Herbs and Phytochemicals: Bergamot (Citrus Bergamia) Polyphenols Prevent Pathophysiological Events Linked To Red Blood Cell Dysfunction During Aging

Herbs and Phytochemicals: Aging is an inevitable biological process that affects all living organisms, including humans. It is characterized by a gradual and irreversible decline in physiological functions and is closely linked to the accumulation of oxidative stress and the associated damage to biological molecules. The free radical theory of aging, proposed by Denham Harman in 1972, suggests that the accumulation of reactive oxygen species (ROS) and other reactive species is a key factor in the aging process. This oxidative stress leads to damage to cellular components, such as lipids, proteins, and DNA, which ultimately results in the dysfunction of cells and organs. As a result, there has been a growing interest in exploring the potential of functional foods rich in phytochemicals to counteract age-related changes and mitigate the detrimental effects of oxidative stress.


 
One such functional food that has gained attention for its potential anti-aging properties is bergamot (Citrus bergamia). Bergamot is a small tree belonging to the Rutaceae family and is primarily cultivated in the region of Calabria, Italy, which offers a microclimate conducive to its growth. While bergamot essential oil has been widely used in cosmetics and the food industry, the pulp and juice of bergamot fruits have only recently been evaluated for their beneficial properties, which include cholesterol reduction, antioxidant effects, and anti-inflammatory properties.
 
The reassessment of bergamot by-products may not only lead to economic advantages by reducing disposal costs but also provide a rich source of nutraceuticals. However, until recently, no scientific study had explored the anti-aging properties of bergamot extracts in human red blood cells (RBCs).
 
Human red blood cells are essential for the transport of oxygen from the lungs to the body's tissues and vice versa. However, their function is compromised as they age, primarily due to the accumulation of oxidative stress and the resultant oxidative damage to cellular components. Reactive species can attack the plasma membrane lipids and proteins of RBCs, leading to lipid peroxidation and protein oxidation, which are indicative of oxidative injury. Additionally, the accumulation of reactive species can trigger glycation reactions, resulting in the increased production of advanced glycation end products (AGEs). The glycation of membrane glycoproteins and hemoglobin can lead to altered rheologic properties of RBCs, reducing their deformability and increasing their density. These changes contribute to the removal of aged RBCs from circulation.
 
One crucial protein in red blood cells is band 3 (SLC4A1/AE1), which serves multiple functions, including maintaining anion homeostasis, connecting plasma membrane lipids with cytoskeletal proteins, and facilitating the binding of various structural proteins and glycolytic enzymes. Hemoglobin, in addition to its primary role in oxygen transport, can serve as an oxygen sensor, influencing the metabolic balance of RBCs. During oxidative stress, the balance between glycolysis and the pentose phosphate pathway (PPP) is disrupted. High levels of oxidative stress lead to the activation of glucose-6-phosphate dehydrogenase (G6PDH) and a shift in metabolism towards the PPP, generating NADPH to fuel endogenous antioxidant systems. Conversely, low oxidative stress levels favor glycolysis, leading to the production of ATP and NADH. This balance is crucial for RBCs to coun teract oxidative insults and maintain their structural and functional integrity.
 
To mitigate the effects of oxidative stress, RBCs possess an efficient cytosolic antioxidant system consisting of non-enzymatic and enzymatic antioxidants. This system protects not only RBCs but also other cells and tissues in the body. The use of natural antioxidants, such as polyphenol-rich extracts, has gained attention as a means of bolstering the body's antioxidant defenses. In this context, the flavonoid fraction of bergamot has shown promise as a source of natural antioxidants.
 
The present Herbs and Phytochemicals investigation aimed to explore the composition of bioactive compounds in bergamot peel and juice extracts and assess their potential protective effects in a model of aging represented by human RBCs exposed to D-Galactose (D-Gal). D-Galactose exposure serves as a model for natural aging, as it induces oxidative stress and replicates the cellular and molecular mechanisms observed during aging. The study investigated the effects of bergamot extracts on oxidative stress, glycation events, and the activation of the endogenous enzymatic defense system in RBCs.
 
The results of the study showed that bergamot peel and juice extracts exerted several protective effects on aging RBCs. They effectively prevented the production of reactive oxygen species (ROS) induced by D-Gal exposure, thus reducing oxidative stress and the associated damage to lipid and protein components of the RBC plasma membrane. This protection extended to the prevention of lipid peroxidation and protein oxidation, which are indicative of oxidative injury to RBCs.
 
Additionally, the bergamot extracts played a vital role in preserving the structure and function of band 3, an essential protein in RBCs responsible for anion exchange and other critical functions. They prevented the alterations in anion exchange kinetics, which can occur during oxidative stress. This suggests that bergamot extracts can help maintain the structural integrity and functionality of RBCs by preserving the functions of band 3.
 
Moreover, the extracts inhibited the production of glycated hemoglobin (A1c), which is associated with aging-related changes in RBCs. A reduction in A1c levels is indicative of the prevention of age-related structural instability and loss of RBC deformability, which are critical factors in microcirculation and tissue oxygenation.
 
The study also examined the activity of endogenous antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD). These enzymes play a vital role in protecting RBCs from oxidative stress. While D-Gal exposure led to an increase in CAT and SOD activity, the bergamot extracts prevented the upregulation of these enzymes. This indicates that the active compounds in bergamot extracts work in synergy with the endogenous antioxidant system to counteract oxidative stress in RBCs.
 
Furthermore, the extracts restored the balance between glycolysis and the pentose phosphate pathway (PPP) in RBCs, which is essential for coping with oxidative stress. The activity of glucose-6-phosphate dehydrogenase (G6PDH), a key enzyme in the PPP, was brought back to control levels, indicating that the extracts help maintain the metabolic plasticity of RBCs and prevent metabolic alterations associated with aging.
 
The redox balance in RBCs, as reflected by the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), was also preserved by the bergamot extracts, further demonstrating their ability to counteract oxidative stress.

In conclusion, this study sheds light on the precise composition of bioactive compounds in bergamot peel and juice extracts and their protective effects in an oxidative stress-related model of cellular aging in RBCs. The findings indicate that the polyphenol-rich extracts of bergamot fruit may effectively counteract oxidative stress-induced alterations in the cellular components of RBCs, including lipids, proteins, and the endogenous antioxidant system. This study identifies bergamot as a promising antioxidant functional food and suggests that dietary supplementation with bergamot or its derivatives may contribute to the prevention or mitigation of pathophysiological events linked to RBC dysfunction during aging.
 
As our understanding of the mechanisms underlying aging in RBCs and the potential benefits of natural antioxidants like bergamot continues to grow, there is a strong foundation for further research and the development of strategies to promote healthy aging and improve the quality of life for individuals as they grow older. This may have significant implications for the prevention and treatment of aging-related health issues and the promotion of overall well-being.
 
The study findings were published in the peer reviewed journal: Frontiers in Physiology.
https://www.frontiersin.org/articles/10.3389/fphys.2023.1225552/full
 
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