The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 11 No.
5 • September 2008
AGE Inhibitors: Potential Therapy for Prevention and/or Treatment of Dementia
It takes “forever” for the FDA to get around to approving new therapies for dementia, one reason being that only xenobiotic drugs have a chance to be approved for that purpose. Natural substances, no matter how potentially useful in protecting against brain aging and dementia, cannot be patented, and hence the approximately $1 billion in developmental costs needed to get FDA approval will never be invested by entities whose owners (shareholders) expect something back for their investments. So we have to wait while xenobiotics are developed, generally as modified versions of natural substances and with (usually) greater risks of toxicity compared to the starting natural substance.
While we are waiting for that, though, we should pay more attention to the potential value of natural products that are readily available now in the marketplace (although the FDA prohibits any claims of prevention or treatment of disease on their labels, unless they are FDA-approved as drugs). Inhibitors of AGEs, advanced glycation endproducts formed as a result of the chemical interaction in the body between amino acids and sugars, have now been reported in a growing scientific literature to be constituents of Alzheimer’s disease plaques and neurofibrillary tangles, to exert chronic oxidative stress on neurons, and to activate glial cells in the brain (that release inflammatory cytokines such as tumor necrosis factor-alpha and free radicals, such as superoxide and nitric oxide). Meanwhile, AGE-inhibiting substances, such as aminoguanidine, carnosine, and pyridoxamine, have been reported to attenuate the development of AGE-related diabetic complications.
Cellular inclusions in aged brain cells include Lewy bodies (as in Parkinson’s disease), lipofuscin (“age pigment”), and others. It has been reported that “Nuclear polymerization of Abeta [amyloid-beta, the substance that forms toxic aggregates in Alzheimer’s disease] is significantly accelerated by AGE-mediated cross-linking.” Abeta-AGE (AGE-modified Abeta) is a more potent activator of microglia than Abeta alone, at least in terms of inducing nitric oxide synthase and nitric oxide production, part of an inflammatory process. It has also been reported that the mitochondrial respiratory chain and the intracellular ATP content of cells are also reduced upon treatment with AGEs. “AGEs induce both proliferation of immune-competent cells and their activation, resulting in a chronic inflammatory response.”
Carnosine has been shown to act as an antiglycating agent (inhibiting the formation of sugar-amino acid chemical interactions that, through further modifications, become irreversible AGEs) on peptides and proteins (such as alpha-crystallin, a protein in the lenses of eyes that becomes opaque through glycation with circulating sugars, such as ribose and fructose, as well as glucose).
Carnosine as a Vasodilator
Interesting new effects are being reported for carnosine. For example, a fairly recent paper found that in preconstricted thoracic aorta rings from Sprague-Dawley rats, carnosine caused significant relaxation of the aorta independently of the endothelium. The fact that the relaxation did not require the presence of the endothelium means that the mechanism did not involve nitric oxide synthase activation; the authors found that the effect was at least in part due to production of cyclic GMP, as occurs when nitric oxide synthase is activated, but also by another pathway. The two constituent amino acids of carnosine, L-histidine and beta-alanine, did not reproduce this effect. L-Histidine had no effect, and beta-alanine actually caused a significant, dose-dependent increase in vascular smooth muscle tone (i.e., an increase in vascular constriction).
Carnosinase Found Almost Exclusively in Brain and Serum
Carnosinase, an enzyme that can break carnosine down into its constituent amino acids, histidine and beta-alanine, is produced mostly in the brain; hence, this regulation must be important to brain function. In fact, it has been reported that histidine levels in the frontal and temporal lobes of Alzheimer’s patients are decreased compared to normal brains, which could be due to carnosinase deficiency. There have been case studies of patients with carnosinase deficiency who have conditions such as progressive mental deficiency, spastic paraplegia, seizures, neurosensory hearing loss, retinitis pigmentosa, and others. Interestingly, carnosinase levels have been reported to decrease during cardiopulmonary bypass surgery. The authors speculate that this may be an adaptive mechanism, since carnosine protects against neurotoxicity in conditions of oxidative stress. The researchers report in this paper their study of carnosinase levels in 37 patients attending a geriatric outpatient clinic.
In this small sample of 37 patients, the scientists reported finding a significant difference between the carnosinase levels in MD (mixed dementia, with vascular lesions) and AD (Alzheimer’s disease), with levels of the enzyme lower in MD than in AD patients and with levels decreasing with the duration of disease. Interestingly, both the AD and MD patients taking antidementia medication (donepezil, galantamine,* memantine) had higher carnosinase activity compared to those not taking a dementia medication. Moreover, carnosinase activity was higher in patients who exercised regularly as compared to those who didn’t.
Although the presence of carnosinase in the brain points to an important regulatory function, we would like to learn a great deal more about how the enzyme works in the brain and how control of carnosine levels and its amino acid constituents contribute to brain function. Possibly carnosinase contributes to the brain’s control of blood flow to various brain areas through the vasodilation of carnosine and the vasoconstriction of beta- alanine, though that is just a speculation on our part.
AGEless™, which contains carnosine and other potent natural antiglycation molecules, includes (in 2 capsules taken 4 times a day) 1336 mg of carnosine.
- Dukic-Stefanovic et al. AGES in brain ageing: AGE-inhibitors in neuroprotective and anti-dementia drugs? Biogerontology 2:19-34 (2001).
- Ririe et al. Vasodilatory actions of the dietary peptide carnosine. Nutrition 16:168-72 (2000).
- Balion et al. Brain type carnosinase in dementia: a pilot study. BMC Neurol 5(7):38 (2007).