Outline:
Passing through the deadly TB (Tuberculosis) around age 10 shortly after the end of WWII, and finally having managed to reach 80, the “average” lifespan of men (males) in this century, I am getting ready to write a few “biochemical” chapters as to how to survive this dangerous world by a “chemical” evolution, instead of “genetic” approach, mainly based on a half-century long “academic” study by myself on the “longevity” about small animals such as C. elegans, Drosophila and mice, as the lifespan of Homo sapiens is “too long” for our biochemical study.
C. elegans, an 1 mm long transparent animal, lives for 14 days at 20oC, but survives only for 1 day at 35oC. This simple observation clearly indicates that our life is a battle against the heat, and we have to think seriously how to survive the current “global warming” mainly due to the increased “CO2 emmission” by ourselves since the end of WWII. Our genetic study on this worm has revealed that a healthy mutant of this worm , which lacks a “pathogenic/ ageing” enzyme called “PAK1” or “TOR” , lives 60% longer than the wild-type at 20oC, and survives 9 times longer than the wild-type at 35oC. This simple “genetic” observation would strongly suggest us that we have to shut-down PAK1 or TOR or both somehow, in order to enjoy a longer and healthier life under the current “global warming”, since we cannot reply on world political leaders or CO2-emitting (coal or petro) mining giants.
Unfortunately, however, under the current “ethical” human regulation, we are not allowed to knock-out any genes including PAK1 and TOR for our better life, although we have been doing the exactly same experiments on any other animals including primates and mice. PAK1/TOR-deficient mice live 60% longer than the wild-type, exactly same as the nematodes! Thus, our alternative approach in order to improve the longevity or survival against the heat due to “global warming” would be a “chemical” (instead of “genetic”) evolution. We have to find a series of natural or synthetic chemicals that are able to shut-down these pathogenic/ ageing enzymes (kinases), surely without any side effects.
According to Charles Darwin (1809-1882)’s well-known "Theory of Evolution", each species evolved through genetic or social changes to be “the best fit for survival”. Penguins which no longer can fly left their homeland (NZ) for good, where their predator (natural enemy) called cats dominate, swam away to settle in Antarctica where no cat lives, due to being too cold! Silk worms invented a safe home called silk cocoon, avoiding their predator called spiders, during their long hibernation (sleep for a few weeks). Thus, we, human being, also have to invent something essential for our survival. Truely, “Necessity is the mother of invention”!
Well, mainly during last two decades, we and many other scientists began to discover more than 2 dozens of PAK1-blockers or TOR-blockers in the nature, and among a stock pile of synthetic compounds. Among the natural PAK1-blockers are propolis, alcohol-extract of honey-bee hives, which contains CAPE (caffeic acid phenethyl ester), Apigenin, or ARC (Artepillin C), depending on where it is harvested. Propolis has been used for therapy of many diseases including both bacterial and viral infection as well as inflammation for over 4,000 years since the ancient Egyptian era. Propolis clearly block PAK1, and probably TOR as well, without any side effect. Fucoidan, a sulphated polysaccharide from brown sea weeds is another example of PAK1-blockers which promote the longevity. Vitamins D3 and K2 are popular examples of safe PAK1-blockers.
Unfortunately, however, many natural PAK1-blockers or TOR-blocker are not so potent, mainly due to poor cell-permeability, water-solubility or instability in our body, and we or other have potentiated their medical efficacy by improving their cell-permeability, water-solubility or stability by a series of chemical modification (or evolution). Vitamin D3 is easily inactivated by CYP24, an enzyme which hydroxylates at position 24 of D3, and MART-10 is a mighty CYP24-resistant derivative of D3 which is 1,000 times more potent than D3. Minnelide is a phosphorylated Pro-drug of Triptolide, and is 3,000 times more water–soluble than the latter. Our “15K” (1,2,3-triazolyl ester of Ketorolac), which is over 500 times more cell-peameable than the old pain-killer (Ketorolac), was made via the CC (Click Chemistry), a great invention by Barry Sharpless at MIT (featured on the book cover) , who received Nobel-prize in chemistry twice (in 2001 and 2022).
Undoubtedly, these “chemical”evolutions would improve our chance to live longer and healthier (with the far better "QOL"), expecially under the current “global warming/heating”.
However, Ivermectin and FK228 (Isotodax) among the most potent PAK1-blockers avaialable in the “clinical” market are unable to pass through BBB (blood brain barrier), due to their large molecular weight (MW) or other unknown reasons, and clearly useless for the therapy of PAK1/TOR-dependent neuronal diseases such as brain tumors, AD (Alzheimer’s disease), PD (Parkinson’s disease), Schizophrenia and some of autistic diseases. Thus, in the future, some of us have to invent the potent “BBB-permeable” PAK1/TOR-blockers from them or other sources by a brand-new chemical evolution (or revolution).
Perhaps in a century or so, when people are firmly convinced that PAK1 gene is not essential for our life, but rather "harmful" (shortening our healthy lifespan), a new "ethical" law might be established so that we can eliminate (or simply silence with SiRNA ) PAK1-gene from egg and sperm so that we can create a new (PAK1-null) species of Homo sapiens called "Geno sapiens" which could live 60% longer than Homo sapiens. This will be a real (genetic) evolution of human beings. Until then we shall stick to the "alternative" (chemical) evolution by taking "PAK1-blockers".
“Necessity is the mother of invention”, and according to Thomas Edison (1847-1931), a great American inventor who devised light bulb and phono-graph among many others, Invention is 1% inspiration and 99% perspiration.
CONTENTS:
Preface
Chapter 1: Inhibitors specific for PAK1 and its upstreams
Chapter 2: Life versus Heat (and other insults)
Chapter 3: PAK1-dependent melanin synthesis
Chapter 4: PAK1-dependent diseases (cancers, infection, AD, PD etc)
Chapter 5: “Natural” PAK1-blockers
Chapter 6: “Synthetic” PAK1-blockers
Chapter 7: Uspstream and downstream of PAK1
Chapter 8: TOR (Target of Rapamycin) versus AMPK
Concluding Remarks
0 件のコメント:
コメントを投稿