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
‘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
mwolfson@stanfordalumni.org