Glycation‐altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age‐related disease (in nondiabetics)

A simple murine model of age-related retinal lesions that precede AMD (AMD-like lesions) was established.

“We established a simple murine model of age-related retinal lesions that precede AMD (hereafter called AMD-like lesions).”

Consuming higher GI diets is associated with >3-fold higher accumulation of AGEs in retina, lens, liver, and brain in age-matched mice.

“Consuming higher GI diets was associated with >3 fold higher accumulation of advanced glycation end products (AGEs) in retina, lens, liver and brain in the age-matched mice”

• Also stated in: § Consuming lower GI diets delays AMD-like lesions · plain

  “We observed ∼3, 7, 8 and 34 fold higher levels of MG-H1 in retina, liver, lens and brain (primarily substantia nigra) from mice of the same age that consumed the higher –as opposed to the lower –GI diet (Figure 2 A-D).”

Mice that consumed the lower versus higher GI diet had significantly reduced severity of hallmark age-related retinal lesions such as basal deposits (p<0.05).

“However, mice that consumed the lower vs. higher GI diet had significantly reduced frequency (p<0.02) and severity (p<0.05) of hallmark age-related retinal lesions such as basal deposits.”

• Also stated in: § Consuming lower GI diets delays AMD-like lesions · plain

  “Notably, eating the lower GI diet was associated with less deposition of basal laminar deposits (p=0.02) and smaller basal laminar deposits (p=0.05; Figure 1B, Figure S1A, B).”

The ubiquitin-proteasome system (UPS) and lysosome/autophagy pathway (LPS) are involved in the degradation of AGEs.

“Data from live cell and cell free systems show that the ubiquitin-proteasome system (UPS) and lysosome/autophagy pathway (LPS) are involved in the degradation of AGEs.”

• Also stated in: § A UPS and an autophagic-LPS collaborate to remove AGEs · hedged

  “Taken together, these data provide the first indication that a UPS and LPS both play roles in the removal of AGEs and they indicate a dynamic flux of AGEs and ubiquitinated species between these compartments.”

Glycatively-modified substrates are degraded significantly slower than unmodified substrates by the UPS.

“Glycatively-modified substrates were degraded significantly slower than unmodified substrates by the UPS.”

• Also stated in: § Glycation induced reduction in UPS proteolytic activity · plain

  “Consistent with findings that total proteolysis is depressed upon glycative stress, glycation of these substrates decreased their susceptibility to degradation (Figure 3D-H)”

Mice that consumed the lower versus higher GI diet had significantly reduced frequency of hallmark age-related retinal lesions such as basal deposits (p<0.02).

“However, mice that consumed the lower vs. higher GI diet had significantly reduced frequency (p<0.02) and severity (p<0.05) of hallmark age-related retinal lesions such as basal deposits.”

• Also stated in: § Consuming lower GI diets delays AMD-like lesions · plain

  “Notably, eating the lower GI diet was associated with less deposition of basal laminar deposits (p=0.02) and smaller basal laminar deposits (p=0.05; Figure 1B, Figure S1A, B).”

AGE-modification of ubiquitin and ubiquitin conjugating enzymes impairs UPS activities.

“Compounding the detriments of glycative stress, AGE-modification of ubiquitin and ubiquitin conjugating enzymes impaired UPS activities.”

• Also stated in: § Glycation induced reduction in UPS proteolytic activity · hedged

  “Taken together, these data indicate that the degradation of AGE-modified proteins requires UPS capacities, and that glycation impairs the ability of ubiquitin and ubiquitin conjugating enzymes to catalyze ubiquitination.”

Eating the lower GI diet was associated with less deposition of basal laminar deposits (p=0.02).

“Notably, eating the lower GI diet was associated with less deposition of basal laminar deposits (p=0.02) and smaller basal laminar deposits (p=0.05; Figure 1B, Figure S1A, B).”

Glycation is without effect on proteasomal activity.

“Surprisingly, glycation is without effect on proteasomal activity (Figure 5E).”

1.5-fold higher levels of AGEs were observed in 22 month old versus 3 month old mouse brains from animals that consumed the same diet.

“and 1.5 fold higher levels of AGEs in 22 month old vs. 3 month old mouse brains from animals that consumed the same diet (Figure S1D, E).”

HOMA-IR levels were higher for high-GI fed mice than low-GI fed mice.

“albeit that HOMA-IR levels were higher for the high-GI fed mice than the low-GI fed mice (Weikel, manuscript in preparation)”

Glycation of αA162 and glutathiolated γ-C crystallin decreased their susceptibility to degradation.

“Consistent with findings that total proteolysis is depressed upon glycative stress, glycation of these substrates decreased their susceptibility to degradation (Figure 3D-H)”

AGEs were subsequently cleared after removal of MGO.

“The AGEs were subsequently cleared after removal of MGO (Figure 3B).”

AGEs are distributed throughout the retina and specifically in areas where AMD-related lesions are found-RPE, Bruch's membrane, and choroid.

“Importantly, immunohistochemical analysis shows that AGEs are distributed throughout the retina and specifically in areas where AMD-related lesions are found- i.e. the RPE, Bruch's membrane and the choroid (Figure 2F vs. E, purple, Figure 1B)”

The ability of Ubc4 to support ubiquitin conjugate formation was inversely related to the extent of glycation.

“However, the ability of Ubc4 to support ubiquitin conjugate formation was inversely related to the extent of glycation (Figure 5C lanes 2-5).”

Addition of equivalent levels of glycated ubiquitin resulted in far lower levels of ubiquitin conjugates than addition of wild-type or modified ubiquitin.

“However, addition of equivalent levels of glycated ubiquitin resulted in far lower levels of conjugates (Figure 5A lanes 3, 4 vs. 2).”

Exposure to 1.7 or 2.5 mM MGO reduced the rate of intracellular protein degradation by 60% and >80%, respectively.

“Exposure to only 1.7 or 2.5 mM MGO reduced the rate of intracellular protein degradation by 60% and >80%, respectively (Figure 3C, left and right panels), coincident with the observed accumulation of AGEs in RPE cells (Figure 3A).”

A major role for the UPS in the degradation of both unmodified and MGO-modified αA162 and glutathiolated γ-C crystallin was confirmed since the degradation was dependent upon ATP.

“A major role for the UPS in the degradation of both unmodified and MGO-modified αA162 and glutathiolated γ-C crystallin was confirmed since the degradation was dependent upon ATP (Figure 3D), a hallmark for the UPS”

Feeding C57BL/6 mice a lower GI diet results in smaller changes in blood glucose levels following intake of glucose.

“The data in Figure 1A establish that feeding C57BL/6 mice a lower GI diet results in smaller changes in blood glucose levels (upper panel), represented as area under the blood glucose curve (AUC) (lower panel), following intake of glucose.”

AGEs accumulate rapidly at rates that are proportionate to the extent of glycative stress.

“AGEs accumulate rapidly at rates that are proportionate to the extent of glycative stress (Figure 3A, also see next section).”

Vastly higher levels of protein carbonyls, a marker of oxidative stress, were observed in retinas of C57BL6 mice fed the higher GI diet.

“Furthermore, vastly higher levels of protein carbonyls (Figure S2), a marker of oxidative stress, were observed in retinas of these and other C57BL6 mice fed the higher GI diet.”

Brief pretreatment of reticulocyte or RPE lysates with MGO significantly impeded the degradation of exogenous unmodified αA162, a model substrate of the UPS.

“Corroborating that glycative stress impairs the catalytic competence of the UPS, we observed that brief pretreatment of reticulocyte or RPE lysates with MGO significantly impeded the degradation of exogenous unmodified αA162, a model substrate of the UPS (Figure S5A,B).”

Eating the lower GI diet was associated with smaller basal laminar deposits (p=0.05).

“Notably, eating the lower GI diet was associated with less deposition of basal laminar deposits (p=0.02) and smaller basal laminar deposits (p=0.05; Figure 1B, Figure S1A, B).”

An 8-fold higher level of MG-H1 was observed in a 76 year old versus a 22 year old human lens.

“Consistent with prior data from various tissues, we observed an 8-fold higher level of MG-H1 in a 76 year old vs. a 22 year old human lens”

Prior to clearance, AGEs were initially in detergent soluble and insoluble fractions.

“Prior to clearance, the AGEs were initially in detergent soluble and insoluble fractions (Figure S9C i.e. lanes 6, 11).”

AGE levels are elevated in the basal areas of affected RPE.

“Levels of AGEs appear to be elevated in the basal areas of affected RPE (Figure 2)”

• cites Farboud et al., 1999Not checked yet

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• cites Crabb et al., 2002Not checked yet

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Glycative stress is related to accumulation of ubiquitin conjugates.

“Glycative stress was also related to accumulation of ubiquitin conjugates.”

Glycative stress induces perturbation of LPS activity.

“We also observed glycative stress-induced perturbation of LPS activity (Figure 6).”

When AGEs and ubiquitin conjugates are chased to the lysosome, they collect at the membranes rather than being effectively internalized.

“When they are chased to the lysosome, they appear to collect at the membranes rather than being effectively internalized where they might be more readily degraded.”

The UPS and LPS in cultured RPE cells can clear AGEs even after exposure to relatively high concentrations of MGO.

“The ability of the UPS and LPS in cultured RPE cells to clear AGEs, even after exposure to relatively high concentrations of MGO, is in keeping with the biological resiliency and function of these cells.”

The study established the first mammalian model in which consuming a lower GI diet is associated with delayed appearance of AMD-like lesions.

“we established the first mammalian model in which consuming a lower GI diet is associated with delayed appearance of AMD-like lesions.”

Animals of the same age that consumed the higher GI diet have higher levels of intracellular AGEs in diverse tissues.

“Furthermore, we observed higher levels of intracellular AGEs in diverse tissues from animals of the same age that consumed the higher GI diet.”

Glycatively stressed RPE has increased levels of ubiquitin conjugates.

“Our finding increased levels of ubiquitin conjugates in many age-related debilities, when cells confront chronic stress (Taylor et al., 2002), and in glycatively stressed RPE”

On average, the lysosomal AGEs are comprised of proteins with higher masses.

“On average, the lysosomal AGEs are comprised of proteins with higher masses.”

AGEs were cleared first from the soluble fraction and only subsequently from the insoluble fraction.

“However, they were cleared first from the soluble fraction and only subsequently from the insoluble fraction (Figure S9C i.e. lanes 9, 14).”

Inhibition of proteolytic potential by blocking the UPS and LPS resulted in a doubling of the ratio of AGEs/ubiquitin conjugates in the ubiquitin conjugate pool in MGO-exposed cells.

“Further, inhibition of proteolytic potential by blocking the UPS and LPS resulted in a doubling of the ratio of AGEs/ubiquitin conjugates in the ubiquitin conjugate pool in MGO exposed cells (lanes 8 vs. 6).”

As AGEs and ubiquitin conjugates accumulate, a greater proportion of these moieties is directed to the insoluble fraction.

“It is noteworthy that the more AGEs and ubiquitin conjugates accumulate, the greater the proportion of these moieties that is directed to the insoluble fraction.”

Observation of >70% higher levels of the most AGEs when MGO-treated cells were exposed to 3MA suggests that autophagic-lysosomal proteolysis is involved in degradation of AGEs.

“The observation of >70% higher levels of the most AGEs when MGO treated cells were exposed to 3MA suggests that autophagic-lysosomal proteolysis is involved in degradation of AGEs (Figure 6A, lane 10 vs. 7 or 14 vs. 11, Figure S6A, lane 6 vs. 3).”

Within the lysosomal fraction, the highest proportion and vast majority of AGEs, including the highest mass moieties, were in the membrane fraction with only low levels in the lumen.

“As noted in Figure S8B (right panel), within the lysosomal fraction the highest proportion and the vast majority of the AGEs, including the highest mass moieties, were in the membrane fraction with only low levels being found in the lumen.”

The phenomenon is systemic, affecting the proteome in retina, brain, and lens.

“The phenomenon is systemic, affecting the proteome in tissues with the highest levels of oxygenation, rapid metabolism and protein turnover (retina and brain) as well as the lowest oxygen tension, slowest metabolism and rates of overall protein turnover (lens).”

In cells exposed briefly to 1mM MGO, AGEs accumulated rapidly.

“In cells that were exposed briefly to 1mM MGO AGEs accumulated rapidly (Figure 3B, Figure 6A lane 2 vs. 1).”

There is a positive relationship between dietary GI and glycative stress-associated lesions.

“In this work, we describe a previously undocumented positive relationship between dietary GI and glycative stress-associated lesions”

At 14hrs after MGO exposure, cells treated with 1mM MGO and UPS or LPS inhibitor retained ∼2-fold higher levels of MG-H1.

“Importantly, at 14hrs after the MGO exposure, cells that had been treated with 1mM MGO and UPS or LPS inhibitor retained ∼2-fold higher levels of MG-H1”

Greater levels of AGEs in cells exposed to both UPS and LPS inhibitors compared to cells exposed to only UPS or LPS inhibitors is consistent with a synergistic role for the LPS and UPS in removal of AGEs.

“The greater levels of AGEs (especially of higher mass) in cells exposed to both UPS and LPS inhibitors compared to cells exposed to only UPS or LPS inhibitors (Figure 6C, top panel, compare lanes 5 vs. 2-4) is consistent with a synergistic role for the LPS and UPS in removal of AGEs.”

Diet-induced systemic glycative stress is etiologic for AMD-like lesions.

“suggesting diet-induced systemic glycative stress that is etiologic for lesions.”

Consuming a higher GI diet promotes AMD-like lesions in mice.

“We found that consuming a higher GI diet promotes these AMD-like lesions.”

• Also stated in: § Consuming lower GI diets delays AMD-like lesions · boosted

  “Since the only difference between the groups was the GI of their food, it is clear that consuming lower GI diets is associated with delayed risk for AMD-like lesions in these mice.”

AGEs accumulate in drusen, clinical markers of early AMD that develop posterior to the retinal pigment epithelial cells (RPE).

“Recent reports document accumulation of advanced glycation end products (AGEs) in drusen, clinical markers of early AMD that develop posterior to the retinal pigment epithelial cells (RPE) (Ishibashi et al., 1998; Farboud et al., 1999; Crabb et al., 2002).”

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• cites Farboud et al., 1999Not checked yet

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• cites Crabb et al., 2002Not checked yet

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The UPS and LPS interact with one another to degrade AGEs.

“indicating that the UPS and LPS interact with one another to degrade AGEs.”

• Also stated in: § A UPS and an autophagic-LPS collaborate to remove AGEs · hedged

  “These apparent functional relationships between the UPS and LPS when cells are under glycative stress are also indicated by finding higher levels of ubiquitin conjugates when cells were treated with higher levels of lysosomal inhibitor (Figure S9A, compare lanes 10-12 vs. 4-6).”

Epidemiologic studies indicate that risks for major age-related debilities including CHD, diabetes, and AMD are diminished in people who consume lower glycemic index diets.

“Epidemiologic studies indicate that the risks for major age-related debilities including CHD, diabetes, and age-related macular degeneration (AMD) are diminished in people who consume lower glycemic index (GI) diets”

• Also stated in: § Introduction · boosted

  “Importantly, it has recently been demonstrated that consuming lower glycemic index (GI) diets is associated with diminished risk for onset or progress of AMD, major age-related life threatening and life-quality limiting debilities including coronary heart disease (CHD), type 2 diabetes, and possibly age-related cataract even in non diabetic subjects”

• cites Salmeron et al., 1997Not checked yet

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• cites Augustin et al., 2002Not checked yet

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• cites Chiu et al., 2007aNot checked yet

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Together these data explain why AGEs accumulate as glycative stress increases.

“Together these data explain why AGEs accumulate as glycative stress increases.”

AGEs have been etiologically related to disease.

“AGEs have also been etiologically related to disease (Chylack et al., 1994; Chylack, 1999; Tian et al., 2005; Tezel et al., 2007; Glenn & Stitt, 2009).”

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• cites Chylack, 1999Not checked yet

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• cites Tian et al., 2005Not checked yet

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The lesions observed in the murine model are similar to alterations that precede AMD in humans.

“The lesions we observed are similar to alterations that precede AMD in humans (Rattner & Nathans, 2006).”

• cites Rattner & Nathans, 2006Not checked yet

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The age-related accumulation of AGEs is due, at least in part, to their resistance to degradation.

“These data support the idea that the age-related accumulation of AGEs is due, at least in part, to their resistance to degradation.”

Glycation impairs the ability of ubiquitin and ubiquitin conjugating enzymes to catalyze ubiquitination.

“and that glycation impairs the ability of ubiquitin and ubiquitin conjugating enzymes to catalyze ubiquitination.”

RPE have the highest proteolytic burden in the body as they engulf and must digest the outer 10% of photoreceptors that are shed every night.

“RPE have the highest proteolytic burden in the body as they engulf and must digest the outer 10% of photoreceptors that are shed every night.”

• cites Snodderly et al., 2002Not checked yet

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Consuming lower GI diets is associated with delayed risk for AMD-like lesions in these mice.

“Since the only difference between the groups was the GI of their food, it is clear that consuming lower GI diets is associated with delayed risk for AMD-like lesions in these mice.”

Exposure to glycative stress results in limited proteolytic potential, consistent with accumulation of AGEs and carbonyls in tissues from high versus low dGI mice.

“These data confirm that exposure to glycative stress results in limited proteolytic potential, consistent with accumulation of AGEs and carbonyls in tissues derived from the high vs. low dGI mice.”

Using a high GI diet, the accumulation of AGEs and other markers of oxidative stress that occurs in the human retina upon aging and AMD can be replicated in the mouse retina, and specifically in RPE.

“Thus, using a high GI diet we can replicate in the mouse retina, and specifically in RPE, the accumulation of AGEs and other markers of oxidative stress that occurs in the human retina upon aging and AMD (Crabb et al., 2002).”

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There appears to be a vicious cycle of diet and metabolism-induced glycative stress, accumulation of AGEs, and attenuated cell and tissue protein homeostasis and dynamics.

“Thus, there appears to be a vicious cycle of diet and metabolism-induced glycative stress, accumulation of AGEs, and attenuated cell and tissue protein homeostasis and dynamics.”

Accumulation of AGEs after brief exposures to higher levels of MGO suggests that the protein degradation machinery cannot keep pace with rates of AGE formation.

“Their accumulation after brief exposures to higher levels of MGO suggests that the protein degradation machinery, which is involved in removing such AGEs, cannot keep pace with rates of AGE formation.”

Substrates that are ubiquitinated with glycated ubiquitin act as inhibitors of UPS-dependent degradation similar to the conjugation-competent but proteolytically incompetent K6W-Ub variant.

“These data indicate that substrates that are ubiquitinated with glycated ubiquitin act as inhibitors of UPS dependent degradation similar to the conjugation competent but proteolytically incompetent K6W-Ub variant (Figure 5B, lane 3)”

The dietary-carbohydrate blood-glucose relationships established in humans and other mouse models can be replicated in mice.

“These findings show that we can replicate in mice the dietary-carbohydrate blood-glucose relationships that had been established in humans and other mouse models (Jenkins et al., 2002; Scribner et al., 2008; van Schothorst et al., 2008; Isken et al., 2009).”

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• cites Scribner et al., 2008Not checked yet

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• cites van Schothorst et al., 2008Not checked yet

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Glycative stress of RPE in culture is an appropriate model for determining mechanisms by which glycative stress promotes accumulation of AGEs and other pathobiochemical and pathophysiologic events in the aging retina.

“The data indicate that glycative stress of RPE in culture is an appropriate model for determining mechanisms by which glycative stress promotes accumulation of AGEs and other pathobiochemical and pathophysiologic events in the aging retina.”

The degradation of AGE-modified proteins requires UPS capacities.

“Taken together, these data indicate that the degradation of AGE-modified proteins requires UPS capacities”

MGO is a primary glycating metabolite of glucose.

“MGO is a primary glycating metabolite of glucose (Brownlee, 2001).”

• cites Brownlee, 2001Not checked yet

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Conditions that favor formation of AGEs were previously associated with cytotoxicity, disease, oxidative stress, senescence and aging, and diminished cell viability.

“because conditions which favor formation of such AGEs were previously associated with cytotoxicity, disease, oxidative stress, senescence and aging, and diminished cell viability (Tessier et al., 1999; Ihnat et al., 2007; Goligorsky et al., 2009; Guix et al., 2009; Vlassara et al., 2009; Wei et al., 2009; Ahmed et al., 2010).”

• cites Tessier et al., 1999Not checked yet

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• cites Ihnat et al., 2007Not checked yet

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• cites Goligorsky et al., 2009Not checked yet

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Modified ubiquitins are less effectively incorporated into the high-mass ubiquitin conjugates that are usual substrates for degradation.

“This indicates that the modified ubiquitins are less effectively incorporated into the high-mass ubiquitin conjugates that are usual substrates for degradation.”

The reduced susceptibility to degradation of AGEs appears to be generalizable since it is observed with different substrates and various proteolytic systems.

“The reduced susceptibility to degradation of AGEs appears to be generalizable since it is observed with different substrates and various proteolytic systems (Figure 3D-H, Figure S4 F, G).”

Drusen in AMD patients contain ubiquitin conjugates.

“It was also shown that drusen in AMD patients contain ubiquitin conjugates (Ishibashi et al., 1998; Crabb et al., 2002)”

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• cites Crabb et al., 2002Not checked yet

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Age-related modification of proteins by sugars or potent glycating sugar metabolites such as MGO results in formation of AGEs such as hydroimidazolone adducts (MG-H1).

“Age-related modification of proteins by sugars or potent glycating sugar metabolites such as MGO, results in formation of AGEs such as hydroimidazolone adducts (MG-H1) (Brownlee, 2001; Thornalley et al., 2003; Pawlak et al., 2004).”

• cites Brownlee, 2001Not checked yet

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• cites Thornalley et al., 2003Not checked yet

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• cites Pawlak et al., 2004Not checked yet

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Effects of dietary GI management are separable from effects of diabetes.

“These data indicate that effects of dietary GI management are separable from effects of diabetes.”

The localization of AGEs in basal RPE is consistent with the localization of drusen, a hallmark of AMD in humans.

“consistent with the localization of drusen, a hallmark of AMD in humans (Ishibashi et al., 1998).”

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Under normal homeostatic conditions, the UPS and LPS maintain the proteome.

“This scheme proposes that under normal homeostatic conditions the UPS and LPS, functioning independently or in concert maintain the proteome (Figure 8, top).”

Glycative stress results in the accumulation of oligomeric AGE-modified ubiquitin conjugates.

“This finding is consistent with the hypothesis that glycative stress results in the accumulation of oligomeric AGE modified ubiquitin conjugates.”

Enrichment of a lysosomal fraction is indicated by observation of cathepsin D and LAMP in the lysosomal fraction and not in the cytosolic fraction.

“Enrichment of a lysosomal fraction is clearly indicated by observation of cathepsin D and lysosomal associated membrane protein (LAMP) in the lysosomal fraction (Figure S8A lanes 11-15) and not in the cytosolic fraction.”

The ability of UPS and LPS in cultured RPE cells to clear AGEs is in keeping with the biological resiliency and function of these cells.

“The ability of the UPS and LPS in cultured RPE cells to clear AGEs, even after exposure to relatively high concentrations of MGO, is in keeping with the biological resiliency and function of these cells.”

When sufficiently functional, these clearance mechanisms protect the RPE from the potential toxicity of AGEs.

“When sufficiently functional, these clearance mechanisms protect the RPE from the potential toxicity of AGEs.”

Limitations to proteolytic capacities along with protein aggregation and insolubilization are etiologic for many common age-related diseases.

“Such limitations to the proteolytic capacities along with protein aggregation and insolubilization are etiologic for many common age-related diseases (Miyata et al., 1997; Sebekova et al., 1998; Kasper et al., 1999; Woltjer et al., 2003; Stitt, 2005; Bedford et al., 2008; Chen et al., 2009; Thornalley & Rabbani, 2009).”

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• cites Sebekova et al., 1998Not checked yet

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• cites Kasper et al., 1999Not checked yet

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Dicarbonyls or other sugar metabolites promote protein modification, aggregation and crosslinking.

“As diagramed in Figure 8, bottom, dicarbonyls or other sugar metabolites promote protein modification, aggregation and crosslinking.”

Glycation may block degrons on substrates.

“Thus, degrons, or amino acid residues that encode susceptibility for degradation on substrates may be blocked.”

The accelerated and coincident accumulation of lesions and AGEs in animals that consumed the higher GI diet suggests that lesions and AGEs are etiologically related.

“The accelerated and coincident accumulation of lesions and AGEs, including carbonyls (Figures 2, S1, S2), in animals that consumed the higher GI diet suggests that these are etiologically related.”

Increased levels of ubiquitin conjugates occur in many age-related debilities when cells confront chronic stress.

“Our finding increased levels of ubiquitin conjugates in many age-related debilities, when cells confront chronic stress (Taylor et al., 2002)”

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Delayed clearance of AGEs in the presence of UPS and LPS inhibitors supports a role for both proteolytic pathways in their clearance.

“Delayed clearance of AGEs in the presence of the UPS and LPS inhibitors supports a role for both proteolytic pathways in their clearance as indicated for other types of altered proteins (Johnston et al., 1998; Kaganovich et al., 2008).”

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• cites Kaganovich et al., 2008Not checked yet

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Accumulation of AGEs when autophagy was inhibited is consistent with a role for an autophagic LPS in removing AGEs.

“The accumulation of AGEs when autophagy was inhibited is consistent with a role for an autophagic LPS in removing AGEs.”

Animals that consume higher GI diets confront elevated glycative stress.

“the data inform that animals that consume the higher GI diets confront elevated glycative stress”

Consuming lower GI diets is related to lower levels of glycation-related fluorescent products in the lens.

“recent reports that consuming lower GI diets is related to lower levels of glycation-related fluorescent products in the lens (Munch et al., 2011).”

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Diminishing glycative stress can be used to confer protection.

“diminishing such stress can be used to confer protection.”

The LPS is engaged upon AGE-accumulation-induced stress.

“Together, these data suggest that the LPS is engaged upon AGE-accumulation-induced stress.”

The inability of damaged proteins to reach an appropriate degradative compartment provides an explanation for the accumulation of insoluble ubiquitin conjugates and AGEs in many age-related syndromes including drusen and cataract.

“This inability of damaged proteins to reach an appropriate degradative compartment (the UPS in the cytosol or the lysosome) provides a novel additional explanation for the accumulation of insoluble ubiquitin conjugates and AGEs in many age-related syndromes including drusen and cataract (Jahngen-Hodge et al., 1992).”

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Colocalization of AGEs in MG-H1-positive puncta with lysosomes when MGO-exposed cells are pretreated with proteasome or lysosomal inhibitors corroborates that an LPS is involved in degradation of AGEs.

“Furthermore, the colocalization of AGEs in MG-H1-positive puncta with lysosomes when MGO-exposed cells are pretreated with proteasome or lysosomal inhibitors corroborates that an LPS is involved in degradation of AGEs (Figure S7, panels 3, 4, right).”

The efficacy of the affinity resin is demonstrated by the ability to recover a majority of the ubiquitin conjugates.

“The efficacy of the resin is demonstrated by our ability to recover a majority of the ubiquitin conjugates (Figure 7, lanes 5-8, bottom).”

Colocalization of ubiquitin conjugates and AGEs in lysosomes suggests that AGEs, some of which are conjugated to ubiquitin but not degraded by the UPS, are directed to the LPS for processing.

“Furthermore, such colocalization of ubiquitin conjugates and AGEs in lysosomes suggests that AGEs, some of which are conjugated to ubiquitin but not degraded by the UPS, are directed to the LPS for processing.”

Insolubilization is a consequence of glycative stress.

“Insolubilization is a consequence of this stress.”

Ubiquitin conjugates increase in neurodegenerative disease and aging.

“conjugates increase in neurodegenerative disease and aging (Jahngen-Hodge et al., 1992; Crabb et al., 2002; Dudek et al., 2005; Bento et al., 2006; Shang, 2006; Maynard et al., 2009).”

• cites Jahngen-Hodge et al., 1992Not checked yet

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• cites Crabb et al., 2002Not checked yet

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• cites Dudek et al., 2005Not checked yet

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Glycative stress burdens the LPS, shuttling more substrates to the lysosome.

“The present results suggest that as with the UPS, glycative stress burdens the LPS, apparently shuttling more substrates to the lysosome.”

Accumulation of AGEs during aging is an indicator of age-related decreased capacity of UPS and LPS.

“accumulation of AGEs during aging (Figure S1) (Ahmed et al., 2003; Morcos et al., 2008) appears to be an indicator of age-related decreased capacity of UPS and LPS (Zhang & Cuervo, 2008; Tonoki et al., 2009; Rodriguez et al.).”

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• cites Morcos et al., 2008Not checked yet

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• cites Zhang & Cuervo, 2008Not checked yet

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Glycated ubiquitin may be incorporated into conjugates, rendering them less susceptible to degradation.

“Glycated ubiquitin may be incorporated into conjugates, rendering them less susceptible to degradation.”

Laboratory animal data provide in vivo corroboration of human epidemiologic associations between consuming lower GI diets and prolonged retinal health.

“In summary, these laboratory animal data provide in vivo corroboration of human epidemiologic associations between consuming lower GI diets and prolonged retinal health.”