Glycation Damage as a Hub of Aging Pathology
Glycation is a form of chemical reaction in which a sugar bonds to a protein or lipid. There are many forms of sugary molecules floating around in our metabolism, but broadly the role of glycation in aging might be divided into two portions, both of which involved what are known as advanced glycation endproducts (AGEs). In the first, short-lived AGEs produce chronic inflammation and otherwise disrupt cell function through their interaction with cell surface receptors such as RAGE and RANKL. This is a prominent feature of metabolic syndrome, type 2 diabetes, and other pathological states of metabolism. In the second, long-lived AGEs accumulate slowly over time, linking together molecules in the extracellular matrix and as a consequence altering the structural properties of tissue. This may be most important in skin and blood vessels, where it contributes to loss of elasticity, but is also apparent in cartilage and bone, where it causes loss of strength and resilience.
In the first case, the solution is to eat less and lose weight, as this can address near all of the prevalent problems related to metabolic disorders in this modern world of cheap calories and indolence. In the second case new biotechnology is required, however: our biochemistry just isn't capable of dealing with persistent AGEs and the cross-links they produce in the extracellular matrix. The most advanced of present approaches involves mining the bacterial world for species capable of breaking down persistent AGEs and extracting the relevant enzymes as the basis for a therapy. This is by no means a popular area of research, however. When it comes to AGEs, most of the scientific community is far more interested in producing pharmaceutical therapies that tinker with short-term AGE balance and consequences in type 2 diabetes. We can hope that this will change in the years ahead.
Glycation is both a physiological and pathological process which mainly affects proteins, nucleic acids, and lipids. Exogenous and endogenous glycation produces deleterious reactions that take place principally in the extracellular matrix environment or within the cell cytosol and organelles. Advanced glycation end product (AGE) formation begins by the non-enzymatic glycation of free amino groups by sugars and aldehydes which leads to a succession of rearrangements of intermediate compounds and ultimately to irreversibly bound products known as AGEs.
The accumulation of AGEs with aging has been found in many parts of the body, including the blood, blood vessel walls, retina, lens, kidney, brain, peripheral nerves, joints, and skin. The build-up of these products results in significant changes in the metabolism, appearance, and biomechanical properties of these organs. AGEs accumulate over time because kidney function decreases with age regardless of the subject having diabetes. However, aging itself is a condition that favors AGE formation and accumulation due to the age-associated increase in oxidative stress.
In addition, repair processes are less efficient. Basal glycation that occurs over a number of years contributes to aging and can lead to various pathologies by exerting deleterious effects that, while similar to those caused by diabetes, are expressed later and often to a lesser degree. In contrast, it can also be hypothesized that the dietary restriction and qualitative and quantitative changes observed in the elderly diet, may limit their consumption of exogenous AGEs.
The accumulation of AGEs during aging is especially notable in structures that contain collagen. A build-up of glycation products is correlated with increased rigidity in the arteries, tendons, and skin. AGEs play adverse proinflammatory roles in osteoporosis and the serum level of soluble RAGE could therefore have a potential diagnostic role in the monitoring of osteoporosis progression. AGEs also play a role in the aging of skeletal muscle. Muscle mass and strength decrease during the aging process, which can increase the fragility and dependence of the elderly. Glycation and oxidation, especially with respect to lipids, also affect the pathophysiological process of age-related macular degeneration and formation of cataracts, thereby disrupting the quality of vision and the visual field.
Minoxidil may play a role in reducing AGE crosslinking. See --
"Chronic treatment with minoxidil induces elastic fiber neosynthesis and functional improvement in the aorta of aged mice"
https://www.researchgate.net/publication/312108559_Chronic_Treatment_with_Minoxidil_Induces_Elastic_Fiber_Neosynthesis_and_Functional_Improvement_in_the_Aorta_of_Aged_Mice
@L Pagnucco: That is a different issue. Minoxidil doesn't, I think, do anything for cross-linking. Rather it spurs a reversal of the loss of elastin. The compound was originally trialed as a treatment for hypertension back in the 1980s, and shown to reduce blood pressure in older individuals by increasing elastin deposition and flexibility in blood vessels. Unfortunately the side-effects proved to be too concerning to make it a worthwhile treatment - it produces significant edema around the heart and changes in heart function, for example.
Reason,
Minoxidil does appear to either reduce glycation, or produce elastin more resistant to crosslinking, e.g., on p.3, the authors state:
"A decrease in the glycation capacity of aortic elastin was also produced by minoxidil treatment."
and, on p.15:
"Finally, the in vitro glycation capacity of
aortic elastin was investigated. Minoxidil treatment substantially decreased by ~20% the capacity of elastin to form AGEs in the presence of glucose over time (Fig. 5H). This protective effect of minoxidil is of particular interest, given the important detrimental processing of macromolecules by non-enzymatic glycation occurring during aging."