Amp Bypass
Breakthrough: Sestrin Switch Mitochondrial Feedback Loop Through Amp Kinase Cascade Demonstrates Ancient Intermediary Metabolic Life Extension Circuit
Summary
In the previous narrative, entitled: STUDIES OF CALORIC RESTRICTION, RESVERATROL AND SIRT1 DEMONSTRATE A ‘METABOTYPE' CONTINUUM FROM CELLULAR REJUVENATION TO AGING TO CANCER, of 2/25/2010, the evolution and maintenance of an ancient aerobic glycolysis system maintained, to a great extent, by mitochondrial ATP production inefficiency and anabolic reducing power that is essentially independent of differential cell type growth factors, was described. Lee et. al. chisel this control system into stone by discovering a lynchpin mitochondrial free radical activated Sestrin switch that directly activates the life extending caloric restriction AMP kinase that down regulates anabolism and institutes mitochondrial biogenesis. (previous narrative available at http://www.scribd.com/doc/27481292/Studies-Of-Caloric-Restriction-And-Resveratrol-Demonstrate-metabotype-Continuum-From-Cellular-Rejuenation-To-Aging-To-Cancer)
The Sestrin Feedback Loop
It turns out that the basic hypothesis of ‘metabotypic' intermediary metabolic control systems having command and control capacities over cell growth factor cascades, has been given a major boost. In the March 5 issue of Science (Vol 327 p.1223, review on p. 1210), J.H. Lee et. al., in an elegantly integrated block of experiments, demonstrate that an ancient oxidative stress protein, called Sestrin (SESN), is up regulated by damaged mitochondrial ROS production, causing SESN to activate the same AMP kinase (AMPK) activated by caloric restriction, which, among other things, inhibits the metabolic control protein, TOR. This inhibition of TOR sets in motion a complex gene cascade that down regulates anabolism, up regulates catabolic autophagy and institutes mitochondrial biogenesis, which in turn, yields decreased ROS, the ROS, then, feedback inhibiting SESN. Thus, they are the first to show a feedback regulatory loop of intermediary metabolism that over-rides cell growth factor signaling.
The Science editors note that Lee et. al. have outlined the key ingredients of a mechanistic metabolic control system, saying: "Sestrin proteins protect fruit flies from the tissue degeneration and disruption of metabolic homeostasis that accompany aging". They also note that the highly evolutionarily conserved SESN system is present in humans in three orthogonal forms. A generalized system pathway chart accompanies the review article on p.1210, allowing us to make some observations relevant to the above ‘metabotype" article.
First, SESN is a ROS feedback homeostasis control switch that can also be activated by the generic cell (tumor) growth suppressor p53. Flaws in the p53 pathway are found in about half of all cancers. Second, in its normal function, SESN helps set life length by acting kind of like a thermostat that is preset and may lose its regulatory sensitivity over time. Without a time tested pharmaceutical agent, practical SESN activation in humans is a long way off. Outside of that, it appears that SESN might ultimately be an excellent life extension and anti-cancer target. Third, the TOR molecule, which controls anabolic activity and mitochondrial biogenesis, can be directly blocked by rapamycin. However, direct TOR blocking is probably too specific and heavy of a hammer because rapamycin is a powerful immune system suppressor used to thwart tissue transplant rejection in humans. Down regulation of tissue transplant immune rejection systems can increase cancer incidence up to ten-fold.
However, direct stimulation of AMPK via the caloric restriction/SIRT or a SIRT bypass pathway, such as resveratrol, still seems rather tempting. Activating the AMPK pathway helps the anti-cancer and life extension pathways upstream of TOR, while bypassing signals that might compromise SESN activation. Direct activation of AMPK basically tells the cell that the p53 cell suppressor system is activated (when it is not) and that the cell growth signaling cascade has been shut down. Surprisingly, cell division is not shut down as well. Instead, cells are just as numerous, but just smaller and much more youthful and efficient. The pathway map yields a pretty good indication of how present life extension results bypass the homeostatic mechanism to mimic SESN activation. It is the functional equivalent of hotwiring around the life length control setting of the SESN thermostat, and forcing the downstream system to run as if on the ‘longest life' setting.
From an evolutionary standpoint, it is easy to see how the SESN to AMPK to TOR to ROS and back to SESN system predates multicellularity and cell growth factor activator and suppressor systems associated with differential cell type control. It operates as a closed metabolic central control loop, and that by its very design, must predate the input branching cell growth pathways that converge into it, as organismic cell type diversity and the need for differential cell growth control evolved over time. The fact that the system has its own command and control and feedback loop that can ignore and over ride extrinsic controls to such a degree that it can dramatically extend life, renormalize cancer cell metabolism, reinitiate damaged cell deletion via apoptosis, up regulate autophagy of flawed organelles and cell debris, as well as initiate the biogenesis of new and efficient mitochondria, all in an integrated fashion that rejuvenates cells, tissues and organs, is further proof of the authenticity of the metabotype concept described in the aforementioned narrative. The Lee et. al. paper is a must read for all life extension aficionados. Appropriately, the Science editorial staff was impressed enough to grace the front cover with the research article's principal participant.
Gregory S. Bambeck Ph.D. and Michael Wolfson J.D., M.B.A.
March 21, 2010
e mail: gregorybambeck@yahoo.com
About the Author
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Can Father God Count on You?
In Genesis, God created man—Adam and Eve—and gave them authority and responsibility over the earth. Because they were tempted by the devil to relinquish their authority to him, Jesus had to come to buy it back by shedding His blood and by His death and resurrection. He conquered and defeated the devil, took all earthly authority away from him and took back the keys of death and hell. Jesus, before He ascended back into heaven, restored this authority to every believer.
Rodney Howard Browne teaches us that if you have accepted Jesus as your Lord and Savior, you have the right to use the Name of Jesus to walk in divine authority over devils and circumstances! With this authority comes a responsibility to do not our own will, but God’s will. God uses people to carry out His will on the earth. If you are a Christian, you are God’s representative on the earth. You are His instrument—His mouth, His hands, and His feet—if you don’t do His will on the earth it won’t be done. If you don’t say it, pray it, and do it, it won’t be done! How important is it to obey God promptly and exactly? Saul learned this lesson, too late.
Then came Amalek [descendants of Esau] and fought with Israel at Rephidim. (Exodus 17:8 AMP) And the Lord said to Moses, Write this for a memorial in the book and rehearse it in the ears of Joshua, that I will utterly blot out the remembrance of Amalek from under the heavens. And Moses built an altar and called the name of it, The Lord is my Banner; And he said, Because [theirs] is a hand against the throne of the Lord, the Lord will have war with Amalek from generation to generation. (Exodus 17:14-16 AMP)
In Moses’ day, God spoke to Esau’s rebellious descendants, the Amalekites, and promised that every remembrance of them would be blotted out from under the heavens.
Samuel told Saul, The Lord sent me to anoint you king over His people Israel. Now listen and heed the words of the Lord. Thus says the Lord of hosts, I have considered and will punish what Amalek did to Israel, how he set himself against him in the way when [Israel] came out of Egypt. Now go and smite Amalek and utterly destroy all they have; do not spare them, but kill both man and woman, infant and suckling, ox and sheep, camel and donkey.
1 Samuel 15:1-3 AMP
Rodney Howard Browne shows us that Saul was God’s chosen vessel to carry out His judgment on Amalek. However, Saul did not obey God—he did not kill every living thing as God had ordered—he left the king and the healthy animals alive. God was furious. He had made a declaration to Amalek and He always keeps His word. In Saul’s disobedience, he made God out to be a liar—which He is definitely not! Because of the seriousness of this offence, Saul lost both his anointing and his throne.
How many times have you asked God to come through for you with something specific in a specified time frame? Who did God use to answer your prayer on time? Aren’t you glad that they obeyed God? What would have happened if they had not? We waited six months for a new van in 1988, because five people were disobedient to the Lord. Finally the sixth person obeyed God and helped us get a brand-new van! We sure were happy about it!
What has God asked you to do to answer another person’s prayer? You most likely had no idea what they asked for, just that God told you to do something for them or say something to them. As you obey God immediately and specifically, you carry out His will and His plan in the earth. If you don’t, you make God go out and find someone else. If you continue to disobey God, He will cease to call on you and you will lose your rewards.
Don’t be the one God has to bypass—be the one that God can depend on to carry out His will and purpose in the earth.
About the Author
Rodney Howard Browne and his ministry team, under the banner of Revival Ministries International, travel about 46 weeks of the year, holding weekly meetings in cities across North America and around the world. They also pastor a church in Tampa, Florida, The River at Tampa Bay, which he founded and which now has 3000 members.
Read Rodney Howard Browne on his other articles online: