Alagebrium (or ALT-711) was an early and ultimately unsuccessful foray into the development of an AGE-breaker drug: a treatment intended to safely break down the build up of advanced glycation end-products (AGEs) that characterize aged tissue. These are chemical cross-links that form as a byproduct of the normal operation of metabolism, and which glue together proteins to cause various forms of harm, such as destroying the elasticity of skin and blood vessels. Eventually this process contributes significantly to age-related disease and death, meaning that any attempt to treat and reverse aging by attacking the causes must include proficient AGE-breakers.
The attempted clinical development of alagebrium followed initially promising studies in rats, but as it turns out the types of AGE important in human tissue are not the same at all, and as a consequence alagebrium had no meaningful effect in human trials. This was sufficiently well determined that you can color me surprised to see that anyone is continuing with the thankless but important work of confirming past negative results for this line of research. But here we have it:
Aging leads to accumulation of irreversible advanced glycation end-products (AGEs), contributing to vascular stiffening and endothelial dysfunction. When combined with the AGE-crosslink breaker Alagebrium, exercise training reverses cardiovascular aging in experimental animals. This study is the first to examine the effect of Alagebrium, with and without exercise training, on endothelial function, arterial stiffness and cardiovascular risk in older individuals.
Forty-eight non-exercising individuals (mean age 70 ± 4 years) without manifest diseases or use of medication were allocated into 4 groups for a 1-year intervention: Exercise training and Alagebrium (200 mg/day); exercise training and placebo; no exercise training and Alagebrium (200 mg/day); and no exercise training and placebo. We performed a maximal exercise test (VO2max) and measured endothelial function. Arterial stiffness was measured using pulse wave velocity. Cardiovascular risk was calculated using the Lifetime Risk Score (LRS).
In the exercise training groups, LRS and VO2max improved significantly (23.9 ± 4.5 to 27.2 ± 4.6 mLO2/min/kg). Endothelial response to the vasoactive substances did not change, nor did arterial stiffness in any of the four groups. In conclusion, one year of exercise training significantly improved physical fitness and lifetime risk for cardiovascular disease without affecting endothelial function or arterial stiffness. The use of the AGE-crosslink breaker Alagebrium had no independent effect on vascular function, nor did it potentiate the effect of exercise training. Despite the clinical benefits of exercise training for older individuals, neither exercise training nor Alagebrium (alone or in combination) was able to reverse the vascular effects of decades of sedentary aging.
Present work on AGE-breaker development is very limited indeed. At the present time it is known that one type of AGE - glucosepane - makes up the overwhelming majority of AGEs present in human tissue, so in theory finding ways to treat and reverse AGE build up in our species is in fact a comparatively simple research and development undertaking. Unfortunately the drug development community has little infrastructure in place for working with this sort of compound, and little interest in building that infrastructure: groups with funding tend to find other things to work on, where there is a shorter and more certain path to producing a useful end result.
This is where the SENS Research Foundation comes into the picture. The Foundation is presently funding research to produce the tools needed to work with glucosepane and thereafter produce technology demonstrations to show that it can be cleared from tissues. Hopefully work on AGE-breakers will pick up again over the next few years as a result of this intervention. This whole situation might not be the best candidate for an example of clearly useful near-term medical research and development that should yield enormous benefits, but yet just isn't happening - but it is certainly up there in the charts. From a distance we might see constant progress, but down in the weeds every field is beset with this sort of problem.