Aptamers to Reduce Inflammatory AGE-RAGE Interaction
Researchers here discuss the use of aptamers that can bind to advanced glycation endproducts (AGEs). This prevents the AGEs from themselves binding to the receptor for AGEs (RAGE), an interaction that provokes inflammation. A sizable presence of circulating, short-lived AGEs is characteristic of the abnormal metabolism of obesity and obesity-related conditions such as type 2 diabetes. It is an open question as to how much of a contribution to the chronic inflammation of aging is provided by AGEs in people of a normal weight, eating a basically sensible diet, however. The only way to find out is to test a therapy of this nature, in which only the contribution of AGEs is suppressed, and then observe the results.
As AGEs have been considered a promising target for therapeutic intervention in various diseases, a large number of compounds have been proposed as AGE formation inhibitors or AGE-RAGE interaction blockers. However, owing to their limited efficacy or potential adverse side effects in vivo, none of these compounds have reached clinical application. DNA aptamers are short single-stranded DNA sequences that can selectively bind to target molecules. Compared with protein antibodies, DNA aptamers have several advantages, including short generation time, low costs of manufacturing, no batch-to-batch variability, and high modifiability and thermal stability. RNA aptamers that can inhibit vascular endothelial growth factors are clinically approved for the treatment of age-related macular degeneration, and a number of aptamers have entered clinical trials, including for ocular diseases, hematologic diseases, and cancer. Recently, we have innovatively developed DNA aptamers raised against AGEs (AGE-Apts) that can inhibit the toxic effects of AGEs.
We herein evaluated the effects of AGE-Apts on muscle mass and strength in senescence-accelerated mouse prone 8 (SAMP8) mice. Eight-month-old male SAMP8 mice received subcutaneous infusion of control DNA aptamers (CTR-Apts) or AGE-Apts. Mice in an age-matched senescence-accelerated mouse resistant strain 1 (SAMR1) group were treated with CTR-Apts as controls. The soleus muscles were collected after the 8-week intervention for weight measurement and histological, RT-PCR, and immunofluorescence analyses. Grip strength was measured before and after the 8-week intervention.
AGE-Apt treatment inhibited the progressive decrease in the grip strength of SAMP8 mice. SAMP8 mice had lower soleus muscle weight and fiber size than SAMR1 mice, which was partly restored by AGE-Apt treatment. Furthermore, AGE-Apt-treated SAMP8 mice had a lower interstitial fibrosis area of the soleus muscle than CTR-Apt-treated SAMP8 mice. The soleus muscle levels of AGEs, oxidative stress, receptor for AGEs, and muscle ring-finger protein-1 were increased in the CTR-Apt-treated mice, all of which, except for AGEs, were inhibited by AGE-Apt treatment. Our present findings suggest that the subcutaneous delivery of AGE-Apts may be a novel therapeutic strategy for aging-related decrease in skeletal muscle mass and strength.