The AGEs, also known as glycotoxins, are the product of the nonenzymatic reaction between reducing sugars and free amino groups of proteins, lipids, or nucleic acids known as the Maillard or browning reaction (Kuzan, 2021, Uribarri et al., 2010). Maillard reaction was first described in the early 1900s when it was discovered that heating amino acids in the presence of reducing sugars develop a characteristic yellowish-brown color (Ellis, 1912, Singh et al., 2001). It is a complex series of reactions that constitute stable irreversible compounds termed AGEs that accumulate over the lifetime of the protein (Thomas, 2011, Yamagishi, 2019).

Under normal physiological conditions, glycation is relatively a slow naturally occurring reaction and a normal part of the aging process resulting in modifications primarily in long-lived macromolecules. The long-lived proteins constituting the extracellular matrix (ECM) and vascular basement membranes including collagen and elastin are highly susceptible to AGEs-mediated crosslinks (Khalid et al., 2022, Vlassara and Palace, 2002). As glucose is the primary fuel source for the brain, sustained glucose levels are required for optimal brain function, so the majority of the proteins include AGEs related modifications to a certain extent. However, certain factors as in hyperglycemic state in diabetes mellitus or impaired renal clearance exacerbate glycation process and AGEs can arise on short-lived molecules as well (Abdel-Wahab et al., 1997, Brings et al., 2017, Singh et al., 2001, Vlassara and Palace, 2002).

AGEs modification of proteins and lipids renders irreversible damage to the biological macro and micro molecules, disrupts their structural and functional integrity, alters molecular conformation, effect enzymatic activity, reduces degradative capacity, promotes crosslinking of circulatory protein, and results in abnormal recognition and clearance by receptors (Singh et al., 2014, Vlassara and Palace, 2002). To date, numerous AGEs compounds have been identified so far in dietary items, human blood, and tissues. Some of the important AGEs have been mentioned in Fig. 1.

Over the last twenty years, there has been an increasing amount of research investigating the role of AGEs in disease development. There is evidence from several studies in animal models and humans to suggest that the accumulation of AGEs in the body could play a role in the aging process and also in the development of chronic diseases (Chaudhuri et al., 2018, Kuzan, 2021). It can contribute to the development of diabetes and its related complications by promoting insulin resistance and impairing insulin secretion (Vlassara & Palace, 2002). AGEs are also involved in neurodegenerative diseases as they can accumulate in the brain and promote the formation of amyloid plaques, a hallmark of Alzheimer’s disease (Li, Liu, Sun, Lu, & Zhang, 2012). Besides these AGEs also participate in the pathophysiology of cardiovascular disease (CVD), sarcopenia, rheumatoid arthritis, renal disease, and other degenerative disorders (Luevano-Contreras and Chapman-Novakofski, 2010, Singh et al., 2014).

There are two distinct methods through which AGEs exert their deleterious effects. The non-receptor-mediated mechanism involves the direct chemical modification of proteins, lipids, and nucleic acids by AGEs leading to impaired cellular function and tissue damage (Saito and Marumo, 2015, Thomas, 2011). The receptor-mediated mechanism involves the binding of AGEs to specific receptors on the cell surface such as RAGE which triggers a cascade of cellular events that can lead to inflammation, oxidative stress, and cellular dysfunction. (Kuzan, 2021, Luevano-Contreras and Chapman-Novakofski, 2010).

Due to the ability of AGEs to increase the risk of chronic degenerative diseases, AGEs are becoming an increasingly popular subject of research in recent years. In this chapter, our focus is on the chemistry and kinetics of the Maillard reaction, different types of AGEs, glycation pathways that lead to the formation of the main identified AGEs, specific receptors of AGEs, and the role of AGEs in the pathogenesis of chronic diseases. We suggest several approaches with a potential therapeutic value that can be targeted to prevent or reduce AGEs accumulation in the body.