Background
In the ageing population, decline in motor function such as reduced walking speed, poor balance, and loss of muscle strength are commonly observed phenomena [
1‐
4]. Most human physiologic systems regress with ageing, independently of substantial disease effects, at an average linear loss rate of 0.34–1.28 % per year between the age of 30 and 70 years [
5]. The age related loss of skeletal muscle mass, which is accompanied by muscle weakness, is an important contributor to functional decline [
6]. More people over the age of 70 are having difficulties performing everyday functions because of motor function related problems [
7]. Impaired motor function is a prominent characteristic of physical frailty and is associated with a wide range of adverse health consequences such as falls, disability, death, hospitalization, and institutionalization [
8,
9]. In addition to physical frailty, longitudinal studies suggest that a decreased level of motor function is associated with a decline of cognitive function and a subsequent development of both mild cognitive impairment and Alzheimer’s disease [
3]. A decline in motor function in older ages could be predicted by biomarkers which could allow for early interventions. Since the early 1980’s, it is proposed that the cross-linking of long-lived proteins mediated by Advanced Glycation End products (AGE’s) may contribute to the age-related decline of the functioning of cells and tissues in normal ageing. AGE’s could, therefore, be a potential biomarker and risk factor for the decline of motor function in the older population [
10].
Advanced glycation End products and ageing
The occurrence of AGE’s is mediated by non-enzymatic condensation of a reducing sugar with an amino group. AGE’s are spontaneously produced in human tissues as an element of normal metabolism which increases with aging [
11‐
14]. The increase of the level of free/unbound and protein bound AGE’s in the blood circulation is also determined by an exogenous intake such as food [
15]. AGE’s are being removed from the body through enzymatic clearance and renal excretion.
It has been proposed that, with ageing, there is an imbalance between the formation and natural clearance of AGE’s, leading to the accumulation of AGE’s in tissues [
16,
17]. In many age related diseases, the accumulation of AGE’s is a significant contributing factor in degenerative processes, especially in renal failure, blindness, cardiovascular diseases, and complications of diabetes mellitus [
13,
18]. Elevated AGE’s levels in patients with diabetes mellitus (DM) is most likely due to an excessive elevation of glucose concentration which consequently accelerates the glycation of proteins [
11,
13,
18]. Furthermore, AGE’s play a role in neurological disorders such as Alzheimer’s Disease (AD) [
13,
19]. Interestingly, Hobbelen et al. [
20] ascertained that patients in early stage of dementia and with DM had a significantly higher risk for the development of muscle stiffness/hypertonia (defined as paratonia) compared to those with dementia but without DM (OR = 10.7, 95 % CI:2.2–51.7). In early stage dementia, paratonia already negatively and significantly impacts functional mobility such as walking speed. As the most common cause of dementia, Alzheimer’s disease, as well as DM, are related to higher serum concentrations of AGE’s, the previous finding in the Hobbelen et al. study prompted the hypothesis that AGE’s may partly or indirect be responsible for the development of paratonia. The pathogenesis of paratonia is unclear and central nervous system changes as well as peripheral biomechanical changes are hypothesized [
20].
Several types of AGE’s have been described and can be categorised into fluorescent cross-linking AGE’s, non-fluorescent cross-linking AGE’s, and non-crosslinking AGE’s. The best chemically characterized AGE’s are Pentosidine (fluorescent cross-linking) and Carboximethyl-lysine (CML, non-cross-linking) [
21]. Cross-linking AGE’s are responsible for an increasing proportion of insoluble extracellular matrix and thickening of tissue as well as increasing mechanical stiffness and loss of elasticity [
12,
22,
23]. Cross-linking AGE’s are considered as being involved in the pathophysiology of arthritis [
24,
25]. In fact, the accumulation of AGE’s in human articular cartilage increases cartilage stiffness and brittleness. Consequently, the cartilage becomes increasingly prone to damage and degeneration [
26,
27]. In rheumatoid arthritis, elevated levels of cross-linking AGE’s in serum and/or synovial fluids also appear to correlate with the levels of inflammatory markers and the disease activity [
24]. Another impact on the musculoskeletal system is within the skeletal bone where AGE-induced crosslinks in the collagen matrix alter the mechanical properties of bone by increasing stiffness and fragility [
27‐
29]. Furthermore, significantly higher AGE’s levels were reported in patients with osteoporosis, thereby increasing the risk of fractures [
28,
30].
Non cross-linking effects are exerted by the binding of AGE’s to the receptor for AGE’s (RAGE). A wide variety of cells express RAGE, and the interaction with AGE’s incites activation of intracellular signalling, gene expression, and production of pro-inflammatory cytokines (such as Interleukin (IL)-6, Tumor Necrosis factor (TNF)-alpha), and free radicals. At the peripheral (tissue) level, these inflammatory processes exhibit powerful proteolytic activity whereby the collagen becomes more vulnerable and tissue elasticity decreases [
31,
32]. At the central level (central nervous system), interaction between AGE’s, Amyloid-beta and hyperphosphorylated tau-protein induce microglia and astrocytes to upregulate the production of reactive oxygen species, pro-inflammatory cytokines, and nitric oxide which affects neuronal function [
11,
32].
Numerous reviews [
16,
33‐
39] on the relation between AGE’s and motor function have been published, but the majority of these studies are narrative reviews and therefore showing most often an indirect relationship. The negative effect of accumulating AGE’s on the biomechanical properties of peripheral musculoskeletal tissues and the central nervous system (CNS), for example accumulation in specific relevant motor-related brain regions, will plausibly have an impact on motor function. However, evidence regarding this subject is fragmented, and a systematic review on this topic is lacking. Therefore, the aim of this study was to systematically review the literature for the direct relationship between circulating and/or tissue AGE’s and motor function.
Discussion
The results of this systematic review indicate that higher levels of AGE’s are independently related to declined walking abilities, inferior ADL, decreased muscle properties (strength, power, mass) and increased physical frailty.
The available literature on musculoskeletal outcomes [
43,
44,
48,
49] support the hypothesis that high AGE’s levels are associated with a decline in muscle function. However, the correlations, Beta coefficients and calculated effect sizes indicate only a moderate relationship. It is known that AGE’s can affect muscle function through a variety of pathways. In fact, AGE’s 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 [
43‐
46,
49,
51]. This is also consistent with studies on sarcopenia in which decreased muscle mass and strength is explained by an overall increase in inflammatory burden [
6]. 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 AGE’s on muscle tissue, thereby impairing muscle function [
45,
46]. It has been considered that impaired muscle function - through AGE’s-induced muscle damage – can contribute to decline in walking abilities and ADL and can also contribute to physical frailty.
It remains ambiguous to what extend ADL involving the upper extremity are affected by high AGE’s level. One small study [
50] reports a relation with upper extremity disability, but further we could not identify which ADL are affected most by AGE’s and if at all are related to upper extremity function. Thereby in a large study [
47] the reported increased risk in inferior ADL is described as the association between baseline AGE’s level and the time to first difficulty on any of the six self-reported ADL items and, although significant, the risk is low (HR = 1.10), therefore the practical importance is unclear.
Furthermore our review shows that the decline of handgrip strength is positively associated with higher AGE levels in three studies [
43,
44,
49]. Interestingly, in the upper extremity shoulder muscles no association with high AGE levels is found in two studies [
48,
50]. The underlying mechanism for this difference in the upper extremity remains unclear and further research is necessary on this topic.
We identified only 8 studies due to strict inclusion criteria for several reasons; 1) We restricted the inclusion to individual studies that reports a direct relationship between AGE’s and functioning which enabled us to calculate effect sizes, association coefficients etc. for direct comparison of the strength of the association. 2) To increase internal validity we were specifically interested in motor functioning so we excluded papers measuring solely an effect on tissue levels. 3) Also we did not include papers that only cover a specific disease (such as Diabetes) to increase external validity. As mentioned previously, AGE’s have an effect on different types of human tissues [
24,
26,
31,
32]. It must be considered that other AGE’s-induced effects, such as effects on the nervous system, ligaments, tendons or joint capsules, could contribute to the decline of physical performance and functions. Future research should, therefore, explore other possible underlying AGE’s related pathways, not only on the pathophysiological changes on the tissue level, but also with a direct relation on motor function.
The current systematic review shows that the relation between AGE’s and motor function is not as strong as most narrative reviews suggest. Although the quality of the included studies was good to moderate, they employed a cross-sectional or observational design, therefore, a causal relationship cannot be inferred. A meta-analysis was not appropriate because of the heterogeneity of the studies.
It is known that, in addition to cognitive decline, accompanying decline in motor function is frequently reported in patients with dementia [
52] and it is suggested that AGE’s formation may explain many biochemical and neuropathological changes in the most common cause of dementia [
13]. However, the results from this review provide no conclusive evidence for a peripheral or a central level effect of AGE’s on motor function in Alzheimer’s disease or other types of dementia. We were unable to locate any study describing the effect of AGE’s on the CNS with a direct relation on motor function. It remains unclear if AGE’s accumulate in specific relevant motor-related brain regions, having their effect on the complex inter-relationship between the distributed motor networks within the CNS as well as with the musculoskeletal structures for generating movement. Future research is required to determine the contribution of AGE’s accumulation on the CNS with a direct relation on the decline in motor function.
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 [
43,
45‐
47], and a relation with tissue CML was found in one study [
49]. One study reported an association with Pentosidine [
48] and two other studies with non-specified skin tissue fluorescent AGE’s [
44,
50]. 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 AGE’s pool [
53]. Although CML is a dominant AGE in blood circulation and correlates with other AGE’s [
14], it is possible that the association between AGE’s and motor function outcome could be different if crosslinking AGE’s such as Pentosidine were assessed.
In five studies, only females [
43,
46,
48] or males [
44,
49] were included, therefore, the reported decline in motor function with elevated AGE’s cannot necessarily be extrapolated to the other gender. Previous longitudinal studies conducted in a large cohort suggest that the relation between serum AGE’s and health elevated levels of serum AGE’s were associated with all-cause mortality, cardiovascular disease, and coronary heart disease mortality only in women [
54,
55]. In contradiction, Whitson et al. [
47] found a significant cross-sectional association between CML and physical activity, exhaustion, and muscle strength as components of physical frailty only among men and not among women. A possible explanation suggested by Whitson et al. is that aged cohorts may be subject to gender-specific survivor bias. They state that the relative significance of CML mediated factors in determining the risk of death is greatest for females prior to menopause but greater for men in advanced ages. If AGE’s have more effect on women, higher-risk women may then be unlikely to participate in studies that measure CML late in life due to the negative health outcomes [
47]. On the other hand, they did find an association with men and women in their longitudinal study on ADL disability. In a comparable cohort, Semba et al. [
45] reported a strong association between men and women and do not report any significant gender differences. Therefore, this raises an additional question of whether or not the effect of AGE’s could be gender specific. Future research should, therefore, include gender-based differences in the effects of AGE’s.
The vast majority of participants included in this review were elderly people older than 64 years (
n = 5433). Interestingly, in two studies [
44,
49], the participants were middle-aged between 37 and 56 years (
n = 387). This indicates that the negative effect of AGE’s on motor function already begins during midlife and, as AGE’s levels increase with ageing, could be an important factor in age related decline in motor function. A high AGE’s 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’s levels. Intensive glycaemic control may be a method to decrease AGE’s formation. CML levels correlate to dietary consumption [
14], therefore, dietary intake is a possible factor that can be influenced. It is suggested that, in order to lower daily AGE’s intake, foods rich in sugar and fat and those prepared by frying or grilling should be avoided [
14,
56]. However, evidence of the harmful effects of long-term exposure to dietary AGE’s is still inconclusive [
15]. Improvements of glycaemic control by regular physical exercise could also attenuate the formation and accumulation of AGE’s [
11,
21,
57]. Elevated AGE’s levels might be an indication to initiate (early) treatment such as dietary advice, muscle strengthening exercises, and functional training to maintain physical functions. However, literature regarding the effects of physical exercise on AGE’s formation is minimal, and the optimal exercise modalities remain ambiguous [
21]. Further research should focus on whether dietary modifications, exercise programs, or medication to reduce AGE’s levels can prevent or counter decline in motor function.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
HD is the first author and was responsible for the conception and design, the acquisition of data, the interpretation of data, and drafting the manuscript. SZ has been involved in the conception and design and has been involved in reviewing the manuscript critically for important intellectual content. SB has been involved in the quality assessment of the included studies, in the data extraction and reviewing the manuscript critically for important intellectual content. IB has been involved in reviewing and revising the manuscript critically for important intellectual content. CS has been involved in revising the manuscript critically for important intellectual content. HH has been involved in the conception and design, reviewing the manuscript critically for important intellectual content, and has given final approval of the version to be published. All authors read and approved the final manuscript.