Abstract
Laboratory and epidemiological data indicate that high blood sugar levels and/or consuming high glycemia diets are linked to multiple age-related diseases, including age-related macular degeneration, cataract, Parkinson’s disease, Alzheimer’s disease, diabetic retinopathy, and, apparently glaucoma. High concentrations of blood sugar and perturbations of the systems that regulate blood sugar lead to the accumulation of advanced-glycation end products (AGEs). AGEs are toxic compounds that are formed from the combination of sugars and their metabolites with biomolecules in a non-enzymatic biochemical reaction called glycation. In vitro and in vivo data indicate that high sugar consumption is associated with accumulation of AGEs in a variety of human tissues. Hyperglycemia, along with an oxidative environment and limited cell proliferation in many ocular tissues, encourages formation and precludes dilution of AGEs and associated damage by cell division. These circumstances make many eye tissues vulnerable to glycation-derived damage. Here, we summarize research regarding glycation-induced ocular tissue dysfunction and its contribution to the onset and development of eye disorders. We also discuss how management of carbohydrate nutrition may provide a low-cost way to ameliorate the progression of AGEs-related diseases, including age related macular degeneration and some cataracts, as they do for cardiovascular disease and diabetes.
Keywords: Advanced glycation-end products, Age-related macular degeneration, Diabetic retinopathy, Cataracts, Diabetes, Aging, Glycemic index, Cornea, Retina, Trabecular meshwork, Vitreous, Retina, Optic nerve
1. Introduction
The “western” lifestyle is spreading across the globe. Associated with this lifestyle is less activity and increased consumption of processed foods. A majority of processed foods contain added sugars or polysaccharides that are broken down rapidly to sugars which raise blood sugar levels (Popkin and Hawkes, 2016). Coincident with the increased adaptation to a western lifestyle is a rapid increase in the prevalence of metabolic syndrome, diabetes and obesity in both developing and industrialized countries, creating a major worldwide health hazard. The current dietary trend is not sustainable in terms of total cost of healthcare. Consequently, to counter the unhealthy dietary habits, governments are beginning to tax high calorie foods or restrict advertisement of unhealthy foods (NHMRC, 2013).
In order to optimize dietary practices, promote healthy aging, and develop policies that improve dietary practices, it is useful to evaluate and review the scientific literature regarding sugar intake and its effects on health. A growing number of reports indicate that chronic exposure to high glycemia diets contributes to increased risk for multiple human disorders including type II diabetes, cerebrovascular, cardiovascular and eye-related diseases. The latter include cataract, diabetic retinopathy and macular degeneration (Aragno and Mastrocola, 2017; Chiu and Taylor, 2011; Semba et al., 2010; Weikel et al., 2012a, 2012b). Although these diseases may have multiple and different etiologies, all of them have been linked to a common pathogenic factor that accelerates under hyperglycemic conditions: the formation of toxic advanced glycation end products (AGEs) (Weikel et al., 2012a, 2012b). Herein, we summarize the current literature that relates the pathological role of AGEs and the loss of function in ocular tissues. We discuss the advantages of nutritional interventions in AGEs-related diseases, highlighting the usefulness of consumption of low-glycemia diets in the management of blood sugar and its benefits for eye fitness.
2. Too much sugar increases AGEs and causes homeostatic imbalance
Current dietary guidelines for Americans recommend limiting sugar to no more than 10% of daily calories (NAS, 2017). However, these recommendations remain aspirational in America (Marriott et al., 2010). For an average man or woman, with average caloric intake of 2000 or 1600 calories, respectively, this would be 200 or 160 calories of sugar, respectively. For reference, one can of cola has about 39 g of sugar and an ice cream has about 15 g of sugar. On average, consumption is threefold the recommended levels (Marriott et al., 2010). Even in healthy individuals acute ingestion of fructose and glucose has been recently shown to lead to unfavorable metabolic and endocrine responses (Cai et al., 2018).
AGEs are a heterogeneous array of compounds that accumulate in multiple human tissues during normal aging and, especially, under conditions of hyperglycemia (Aragno and Mastrocola, 2017; Chiu and Taylor, 2011; Semba et al., 2010). Laboratory animal and human studies indicate that elevated blood sugar levels are associated with the accumulation of cytotoxic AGEs that are thought to play a role in the aging process as well as to contribute to the onset and exacerbation of age-related diseases (Frimat et al., 2017; Semba et al., 2010; Uchiki et al., 2012; Weikel et al., 2012b). AGEs accumulate particularly rapidly in tissues with a low capacity of regeneration (Semba et al., 2010; Weikel et al., 2012a, 2012b).
Retinal pigmented epithelia cells have the highest proteolytic burden in the body because each RPE cell must digest the outer tips of 30 photoreceptor cells that are shed each morning. Usually, RPE cells do not proliferate. The vast majority of lens cells also do not proliferate. Thus, in these cells, opportunities for dilution of AGEs by replication, or repair of AGEs-associated damage, are limited, making hyperglycemic conditions a major risk factor for eye diseases.
AGEs arise from two main sources: exogenous and endogenous. Exogenous AGEs are ingested and these are found at highest levels in cooked or highly processed foods (Uribarri et al., 2010; Vlassara et al., 2016). Upon digestion, AGEs can be absorbed and released into the blood (Koschinsky et al., 1997a). Nevertheless, only 10% of consumed AGEs are intestinally absorbed and one-third of these AGEs are quickly excreted in the urine within 48 h, thus removed from the circulation (He et al., 1999; Koschinsky et al., 1997b; Rabbani and Thornalley, 2015). In spite of the renal clearance of circulating AGEs, exogenous AGEs contribute around 30% of the total AGEs in our body (Uribarri et al., 2010) and increased levels of serum AGEs are found in patients with renal failure (Uribarri et al., 2003). Among dietary AGEs that are also found in plasma and urine are Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) (Scheijen et al., 2018).
Endogenously formed AGEs create the largest burden of AGEs in the body. These are formed in vivo as result of the exposure of biomolecules to reactive sugars. Thus, it is not surprising that elevated levels of different types of AGEs were described in diabetic conditions more than three decades ago (Ahmed et al., 1986; Miyata and Monnier, 1992; Sell et al., 1991). The formation of these endogenous AGEs requires several reactions between sugars (or their metabolites) with other biomolecules and these reactions are summed up by the term glycation. Glycation is a spontaneous chemical process in which unstable Schiff bases and Amadori products are formed through a reaction between α-amino group of the N-terminal amino acid or the ε-amino groups of lysines and arginines within proteins and the aldehyde or ketone group of the reactive sugar (Stitt, 2001). These intermediates of glycation are reversible and exist at levels that are proportional to the free sugar. However, they are unstable, and due to the complex biochemical processes of condensation, oxidation, re-arrangement, dehydration and degradative reactions, they form a myriad of irreversible, toxic and heterogeneous compounds. Collectively, these are called AGEs (Rabbani and Thornalley, 2015).
Curiously, the molecule of glucose is not a highly reactive sugar in most biological contexts, and AGEs formation derived directly from glucose might take weeks. However, other types of sugars (i.e. fructose) or intermediates derived from glycolysis (i.e. glyceraldehyde-3-phosphate or glucose-6-phosphate) are much more reactive, resulting in an accelerated production of reactive dicarbonyls that culminates in a faster production of AGEs (Hamada et al., 1996; Sadowska-Bartosz et al., 2014; Suarez et al., 1989) (Fig. 1). Of note, the high oxygen concentration and environmental oxidative stress in vascularized parts of the eye contribute to the processes of oxidation that accelerate AGEs formation, making them especially vulnerable to the accumulation of AGEs. Low protein turnover rates in the lens also result in high levels of AGEs in the aged lens, despite the lens being a low oxygen tension environment.
Fig. 1. Formation of AGEs and protective modulatory systems.
AGEs can be slowly formed from high concentration of blood sugar through the Maillard reaction (non-enzymatic chemical reaction between amino groups on proteins by reducing sugars) or faster through the reaction with alpha-dicarbonyls. Reactive dicarbonyls include methylglyoxal (MGO), glyoxal, or 3deoxyglucosane (3DG). AGEs include carboxymethyl-lysine (CML), carboxyethyl-lysine (CEL), methylglyoxal-derived hydroimidazolone (MGH1), etc. Protective anti-AGEs mechanisms (highlighted in green) consist of detoxifying routes such as glyoxalase pathway and protein quality control system that include ubiquitin-proteasome system (UPS) and autophagy.
Given the burden of high levels of AGEs, proficient cellular protective mechanisms are required to avoid their deleterious effects. There are multiple capacities to limit the accumulation of AGEs (Fig. 1, highlighted in green). One of these defense mechanisms is the glyoxalase system, a ubiquitous detoxification pathway that converts highly reactive AGEs intermediates (i.e. methylglyoxal or glyoxal) into less reactive biomolecules such as lactate or glycolate (Sousa Silva et al., 2013; Thornalley, 2003). The process involves the sequential activities of two thiol-dependent enzymes, glyoxalase І and glyoxalase ІI, that reduce methylglyoxal to lactate in the presence of glutathione (Thornalley, 2003).
Proteolytic pathways also contribute to protection by searching out and destroying intracellular AGEs. Two major degradative capacities are involved in the clearance of AGEs: the ubiquitin-proteasome system (UPS) and autophagy (Eisermann et al., 2017; Takahashi et al., 2017; Taylor, 2012; Uchiki et al., 2012) (Fig. 1). UPS is a degradative system in which soluble substrates are tagged with ubiquitin and targeted to the proteasome for degradation. Autophagy is a proteolytic route by which substrates are delivered into the lysosomes and degraded by lysosomal proteases. This releases amino acids for recycling. Although these two capacities were thought to be independent degradative routes, recent literature supports a crosstalk and interplay between UPS and autophagy (Bejarano and Cuervo, 2010; Ji and Kwon, 2017). Information about the nature of the AGEs that are targeted for degradation to either proteolytic system or which molecular determinants are involved in the delivery of AGEs is scanty (Uchiki et al., 2012). Recent findings from our group indicate that the UPS and autophagy remove different populations of toxic AGEs, as reported for other pathogenic proteins (Caballero et al., 2018; Ciechanover and Kwon, 2015). The induction of autophagy could also be a compensatory mechanism or complementary capacity when UPS function is insufficient (i.e. after the glycative inhibition of proteasome subunits) (Moheimani et al., 2010; Queisser et al., 2010; Uchiki et al., 2012).
In sum, the human body has defense mechanisms to avoid the burden of AGEs. Nevertheless, consumption of high sugar diets, altered glucose metabolism conditions (i.e. diabetes, insulin resistance or hyperglycemia) or the decline of proteolytic activities with age (Morimoto and Cuervo, 2014) may lead to the accelerated formation and accumulation of these damaging compounds in many tissues.
3. Pathophysiology of AGEs in ocular tissues
Although the exact pathogenic mechanisms remain to be elucidated, emerging evidence suggests a significant role for AGEs in the etiology of multiple age-related disorders, including ocular diseases (Kandarakis et al., 2014; Semba et al., 2010; Shang and Taylor, 2012; Stitt, 2001; Weikel et al., 2012a). AGEs are deposited intracellularly or in the extracellular environments thus participating in the onset of the ocular damage in different ways (Fig. 2). For example, AGEs in circulation may bind at the plasma membrane to cell surface receptors, including scavenger receptors. The best-studied AGE-receptor is called receptor for advanced glycation end-products (RAGE or also AGER), a transmembrane receptor of the immunoglobulin superfamily (Neeper et al., 1992). When AGEs are bound to RAGE, several signaling pathways are activated, including Ras/MAPK/NF-κB, JAK/STAT, and Rac1/Cdc42 leading to oxidative stress and NF-κB activation (Huang et al., 2001; Hudson et al., 2008; Lander et al., 1997) Other receptors capable of binding AGEs are AGE-R1/OST-48/p60, AGE-R2/80K-H/p90, AGE-R3/ galectin-3, SR-A (I/II), SR-B/CD36, SR-BI, SR-E/LOX-1, FEEL-1/FEEL-2 (Araki et al., 1995; Jono et al., 2002; Li et al., 1996; Ohgami et al., 2001a, 2001b, 2002; Tamura et al., 2003; Vlassara et al., 1995).
Fig. 2. Pathophysiology of AGEs in ocular tissues.
AGEs can 1) accumulate extracellularly and alter the biochemical properties of the extracellular matrix, 2) bind to plasma membrane receptor, triggering nuclear translocation of specific transcription factors or 3) AGEs formed intracellularly induce protein-crosslinking that alter conformational structure of proteins affecting their activities. Accumulation of elevated levels of intracellular aggregates is thought to be cytotoxic.
Alternatively, glycation per se can modify biochemical properties of specific proteins, altering intramolecular function and protein-protein interactions by intermolecular crosslinking and interfering with the functionality of those glycated targets. Typical examples are the glycation of proteins in the extracellular matrix (i.e. collagens fibers) and glycation of intracellular proteins such as crystallins in lens fiber cells (Fig. 2). For example, intracellular protein crosslinking, including glycation associated crosslinking, results in lens stiffening upon aging. Perhaps the trabecular meshwork is subject to the same influences (see below). Extracellular fibers are also modified via glycation-mediated crosslinks resulting in a loss of flexibility and enhanced susceptibility to mechanical stress (Dyer et al., 1993; Taylor et al., 1995).
In the following sections, we summarize the literature about the detection of AGEs in ocular tissues and their role in initiation and progression of sight threatening disorders.
3.1. Cornea
AGEs accumulate in the corneal stroma and lamina during normal aging. A specific example is glycation and crosslinking of corneal collagen (Malik et al., 1992). Some AGEs fluoresce. Higher values of corneal AGE fluorescence are found in patients with proliferative diabetic retinopathy compared to control subjects (Sato et al., 2001). Furthermore, enhanced levels of AGEs are detected in diabetic cornea with a more prominent reactivity in stroma, basal laminae and Bowman’s membrane. Importantly, collagen crosslinking appears to be involved in the central corneal thickening, which alters corneal biomechanics properties (Brummer et al., 2011; Kaji et al., 2000; Sady et al., 1995). In vitro data showed that AGEs can delay corneal epithelial wound healing and also induce apoptosis in human corneal epithelial cells through increased generation of intracellular ROS via NADPH oxidase activation and upregulation of JNK and p38 MAPK pathways (Shi et al., 2013a, 2013b). Glycation in the stromal matrix is thought to increase aggregation of collagen fibrils in the cornea contributing to diabetic keratopathy (Kim et al., 2011; Zou et al., 2012). High concentrations of AGEs are also found in vivo in the corneal epithelium, basement membrane and stromal keratocytes of long-term diabetic monkeys and in streptozotocin-injected Sprague-Dawley rats (Kim et al., 2011; Zou et al., 2012).
3.2. Lens
The lens is probably the eye tissue in which the pathogenic role of AGEs has been best characterized at the molecular level both in normal aging and in a diabetic context (Abiko et al., 1999; Ahmed et al., 1997; Chellan and Nagaraj, 1999; Frye et al., 1998; Lyons et al., 1991; Matsumoto et al., 1997; Nagaraj et al., 2012; Pokupec et al., 2003; Stevens et al., 1978; Tessier et al., 1999; Zarina et al., 2000). The role of sugar in diabetic cataract has been extensively studied and several reports established a plasma glycemic threshold above which incidence of diabetic cataract increases exponentially (Nagaraj et al., 1996; Swamy-Mruthinti et al., 1999). Higher levels of AGEs are found in diabetic patients (Hashim and Zarina, 2011; Pokupec et al., 2003).
As might be expected, protein glycation increases dramatically with age (Raghavan et al., 2015; Tessier et al., 1999). Associated with this glycation are covalent crosslinking of crystallins, resulting in altered tertiary structure, and aggregation. Chaperone activity is also lost and lens fiber cell integrity is compromised (Chellan and Nagaraj, 1999; Shamsi et al., 2000). For example, αA-crystallin and γB-crystallin have been shown to be thus modified, resulting in aggregation, insolubility, and lens opacity (Beswick and Harding, 1987; Casey et al., 1995; Kumar et al., 2007; Nahomi et al., 2013; Perry et al., 1987).
The lens capsule is also a target for glycation. Recently, different AGEs were found accumulated in human lens capsules in an age-dependent manner, with higher levels observed in cataractous lens capsules compared to normal lens capsules (Raghavan et al., 2015). It was suggested that AGEs in the lens capsule could promote the TGFβ2-mediated fibrosis of lens epithelial cells during posterior capsule opacification (Raghavan et al., 2015).
In addition, in vitro and in vivo data support a cytotoxic effect of AGEs on the vitality of lens epithelial cells through the induction of apoptosis in a NF-κB-dependent manner, suggesting that AGEs accumulation might be a causative factor of injury to the lens epithelium (Hashim and Zarina, 2011; Kim et al., 2012). We also demonstrated that lens proteolytic potential is compromised upon aging (Jahngen-Hodge et al., 1992; Jahngen et al., 1986a, 1986b, 1990; Shang and Taylor, 1995). This would have the effect of accelerating accumulation of AGEs, and associated pathology.
Both carbohydrate restriction and calorie restriction, and compounds inhibiting the accumulation of AGEs have shown efficacy to delay cataract progress in humans and mice (Chiu et al., 2010; Nagaraj et al., 2002; Swamy-Mruthinti et al., 1996; Taylor et al., 1995). Several other studies report anti-cataract activity of dietary flavonoids through the reduction of glycation-induced protein aggregation (Du et al., 2017; Muthenna et al., 2012; Patil et al., 2016). Interestingly, treatment with an AGE cross-link breaker has been shown to be sufficient in disrupting aggregates from diabetic human lenses (Hollenbach et al., 2003).
3.3. Vitreous humor
Structural changes in the vitreous humor are associated with normal aging, but are detected earlier in diabetic conditions. These include posterior vitreous detachment and liquefaction (Gehl et al., 2016; Stitt et al., 1998; van Deemter et al., 2009). Glycation seems to play a pathologic role in vitreous degeneration in diabetic vitreopathy, and is associated with aberrant crosslinks in collagenous fibrils (Sebag et al., 1992). Glycated collagen dissociates from hyaluronan, a hydrophilic glycosaminoglycan, destabilizing the vitreous gel structure and causing morphological changes within the cortical gel, leading to vitreous dysfunction (Sebag et al., 1992; Stitt et al., 1998). From a chemical perspective, it is likely that the hyaluronan is also subject to glycative modification, but this remains to be fully investigated. Vitreous AGE-associated fluorescence increases in a glucose-concentration dependent manner in streptozotocin-induced diabetic rats (Villa et al., 2017). Data from ex vivo porcine vitreous show that AGEs accumulation compromises the vitreous permeability, thus impeding the diffusion of molecules (Lee et al., 2015). Changes in vitreous permeability might increase the retention of cytokines or drugs, with implications in the pathogenesis of ocular diseases such as diabetic retinopathy. High glucose concentrations in bovine vitreous recapitulates the phenotype of crosslinked-collagen fibers and, interestingly, the process is inhibited by aminoguanidine, an inhibitor of AGE formation (Stitt et al., 1998).
3.4. Retina
Similar to cornea, lens and vitreous, retinal AGEs increase with age and diabetes, especially in the outer retina. This insult has been proposed as a major pathological factor in age-related macular degeneration (AMD) (Glenn and Stitt, 2009; Karachalias et al., 2003; Nagaraj et al., 2012; Uchiki et al., 2012). Modification due to glycation is thought to lead to thickening and changes in the physical properties of Bruch’s membrane and extracellular matrix, causing a dysfunctional outer retina. Extracellular deposits, called drusen, and changes in biomechanical properties of Bruch’s membrane are two of the major early features of AMD. Interestingly, Bruch’s membrane and drusen deposits display high AGE-immunoreactivity in an age-dependent manner (Farboud et al., 1999; Handa et al., 1998, 1999). Additionally, higher AGEs levels are found in AMD-patients compared to control subjects as well as in AMD-mouse models (Hammes et al., 1999; Handa et al., 1999; Rowan et al., 2014, 2017; Uchiki et al., 2012; Weikel et al., 2012b). In addition, thickening of Bruch’s membrane and breakdown of the blood retinal barrier takes place even in non-diabetic animals when infused with pre-formed AGEs (Clements et al., 1998; Stitt et al., 2000).
Another complication is that high concentrations of AGEs result in aberrant levels of platelet derived growth factor B (PDGF-B) and vascular endothelial growth factor (VEGF). This is thought to contribute to the early vascular damage in diabetic retinopathy (Handa et al., 1998; Kandarakis et al., 2015; Lu et al., 1998; Murata et al., 1997). In addition, exposure to glycative stress compromises the vitality of cells within the retinal pigment epithelium (Reber et al., 2002; Roehlecke et al., 2016; Wang et al., 2016; Yamagishi et al., 2002). As indicated above, these cells are ultimately responsible for the maintenance of the functionality of photoreceptors and the integrity of choriocapillaris.
Hyperglycemia is also associated with compromises to inner vasculature, particularly in diabetic patients. This is associated with accumulation of AGEs in Müller glia (Chiarelli et al., 1999; Curtis et al., 2011; Gardiner et al., 2003; Hammes et al., 1998; Stitt et al., 1997). High levels of diet-induced AGEs have been associated with Müller glial malfunction in diabetic retinopathy (Curtis et al., 2011; Zong et al., 2010).
As with lens and cataract, compounds that inhibit AGEs formation delay the onset of diabetic retinopathy, at least in animal models (Gardiner et al., 2003; Hammes et al., 1991, 1994, 1995). Also, consistent with a role for AGEs in the initiation of diabetic retinopathy, the overexpression of glyoxalase 1, the limiting enzyme in the methylglyoxal-detoxifying glyoxalase system, reduces retinal AGEs in diabetic rats (Berner et al., 2012).
Recently it has been shown that specific loss of autophagy, one of the proteolytic activities involved in the clearance of AGEs, in the retinal pigment epithelium also induces AMD-features in an age-dependent manner with a concomitant accumulation of AGEs (Zhang et al., 2017). Compromised redox status of glycatively/oxidatively stressed RPE can also lead to cytotoxicity due to limited UPS activity (Jahngen-Hodge et al., 1997).
3.5. Optic nerve
Several reports suggest pathophysiological roles for AGEs in the development of optic neuropathy (Amano et al., 2001; Terai et al., 2012; Tezel et al., 2007; Wang et al., 2009). AGEs are detected in the lamina cribrosa, the collagenous matrix that supports the optic nerve axonal structure, and these levels increase with age (Albon et al., 2000). It is thought that glycation of matrix proteins might decrease the flexibility of the lamina cribrosa, negatively influencing the function of the optic nerve. Immunoreactivity of AGEs and the receptor RAGE in the optic nerve head is more prominent in eyes from glaucoma donors that in age-matched individuals (Tezel et al., 2007). AGE accumulations in the optic nerve, around vessel and in cribriform plates, are also described in streptozotocin-induced diabetic rats, as well as in diabetic patients (Amano et al., 2001; Terai et al., 2012). AGE inhibitors partially reduced the level of glycation in the optic nerve in aged rhesus monkeys and in streptozotocin-induced diabetic rats (Ino-ue et al., 1998; Kiland et al., 2009).
3.6. Trabecular meshwork
Degeneration of the trabecular meshwork leads to pathogenic elevated eye pressure in glaucoma, although the causes remain unknown. Hints about mechanism may be gleaned from in vitro experiments. Exposure to glycative stress enhances cellular senescence of cultured human trabecular meshwork cells and decreased survival (Park and Kim, 2012). However, to date it is unclear whether AGEs might affect the physiological function of the trabecular meshwork in vivo or if glycation might influence the intraocular pressure by altering the aqueous outflow pathway. By analogy to the other tissues discussed above, it seems reasonable to anticipate that protein crosslinking and accumulation of debris within the trabecular meshwork would exacerbate outflow and related to glaucoma. However, no association was found between primary open-angle glaucoma and RAGE polymorphisms (Moschos et al., 2017).
4. Glycemic index: nutritional intervention to fight AGEs-derived toxicity in the eye
Different approaches have been proposed to prevent the accumulation of AGEs and associated pathologies. While there have been some successes in reducing AGEs accumulation by inhibiting Amadori product formation, breaking AGEs crosslinks, or by preventing the interaction of AGEs with receptors at the plasma membrane (Engelen et al., 2013), delaying the formation of these moieties seems promise the most practical and simplest approach. We proposed that limiting dietary glycemia would optimize blood glucose levels, and limit formation of AGEs and the associated pathology in ocular tissues (Ludwig, 2002; Rowan et al., 2017; Uchiki et al., 2012; Weikel et al., 2012a; Whitcomb et al., 2015).
The recent, nascent literature is unanimous in suggesting that the consumption of lower glycemic index foods is salutary (Chiu and Taylor, 2011). For the same caloric content, lower glycemic index foods release glucose into the blood stream more gradually. For example, vegetables and whole grains are slowly digested, and release glucose gradually into the bloodstream, while white bread or refined sugar are foods that rapidly break down during digestion, and are easily converted into glucose that is quickly released into the blood. Crucially, every study published to date indicates that consuming lower glycemia diets diminishes risk for onset and progress of AMD and cortical cataract (Chiu et al., 2011; Chiu et al., 2006a, 2006b, 2007b, 2007a; Weikel and Taylor, 2011; Weikel et al., 2012a). Interestingly, a recent study reported that low-GI diets could exert a protective effect in retinal microvasculature (Sanchez-Aguadero et al., 2016). Together, this literature implies that changing diets from high to lower glycemia may provide a simple, low cost, readily achievable way to delay progress of AMD or even reverse it (Rowan et al., 2017). We calculate that by changing five slices of white bread to five slices of whole grain bread one can achieve healthier dietary glycemia. This would save about 100,000 people from AMD in 5 years (Chiu et al., 2006a, 2007a, 2007b; Kaushik et al., 2008). This data is consistent with findings that animals fed high-GI diets show an accumulation of AGEs and increased retinal lesions and AMD-like phenotypes (Rowan et al., 2017; Uchiki et al., 2012; Weikel et al., 2012b). Unfortunately, the typical American diet is a high-GI diet (Chiu and Taylor, 2011).
5. Conclusions and considerations for future research
Aging and hyperglycemia induce the accumulation of AGEs and a myriad of sequelle that compromise cellular and organ function. This includes compromises to cellular proteins and their functions, cellular protein editing capacities, limited flexibility, perhaps enhanced compression, limited outflow and increased pressure. Aging is associated with a decline of anti-AGE pathway capacities. A significant body of data suggests that AGEs play a pathological role in cataracts, AMD or diabetic retinopathy. Accumulation may also be involved in glaucoma or diabetic keratopathy as well as diabetic optic neuropathy. Intervention trials could be appropriate, but these are costly and time-consuming. Since they appear to be without risk for users, diets that emphasize whole grains would appear to confer benefits with regard to these diseases (Chiu et al., 2011; Chiu et al., 2007a, 2017; Hogg et al., 2017; Nunes et al., 2018; Weikel et al., 2012a). More elucidation of mechanisms would justify the required blinded control human studies that would confirm the laboratory and epidemiologic findings and pave the way for new dietary guidelines for Americans for preserving vision for the burgeoning elderly population.
Acknowledgments
This work was funded by NIH RO1 EY 13250, RO1 EY21212, RO1 EY26979, USDA contract 1950–510000-060–03A U.S. Department of Agriculture-Agriculture Research Service (ARS) and USDA AFRI Grant 12212122. The authors declare no competing financial interests. We are grateful to Elizabeth Whitcomb, Sheldon Rowan, Jonathan Volkin and Opeoluwa Olukorede for critical reading and editorial help.
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