Aging Disease - The Effects of AGE (Advanced Glycation End-Product) Protein Cross-Linking
The Effects of AGE (Advanced Glycation End-Product)
Protein Cross-Linking in Aging Disease
Recent advances and discoveries in numerous biological, medical, and technical fields call into question whether the aging process should be considered an absolute ending decree on life and lifespan or be classified as a disease which causes progressive deterioration of biological matter and processes. Maximum human lifespan has never been scientifically established, only statistically assumed. Given that other lifeforms experience great longevity, it is only logical and reasonable to expect that there may be a much higher limit to how long Homo sapiens can live, despite the number crunching proliferated by actuarial and economical scientists. A multitude of examples exist of lifeforms that either live continuously or for very lengthy time spans - not counting periods of dormancy or externally imposed premature death, for instance: Turritopsis doohmii, the immortal jellyfish that continually regenerates itself; numerous ocean microorganisms estimated to have live over 100,000 years (Morono et al., 2020); sponges from the Hexactinellida Class believed to have lived over 8,000 - 11,000 years thus far (Jochum, et al., 2012), multiple species of trees of the Pinales Order that have a documented age of over 4000 years; Somniosus microcephalus, the Greenland Shark, authenticated to live over 400 years (Nielsen et al, 2016), and Balaena mysticetus, the Bowhead Whale attested to live at least 211 years(George et al., 1999).
Given the countless examples of long-lived life that surround us, how can we rationally and empirically continue to believe that our life is limited to no more than a few years past 100? "It's always been this way" is a lame excuse for not pressing the limits of our existing knowledge to try to find true answers. Bulterijs et al. (2015) walks through the plethora of poor attempts at rational and non-rational reasoning that continue to be proffered as absolution for not removing the blinders of past learning and superstition that seem to embed themselves as "truth" in our cultural beliefs on death. His characterization of aging as a disease is well grounded in logic and scientific evidence and simply put says aging is a universal, multi-systemic process with underlying causes that like other diseases, gradually erode biological stasis to the point of succumbence. AGE related maladies are perfect examples of this issue.
Herein, one of these underlying causes of aging disease is presented, advanced glycation end-product (AGE) protein cross-linking. Glycation is spontaneous, does not require enzymes, and can occur in combination with amino groups of proteins, DNA, and lipids to form Amadori products (Kim et al., 2017). As an example, the O=CH- (aldehyde group) of the C1 carbon of glucose can combine with a lysine molecule in an amino acid to create a double bond between the glucose C1 carbon and the lysine nitrogen (Schiff base). An Amadori product may then be formed when the molecule rearranges itself so that the hydrogen ion bonds back to the nitrogen atom. Over subsequent time free radicals, reactive oxygen species (ROS), and other compounds with free radical components can interact with Amadori products through oxidation, dehydration, and cross-linking to create advanced glycation end-product (AGEs) (Ansari & Dash, 2013; Kim et al., 2017). One can compare these irreversible AGEs to the compounds that were originally discovered during cooking to caramelize foods (Maillard reaction) (Kim et al., 2017). These toxic end products cause cell senescence and death due to their inherent toxic nature, inability to be broken down, and their susceptibility to aggregation with other proteins and molecules (Nagaraj et al., 2013).
On the macro level, the affects of AGEs in the disease of aging are systematic, causing disruption throughout the body, many of these maladies being denoted by additional contextualized disease names. Cataracts and other eye illnesses are some of the more well known results of AGE involvement. As AGEs accumulate, lens tissue can become clouded, the retina infiltrated, and optic nerves destroyed (Crabbe, 1998; Kamei et al., 2001; Nagaraj, 2008; Nagaraj, 2012; Zarina et al., 2000). Recent studies regarding how AGEs adversely affect the cardiovascular system including heart and arterial disease do however bring hope with the advent of new AGE breaking pharmaceuticals (Zieman & Kass, 2004; Goldin et al. 2006). Although this remedy is applauded and will certainly help save lives, it does not address the nature of the cause of AGEs, a venture that needs to be funded by advanced exploration into the disease of aging. Finding ways to prevent health issues before they tear apart a body is always preferable to the after effects. This is readily apparent when faced with systematic collagen destruction, including sudden ligament rupture and connective tissue failure due to AGE involvement (Chen et al., 2018; Gouldin et al., 2022).
A deeper literature review would undoubtedly uncover issues involving AGEs throughout all systems and tissues in the body. Introspection into the finite details of how AGEs affect the body is an excellent foundation for further synthesis into a higher level view of the AGE issue. It takes both solid detailed data and consolidated assessment to completely define a problem. Only then can we begin to better grasp the larger issue we are faced with. Currently we have allowed ourselves to be overwhelmed by the trees in the forest. As any great tactician is well aware, one needs to step back from battle to properly determine the obstacles and to formulate a proper plan of attack. So it is with the disease of aging, both are necessary and in need of greater attention.
References
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