and premature removal from the circulation [11].

Our study concludes that organismal aging negatively affects the oxidative stress markers and membrane transport systems in both the young and old erythrocytes. The DHT-induced progeria-like premature aging in rats resembles natural aging process in terms of erythrocyte senescence. This study further substantiates our findings of the previous study on DHT-induced premature aging rat model proving its suitability to study age-related changes.

 

Source:

http://doi.org/10.1155/2018/5028925

 

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