Breakthrough: Sestrin Switch Mitochondrial Feedback Loop Through AMP Kinase Cascade Demonstrates Ancient Intermediary Metabolic Life Extension Circuit.
By Gregory S. Bambeck Ph.D. and Michael Wolfson J.D., M.B.A.
Summary
In the previous narrative, entitled: STUDIES OF CALORIC RESTRICTION, RESVERATROL AND SIRT1 DEMONSTRATE A â??METABOTYPEâ?? 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 can be googled via Bambeck, resveratrol, etc.)
The Sestrin Feedback Loop
It turns out that the basic hypothesis of â??metabotypicâ?? 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: â??Sestrin proteins protect fruit flies from the tissue degeneration and disruption of metabolic homeostasis that accompany agingâ??. 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 â??metabotypeâ?? 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 â??longest lifeâ?? 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 articleâ??s principal participant.
Gregory S. Bambeck Ph.D. and Michael Wolfson J.D., M.B.A
March 21, 2010
e mail: gregorybambeck@yahoo.com
mwolfson@stanfordalumni.org