In this open access review paper, researchers discuss the associations and possible contribution of advanced glycation end-product (AGE) accumulation to the age-related decline in motor function, though given that they focus on short-lived forms of AGE and omit mention of glucosepane, I suspect that the relevance of their conclusions is limited. The differences between types of AGE are important, and they can't all be lumped together based on the study of just one type. In particular the contribution to aging from AGEs that cross-link versus AGEs that promote inflammation is quite distinct.
Where do AGEs come from? They are a class of waste produced by the normal operation of cellular metabolism, and which can also arrive in the diet. They accumulate in tissues with advancing age. There are various types of AGE, but the important ones are the long-lasting varieties based on glucosepane that the body cannot effectively break down. They form cross-links in the extracellular matrix, degrading tissue function by altering its structural properties, as is the case in age-related loss of elasticity in skin and blood vessels. Other classes of AGEs - such as N(6)-carboxymethyllysine (CML) - are probably involved in different ways in the progression of age-related disease and especially in metabolic dysfunctions such as type 2 diabetes, as they can increase chronic inflammation through their interactions with cells. These types are better studied than glucosepane, but they can be broken down and cleared by our biochemistry, their levels are quite dynamic over short time frames, and it isn't completely clear as to the degree to which their accumulation is secondary to other forms of age-related dysfunction, or even to diet and lifestyle choices.To tackle the inexorable increase in glucosepane cross-links, however, it is definitely the case that a viable strategy is the development of therapies to clear these damaging and unwanted molecules.
Diminishing motor function is commonly observed in the elderly population and is associated with a wide range of adverse health consequences. Advanced Glycation End products (AGE's) may contribute to age-related decline in the function of cells and tissues in normal ageing. Although the negative effect of AGE's on the biomechanical properties of musculoskeletal tissues and the central nervous system have been previously described, the evidence regarding the effect on motor function is fragmented, and a systematic review on this topic is lacking. Therefore, a systematic review was conducted from a total of eight studies describing AGE's related to physical functioning, physical performance, and musculoskeletal outcome which reveals a positive association between high AGE's levels and declined walking abilities, inferior activities of daily living (ADL), decreased muscle properties (strength, power and mass) and increased physical frailty.
The available literature on musculoskeletal outcomes support the hypothesis that high AGEs levels are associated with a decline in muscle function. However, the correlations and calculated effect sizes indicate only a moderate relationship. It is known that AGEs can affect muscle function through a variety of pathways. In fact, AGEs can alter the biomechanical properties of muscle tissue, increasing stiffness and reducing elasticity through cross-linking and upregulated inflammation by RAGE binding and endothelial dysfunction in the intra-muscular microcirculation. This is also consistent with studies on sarcopenia in which decreased muscle mass and strength is explained by an overall increase in inflammatory burden. Examining the studies in this review that report decline in walking abilities, it is suggested by the authors that this decline is also attributed to the effects of AGEs on muscle tissue, thereby impairing muscle function. It has been considered that impaired muscle function - through AGEs-induced muscle damage - can contribute to decline in walking abilities and ADL and can also contribute to physical frailty.
It is important to realise that, in this review, decline in motor function was primarily associated with elevated CML levels. Association with circulating CML was determined in four studies, and a relation with tissue CML was found in one study. One study reported an association with Pentosidine and two other studies with non-specified skin tissue fluorescent AGEs. It is suggested that fluorescent and non-fluorescent AGE's such as CML behave similarly and fluorescence may be employed as a marker for the total skin tissue AGEs pool. Although CML is a dominant AGE in blood circulation and correlates with other AGEs, it is possible that the association between AGE's and motor function outcome could be different if crosslinking AGEs such as Pentosidine were assessed.
The vast majority of participants included in this review were elderly people older than 64 years. Interestingly, in two studies, the participants were middle-aged between 37 and 56 years. This indicates that the negative effect of AGEs on motor function already begins during midlife and, as AGE levels increase with ageing, could be an important factor in age related decline in motor function. A high AGE level, as a biomarker, therefore, could predict a decline in motor function later in life. This could also imply that preventive interventions should start as soon as possible as part of healthy ageing. In accordance with the results of this review, it would be interesting to investigate whether motor function can be improved by reducing AGE levels. Intensive glycaemic control may be a method to decrease AGEs formation. CML levels correlate to dietary consumption, therefore, dietary intake is a possible factor that can be influenced.