As we age, both chronologically and biologically, our regenerative capabilities tend to be less robust. As it is intuitive, one need not go into examples of this to any extent and for those of us over the midpoint in our lives we know it all too well. One aspect of our cellular health that shows itself during aging is the decline in the ability of stem cells to replicate. Stem cells serve as major part of our internal repair system, dividing theoretically without limit to replenish other cells. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function. However, we do know that this is not the the case as stem cells do loose their viability. This loss of viability is often termed “stem cell exhaustion”.(1) It has been generally accepted that stem cell proliferative decline is a systemic phenomenon and is why there is a general decline in tissue regeneration throughout the individual that is basically correlated with aging.
Studies on stem cell function/dysfunction is difficult to conduct due to the possibilities that changes identified in stem cells can be intrinsic or possibly imposed on the stem cells by the aged environment in which they reside. However Conboy and Rondo (2) using a process known as heterochronic parabiosis (the physical pairing via tissue connective processes of two animals of different ages to test cell and tissue aging phenomenon) showed that stem cell have an intrinsic as well as extrinsic action in the body’s tissue regenerative processes. Transplantation of stem cells not only achieved a direct intrinsic tissue derived effect in many cases but also an extrinsic effect on systemic functionalities; possibly through secretion factors. But bottom line, stem cell exhaustion plays a significant role in both local and overall aging phenotype development.
So how does advanced glycation end products (AGEs) impact and compromise stem sell viability? You will remember that various by-products of metabolism, such as reactive carbonyl species glyoxal and methylglyoxal are potentially harmful to cells and tissues by having a damaging role in many physiological and pathological processes. These molecules, which are naturally occurring by-products of glucose metabolism, can form covalent adducts (these are the AGEs).
One example of this (you may remember this in a different context) is the ability of glyoxal to form AGEs in bone marrow-derived telomerase-immortalized stem cells.(3) In vitro, glyoxal induces irreversible cellular senescence. This senescence was downstream from development of AGEs – in this, case carboxymethyl-lysine. This was accompanied by increased DNA damage within stem cell which often leads to cellular senescence and ultimately apoptosis of the stem cells.
A study by Voos et al (4) is another example of the results of AGEs’ effects on stem cells. This study looked at progenitor stem cells occurring in individuals with type II diabetes (these people have typically increased AGE levels) and how the diabetes can affect the repair of damaged myocardial tissue. Circulating bone-marrow-derived cells, endothelial progenitor cells, are able to maintain and replace differentiated cells within their own specific tissue as a consequence of physiological cell turnover or tissue damage due to injury. Decreased number of peripheral blood progenitor stem cells has been associated with endothelial dysfunction. Generalized cellular dysfunction is recognized in diabetics due to the hyperglycemic state and resultant increased exposure to AGEs. The Voos study demonstrated that AGEs inhibited both the proliferation and migration of stem cells and induced the production and release of pro-inflammatory cytokines. In this case of AGEs stimulated production of cytokines, especially TNF-α (tissue necrosis factor alpha) inhibited stem cell growth and migration. This is yet another example of how AGEs can cause stem cell loss of viaility.
The fact that AGEs inhibited the proliferation of progenitor cells in diabetics is not surprising. What is surprising is that even in young, apparently healthy, individuals this can be the case. In a study by Ueda et al (5) demonstrated that the serum level of AGEs was correlated with decreased of circulating endothelial progenitor stem cells in apparently healthy subjects thus showing that “AGEs may be a biomarker that could predict the progression of atherosclerosis and future cardiovascular events” later in life. So we see here how AGEs’ affect stem cells and in so doing hasten this aspect of aging.
- Lopez-Otin, C. et al, The Hallmarks of Aging, 2013, Cell, 153, 1194-1205
- Conboy, I.M., Rondo, T.A., Heterochronic parabiosis for the study of the effects of aging on stem cell and their niches, 2012, Cell Cycle, 11, 2260-2267
- Larsen, S., et al, Glucose metabolite glyoxal induces senescence in telomerase-immortalized human mesenchymal stem cells, 2012, Chem Cent J, 6:18
- Voo S., et al, Diabetes mellitus impairs CD133+ progenitor cell function after myocardial infunction, 2009, J. Intern Med 265:238-249
- Ueda, S., st al, Serum levels of advanced glycation end products (AGEs) are inversely associated with the number and migratory activity of circulating endothelial progenitor cells in apparently healthy subjects. 2012, Cardiovasc Ther 30 (4) 249-54
Nick Pokoluk is a biochemist, certified Six Sigma Black Belt and certified wellness coach with over forty years experience in the pharmaceutical, medical device and wellness industries and is currently Director of Research for Troy Healthcare, LLC. npokoluk@wwtpi.com and on twitter @veganbiochemist
