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

Tomoaki Uchiki, Karen A. Weikel, Wangwang Jiao, Fu Shang, Andrea Caceres, Dorota Pawlak, James T. Handa, Michael Brownlee, Ram Nagaraj, Allen Taylor

Research output: Contribution to journalArticle

Abstract

Epidemiologic studies indicate that the risks for major age-related debilities including coronary heart disease, diabetes, and age-related macular degeneration (AMD) are diminished in people who consume lower glycemic index (GI) diets, but lack of a unifying physiobiochemical mechanism that explains the salutary effect is a barrier to implementing dietary practices that capture the benefits of consuming lower GI diets. We established a simple murine model of age-related retinal lesions that precede AMD (hereafter called AMD-like lesions). We found that consuming a higher GI diet promotes these AMD-like lesions. 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. 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, suggesting that higher GI diets induce systemic glycative stress that is etiologic for lesions. Data from live cell and cell-free systems show that the ubiquitin-proteasome system (UPS) and lysosome/autophagy pathway [lysosomal proteolytic system (LPS)] are involved in the degradation of AGEs. Glycatively modified substrates were degraded significantly slower than unmodified substrates by the UPS. Compounding the detriments of glycative stress, AGE modification of ubiquitin and ubiquitin-conjugating enzymes impaired UPS activities. Furthermore, ubiquitin conjugates and AGEs accumulate and are found in lysosomes when cells are glycatively stressed or the UPS or LPS/autophagy are inhibited, indicating that the UPS and LPS interact with one another to degrade AGEs. Together, these data explain why AGEs accumulate as glycative stress increases.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalAging Cell
Volume11
Issue number1
DOIs
StatePublished - Feb 2012

Keywords

  • Age-related macular degeneration
  • Aging
  • Glycemic index
  • Proteolysis
  • Ubiquitin

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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