The pathological role of the non-enzymatic modification of
proteins by reducing
sugars has become increasingly evident in various disorders. It is now well established that early glycation products undergo progressive modification over time in vivo to the formation of irreversible cross-links, after which these molecules are termed "AGEs (
advanced glycation end products)". AGEs have been implicated in the development of many of the pathological sequelae of diabetes and aging, such as
diabetic microangiopathy,
ischemic heart disease and
neurodegenerative diseases. Recently, digested food-derived AGEs are also found to play an important role in the pathogenesis of AGE-related disorders. Diet is a major environmental source of pro-inflammatory AGEs. Indeed, restriction of dietary
glycotoxins decreases excessive AGE levels and subsequently reduces the inflammatory responses in patients with diabetes. These observations suggest that inhibition of absorption of
dietary AGEs may be a novel target for therapeutic intervention in the above-mentioned AGE-related disorders.
AST-120 (
Kremezin) is an oral adsorbent that attenuates the progression of
chronic renal failure (CRF) by removing
uremic toxins. We have recently found that
AST-120 binds to
carboxymethyllysine (CML), one of the well-characterized, digested food-derived AGEs in vitro and that administration of
AST-120 decreases serum levels of AGEs in non-diabetic CRF patients. These findings suggest that digested food-derived AGEs such as CML may be a novel molecular target for oral adsorbent
AST-120 and that
AST-120 could exert beneficial effects on CRF patients by adsorbing diet-derived AGEs and subsequently decreasing serum AGE levels. If our speculation is correct,
AST-120 may have therapeutic potentials for the treatment of patients with various AGE-related disorders as well. In this paper, we would like to propose the possible ways of testing our hypotheses. Does the long-term treatment of
AST-120 decrease serum and tissue levels of AGEs in diabetic patients? Does this treatment also reduce the risk for the development and progression of
diabetic vascular complications such as
diabetic retinopathy or
ischemic heart disease? If the answers are yes, do the serum and/or tissue levels of AGEs after
AST-120 treatment predict its beneficial effects on
diabetic vascular complications? How about the effects of
AST-120 on
Alzheimer's disease, another AGE-related
neurodegenerative disorder? Does the treatment of
AST-120 reduce the risk for
Alzheimer's disease and/or improve the
cognitive impairment of patients with this disorder? These prospective studies will provide further valuable information whether the inhibition of absorption of
dietary AGEs by
AST-120 could be clinically relevant.