**11. AGEs breakers**

The AGEs which have undergone cross-linking are very stable products and their concentration, especially in long-lived matrix proteins, increases with age. AGEs inhibitors are ineffective against formed AGEs and compounds which can break the cross-links are required. The AGEs breaker compounds can prove invaluable to slow down the aging process, and in the treatment of established stages of diseases such as diabetes, Alzheimer's, atherosclerosis and rheumatoid arthritis.

The first AGEs breaking compound reported was phenacylthiazolium bromide (PTB) in 1996. PTB breaks the covalent cross-links of AGEs [204]. Administration of PTB (10 mg/kg/day, intraperitoneal for 4 wks) reduced the amount of IgG bound to the surface of red blood cells in diabetic rats [153]. However, PTB is not stable.

The search for a stable derivative of PTB resulted in the synthesis of ALT 711 (4,5 dimethylthiazolium) [205]. ALT 711 (now known as alagebrium) reduced arterial stiffness in streptozotocin-induced diabetic rats [205]. In aging rats, ALA (10 mg/kg for 16 weeks) also increased glutathione peroxidase and superoxide dismutase activities and reduced oxidative stress [206]. Alagebrium improved impaired cardiovascular function in older rhesus monkeys [207]. Alagebrium demonstrated promising results and a good safety profile in phase 2 clinical trials. In a clinical study involving 93 subjects, 50 yrs and older, with evidence of vessel stiffness (pulse pressure ≥60 mm Hg, systolic blood pressure ≥140 mm Hg, and large artery compliance ≤1.25 mL/mm Hg), alagebrium (210 mg, once per day for 56 days) improved arterial compliance [208]. In another group of 13 patients aged 65±2 yrs with systolic hypertension (systolic blood pressure > 140 mmHg, diastolic blood pressure <90 mm Hg), alagebrium (210 mg/kg twice a day for 8 weeks) reduced vascular fibrosis and markers of inflammation [209]. Alagebrium (administered for 16 weeks) decreased left ventricular mass and improved left ventricular diastolic filling in another trial in 23 patients with diastolic heart failure [210, 211].

However, in a recent study [212] involving 102 patients (aged 62 ± 11 years) with heart failure (left ventricular ejection fraction (LVEF ≤0.45), alagebrium (400 mg/day/36 wks) did not improve exercise tolerance and systolic dysfunction, and no changes were observed in a number of secondary endpoints. Thus, the authors could not verify the claims that alagebrium has beneficial effects in systolic heart failure [212].

Alagebrium has been reported to be a weak inhibitor of thiamine diphosphokinase and is unlikely to interfere with thiamine metabolism at therapeutic concentrations [213]. However, the authors urge caution when new AGE-crosslink breakers based on thiamine are designed, to make sure they are not potent inhibitors of thiamine diphosphokinase.

In the studies described above alagebrium has been studied mainly for its chronic effects on AGEs as an AGEs breaker. We investigated whether alagebrium also has acute preventive effects against the reactive dicarbonyl, MG, in 12 wk old male Sprague-Dawley rats [66]. Our results showed that alagebrium also has acute (< 6 h) MG scavenging ability [66]. AGEs are formed slowly over a time ranging from 24 h to up to 7 days and more. Therefore, the attenuation of MG-induced acute effects (seen within 6 h of MG administration) is most likely due to scavenging of MG by alagebrium. Thus, alagebrium significantly attenuated the significant increases in MG levels in the plasma, and different organs (measured 2 h after administration), and also attenuated MG-induced impaired glucose tolerance and the reduced insulin-stimulated glucose uptake by adipose tissue. In an *in vitro* assay in which MG (10 μM) was incubated with or without alagebrium (100 μM) for different times at 37° C, alagebrium significantly reduced the amount of detectable MG [66]. Our results strongly indicate an acute MG scavenging effect of alagebrium which can add to its AGEs breaking ability. More direct evidence of interaction of alagebrium and MG using mass spectrometry would be very useful. We have also recently shown that alagebrium significantly attenuated the deleterious effects of chronic MG administration for 4 wks on glucose tolerance and pancreatic islet β-cell function in male Sprague-Dawley rats [72].

In conclusion, MG and AGEs are very likely to be involved in the initiation and or progression of the aging process. Commonly available pharmacological compounds to investigate these roles of MG and AGEs, such as aminoguanidine, are non-specific, whereas some of the newer compounds appear promising in inhibiting AGEs formation at multiple steps in the pathway in *in vitro* studies. However, more *in vivo* studies are required before their therapeutic potential can be established. A more dedicated effort is necessary to identify newer anti-MG and anti-AGEs compounds which are more specific and safer before more can be done about their therapeutic potential.
