In today's open access paper, researchers propose the use of sodium 4-phenylbutyrate to inhibit protein glycation, reducing the creation of advanced glycation endproducts (AGEs) in the body, and thus limit the contribution of this class of compounds to aging and disease. AGEs are quite varied and comparatively poorly studied; it is still the case that new ones are being found, and there is considerable room for debate on which AGEs are more or less important to aging and outcomes of metabolic diseases such as diabetes. Short-lived AGEs, easily broken down, are inflammatory via the receptor for AGEs (RAGE), and this may be their primary contribution to aging and disease. Persistent AGEs, on the other hand, can form lasting cross-links that stiffen tissues such as blood vessel walls, causing conditions such as hypertension.
In studies like the one noted below, it is usually quite unclear as to whether or not a useful range of AGEs are being inhibited. In other words, whether the approach is better applied to treating metabolic disorders, to lower the large amounts of short-lived AGEs that are causing inflammation, or whether it might help to slow the progressive accumulation of cross-links with age. Further, the AGEs relevant to aging and disease are thought (and in some cases shown) to be different between mammalian species. This has been quite problematic in past attempts to produce drugs that can break down AGEs in order to produce therapeutic benefit. For example, this is why the development of the AGE-breaker drug alagebrium failed.
Ultimately, however, a therapy that has to be applied constantly in order to slow the accumulation of damage (such as persistent AGE cross-links in tissues) is a poor alternative to a therapy that can be applied intermittently to remove damage (such as by breaking down existing persistent AGE cross-links). Prevention of contributing causes of aging is not that helpful to those who are already old. That makes the class of approach here less interesting when compared with, say, the AGE-breaking enzymes under development at Revel Pharmaceuticals.
Glycation is a non-enzymatic chemical reaction that occurs between a ketone or aldehyde group of fructose or glucose and an amino acid residue or the hydroxy-group of a protein or lipid, and is often referred to as the Maillard reaction. Protein glycation occurs through a complex series of very slow reactions in the body, including the formation of the stable Amadori-lysine products (Schiff bases). These give rise to advanced glycation end-products (AGEs).
It is hypothesized that the production and accumulation of AGEs have causal roles in the development of the complications associated with aging and lifestyle-related diseases, such as diabetes, atherosclerosis, and hyperlipidemia. Furthermore, the production and accumulation of AGEs are involved in the development of other diseases, such as cardiovascular diseases, cerebrovascular disorders, chronic renal failure, Alzheimer's disease, and Parkinson's disease. Therefore, the identification of safe treatments that can inhibit glycation is required, as they may exhibit anti-aging effects, or serve as a therapeutic option for prevention of diseases associated with glycation.
In the present study, the ability of sodium 4-phenylbutyrate (PBA) on inhibition of glycation was assessed. In vitro, PBA inhibited the glycation of albumin and collagen by up to 42.1% and 36.9%, respectively. Furthermore, when spontaneously diabetic KK mice were administered PBA (20 mg/day) or vehicle orally, glycosuria developed rapidly in the control mice, but after 6 weeks, only one treated mouse was glycosuric. In addition, the weight gain and HbA1c levels were significantly lower in the treated mice compared with the untreated mice. These results suggested that PBA also inhibited glycation in vivo. Further studies are required to determine whether PBA may be effective for the therapy or prevention of aging or lifestyle-related diseases caused by the accumulation of AGEs. The method of administration and the side-effects of PBA have already been established as PBA is already used clinically. Therefore, the repurposing of PBA for reducing AGE levels may be a potential option to reduce complications associated with aging.