Hector Warnes’ response to Joseph Knoll’s replies

Joseph Knoll: The Discovery of the Enhancer Regulation in the Mammalian Brain and the Development of the Synthetic Enhancer Substances


            I am most grateful for Professor Knoll’s replies to my comments!  He obviously has the profile of a great scientist and a life-long researcher into  enhancer regulation  in the mammalian brain. Deprenyl was the first selective inhibitor of B-type MAO without  the cheese effect.  Over several decades, Professor Knoll’s  attention was drawn to its catecholaminergic activity enhancer (CAE) effect. It led him further to develop other synthetic enhancer substances such a  the beta-phenylethylamine (PEA) and, later, the BPAP, a tryptamine-derived synthetic enhancer substance:

            “The realization that during the uphill period of life, from weaning until sexual maturity, enhancer regulation in the catecholaminergic and serotoninergic neurons work on a higher activity level, sexual hormones terminate the hyperactive phase, and this change is beginning a downhill period of life seems to me to throw light on the essence of human aging.” I would add that there are several changes that take place in the organism during the inexorable process of aging besides the ones that Professor Knoll names as "essential": DNA damage, oxidative stress; proteotoxic stress; telomere shortening; increase of free radicals that may damage cells, particularly its mitochondria; impairment of the immune response; susceptibility to cancer; vascular disease; and others pathologies which Professor Knoll may not have considered as "essentials," but rather secondary to the CAE.

            Professor Knoll (1992) has shown that enhancer substances (CAE) given to rats in life-long maintenance doses significantly prolongs their life. He went further by depleting more than 90% of  the rat's norepinephrine and dopamine from their stores in nerve terminals by using tetrabenazine.  The depletion was reversed by the treatment of rats with BPAP. 

            As far as I am aware, no clinical studies were done in humans that confirm his findings in rats. There has been abundance of new Senotherapeutic agents that  have raised hope about improving the quality and the life-span of humans, but these were later dismissed or shown to require further investigations. I would like  just to mention those anti-aging agents that are flooding  the market, such as  antioxidants (free radicals which  may damage the cells), growth hormones, L-carnitine, telomerase (which mantains the telomere length), melatonin, carnosine, delta sleep inducing peptide (as we know delta sleep decreases to a minimal percentage with aging), caloric restriction mimetic drugs (rapamycin), mitoq (a mitochondria targeted antioxidant), metformin and even stem cells. Many were discarded, such as Aslan’s decades ago treatment with procaine, or, more recently, resveratrol. 

            I would admit my own ignorance regarding the life-long meticulous research of Professor Knoll. I would like to ask him if he was able to compare the same strain of rats treated chronically with CAE with another number of rats of the same strain treated with another anti-aging compound that has shown to be as  promisory. I would not mind myself taking Deprenyl to ameliorate the usual symptoms of old age not related to illness.


August 24, 2017