The Life Extension Pathway, Resveratrol etc. and Cancer Control: Mitochondrial Biogenesis Duality, the Metabolic Mechanism and Practical Applications.
Gregory S. Bambeck Ph.D. and Michael Wolfson J.D., M.B.A.
Kent, Ohio U.S.A. 44240
SUMMARY STATEMENT: Cancer, heart disease and diabetes II, the three largest killers of the first and second world nation's human beings (85%), and their disease antithesis, a healthy squirt from the fountain of youth, are finally defined under a singular unifying global hypothesis. Experimental molecular mapping proves that the regulatory pathway mechanisms define it as a true, real and clinically demonstrated system for the first time. Publicly available, practical and easily workable disease blocking and life extension implementation are readily available to anyone. There are three sections: ABSTRACT; PATHWAY MECHANISMS; PRACTICAL APPLICATIONS. Read on!
ABSTRACT
Full mitochondrial biogenesis is a two phase temporal process consisting of an early phase primarily associated with anabolism, cell replication and the making of over a thousand constitutive mitochondrial proteins that create new, but NADH to OX/PHOS inefficient mitochondria. Between these replication events, cell homeostatic controls up regulate a late phase set of mitochondrial respiratory chain proteins that create efficient NADH to OX/PHOS associated with a shift toward catabolism and autophagy of dysfunctional mitochondria and other cell debris. The early phase (neogenesis) supports cell growth, rejuvenation and whole body vitality in the short term, while the late phase (regenesis) supports cellular housekeeping and repair functions in the life extending long term. The immediate upstream effector of mitochondrial biogenesis is the mitochondrial proliferator co-activator (PGC-1alpha). Its up regulation institutes neogenesis and its down regulation institutes regenesis. Caloric restriction (CR) activates regenesis by up regulating adenosine monophosphate activated kinase (AMPK), while cancer activates neogenesis in the absence of regenesis by down regulation of the same AMPK pathway, upstream of PGC-1alpha. Recent ‘rediscoveries' show that a cancer cell metabolism proposal of 1980, is correct in its many metabolic particulars. Most cancer cells are mutationally glycolytic fetal enzyme driven ‘sugar junkies' supported by obligate mitochondrial ATP production inefficiency. Cancer cells are stuck in this cell growth drive state (metabotype), and become relentlessly replicative under the influence of mitogens. Recent genuine discoveries show that inhibition of the life extending CR pathway supports this ‘sugar junkie' growth state by creating and maintaining inefficient and neogenic mitochondria in the presence of forced hyperglycolysis. Blocking fetal glycolysis and re-establishing the CR pathway pattern creates the regenesis of efficient mitochondria and halts cancer cell growth, and can sometimes even initiate cancer cell apoptosis. We describe the pathway mechanism as a unidirectional feedback loop starting with the CR target, AMPK, and how it regulates mitochondrial biogenesis, the reactive oxygen species (ROS) output, of which, feeds back to AMPK. We also make sense of CR mimetic resveratrol, and its bioavailability in this context, and further employ these understandings to envision simple nutriceutical and lifestyle synergies to fight cancer, the major diseases of aging and even aging itself.
PATHWAY MECHANISMS
To make this easy to understand, we wish to start with some rules of the road. First, when we use the adjective ‘chronic' or prefixes like ‘hypo' or ‘hyper', we are referring to aberrant, unnatural or man-made over impacts upon normal homeostatic systems or typical physiological shiftings in standard metabolic systems. These words are used to emphasize a principal or powerful effect of some kind. Second, since CR is the ‘gold standard' of life extension, we will use it as a ‘home base', or reference point, that most of our forays will diverge from, and then return to. Third, we will focus primarily on the unidirectional multi-toggle switch feedback cycle from AMPK to target of rapamycin (TOR) to PGC-1alpha to ROS to sestrin (SESN) and back to AMPK, with the up regulation of AMPK effectively down regulating every other component of the cycle downstream of it. Since the system is a closed feedback loop, everything is upstream of everything else as well as downstream of everything else, like the proverbial snake that eats its tail. However, extrinsic factors affecting any component can over ride their immediate upstream regulators, as we will often point out. Memorizing, or keeping a note pad with this simple AMPK, TOR, PGC-1alpha, ROS, SESN circuit, as a principal reference point, keeps the discussion grounded.
We will begin with a brief outline of the CR pathway. Most simply put, CR activates AMPK which down regulates TOR. Down regulated TOR shifts cell metabolism away from anabolism and toward catabolism, initiates autophagic clean up of cell debris, such as dysfunctional mitochondria and down regulates PGC-1alpha. When down regulated, PGC-1alpha results in the regenesis of existing mitochondria by initiating the transcription of mitochondrial respiratory chain proteins that efficiently link NADH to OX/PHOS ATP production. This causes mitochondrial ROS production to fall, which in turn, down regulates the ROS sensor, SESN. SESN then down regulates its stimulation of AMPK, causing the circuit to rebalance back toward its homeostatic center. Note here that active SESN up regulates AMPK and inactive SESN fails to activate, so its up regulation is active while its down regulation is passive. Thus, continued CR will bypass SESN and chronically up regulate AMPK to constantly enhance the CR pathway to reduce mitochondrial ROS. Elevated ROS is the principal life shortening component in the system, and thus, its repression is the largest single life extender known. This example demonstrates that increased AMPK activity causes a decrease in all the other four (TOR, PGC-1alpha, ROS, SESN) components in the unidirectional feedback loop. Conversely, decreased AMPK activity, as in p53 dysfunctional cancer cells, causes the up regulation of the same four components down stream of it, which incidentally, causes the neogenesis of inefficient mitochondria.
As exemplified by our CR model, AMPK to TOR to PGC-1alpha are the principal mitochondrial biogenesis inputs and their responses, while ROS to SESN are the principal mitochondrial outputs and their responses. We know that there are many steps between each of these five major toggle switches and that there are also myriads of branching pathways and gene up and down regulations stemming into and from each toggle switch, but they will be mentioned in passing only as needed, because it is the central unidirectional cycle that is critical to the cancer, diseases of aging decline and life extension metabolics we key on, herein. Very elegant and evolutionarily apt extensions of this central and related circuits and their nutrient sensing pathways can be found in Science, vol.327, 3/5/2010 p.1210 and vol.328, 3/16/2010 p.324. Lastly, the central focus, here, is on cellular bioenergetics and metabolics because these functions hail back to single cell eukaryotes and have finally earned their seat at the cancer cell control systems round table along with telomeres, growth factors, apoptosis etc. Later, we will see how the AMPK, TOR, PGC-1alpha, ROS, SESN circuit is the exact same circuit controlling cancer and life extension, albeit operating in the opposite direction. We shall also see that cancer ‘cure', or at least control, and CR share the exact same circuit when operating in the same direction, with mutationally driven hyperglycolysis being the lone but critical cancer stand out. But first, let's look at each major component in the system.
AMPK stands at the headwaters of the CR pathway. AMPK monitors cellular energy charge by being sensitive to the AMP/ATP ratio, which generally represents the fuel nutrient availability in the cell. High concentrations of the energy rich ATP molecule represent fuel nutrient sufficiency and concomitant low AMP. Conversely, high AMP and low ATP indicate low fuel availability as in CR, which up regulates AMPK via AMPK kinase. Increases in AMPK can inhibit TOR by countermanding the growth factor pathways that activate TOR. Things that activate AMPK inhibit TOR, and things that inhibit AMPK activate TOR. Things that activate AMPK initiate the CR pathway and support life extension and inhibit the cancer metabotype. Standing directly upstream of AMPK, SESN activates AMPK when it self is activated by the cancer cell growth suppressor (p53) or by ROS, mostly of mitochondrial origin. The P53 protein is pro-apoptotic and its inhibition or dysfunction is found in about half of all cancers. Components or systems that reduce AMPK activity shorten life expectancy and promote the cancer metabotype. CR mimetics extend life expectancy and inhibit the cancer metabotype.
This last effect is exemplified by the anti-type II diabetic drug, metformin which is a direct activator of AMPK, causing the typical CR reduction in insulin resistance and the downstream inhibition of TOR. Metformin has been found to increase life expectancy in cancer victims, diabetics and healthy animals. Direct activation of AMPK by metformin enhances the ROS activated SESN switch or can over ride SESN inactivation by faulty p53. Intracellular concentrations of resveratrol in the 20 to 50 uM range activate AMPK similarly to metformin. Dietary free resveratrol rarely attains concentrations above the low single digits of uM. Metformin is our best known chemical example of a CR mimetic.
Now, let us take a brief tour of TOR. In our unidirectional metabolic loop activator model, TOR is the first primary target downstream of AMPK. TOR is a major NADH/NAD redox sensor and a master metabolic regulator switch involved in a dizzying array of integrated pathways, which can be found in a web search under ‘mammalian target of rapamycin'. Fortunately, several major converging and diverging pathways impinge upon and emerge from TOR, allowing us to simplify matters. For instance, mitogens, growth factors, hormones and AMPK act upon TOR through a common intermediate called TSC2. Thus, in a functionally simplified sense, TOR responds to a delicate balance of AMP/ATP energy charge, NADH/NAD redox state, fuel nutrient availability, mitogens, growth factors, growth factor suppressors and genotoxic ROS load. TOR outputs are as multifunctional as its inputs, but are most commonly associated with the integrated regulation of mutually exclusive anabolic or catabolic systems.
The down regulation of TOR by elevated AMPK activity (by CR, for example) institutes a shift toward catabolic efficiency in support of the caloric restriction demands for maximum energy output from maximum fuel conservation under nutrient fuel limiting conditions. In this regimen, another TOR pathway institutes increased mitochondrial respiratory efficiency through the regenesis pathway, and still another TOR pathway up regulates the autophagy of cellular debris and dysfunctional mitochondria. Cellular efficiency, ROS reduction and elevated housekeeping functions increase life expectancy and foster disruption of the cancer metabotype. This process can also be enforced by the TOR inhibitor and foreign tissue rejection suppressor, rapamycin. Rapamycin can facilitate life extension by pulling an end around AMPK and directly inhibiting TOR to switch the cellular drive state from anabolism to catabolism, and also very importantly, push mitochondria into the state of regenic efficiency by down regulating PGC-1alpha.
Finally, as the last major element in the mitochondrial biogenesis input side of the unidirectional loop, a short summary of PGC-1alpha function might be in order. When PGC-1alpha is activated, it turns on over a thousand genes which are devoted to the very complex but singular mega-function of building more mitochondria (neogenesis). As we saw, when TOR is up regulated, it in turn, up regulates PGC-1alpha, and the building of all of the mitochondria except the respiratory chain, is instituted. The respiratory chain transcription elements can only be constructed when PGC-1alpha is down regulated, later. Chronic stimulation of PGC-1alpha via chronic up regulation of TOR by growth hormone keeps mitochondria in a state of neogenesis with impoverished regenesis, which is a high ROS generator.
This nowhere more manifest than in the cancer cell metabtype. When mitochondrial respiratory NADH to OX/PHOS coupling is compromised by neogenesis without regenesis, the mitochondria, although primarily catabolic in function, actually enhance anabolism by supporting increased glycolisis and, thereby, shift the balance of glycolytic products, mitochondrial feedstocks and NADH reducing power toward cell building, all supported by an increase in the glycolytic to mitochondrial ATP production ratio. In his dissertation at Kent State University on mitochondrial alterations in a lymphoblastic lymphoma transplanted into DBA/1J mice, in 1980, Bambeck reviewed dozens of cancer type cell mitochondria, and saw a pattern. He provided a detailed catabolic chart, a general NADH cell nutrient and building block flow chart and an extensive narrative describing these connections. The AMPK, TOR, PG C-1alpha mitochondrial input side of the CR pathway, only now available, finally supply the control elements that prove his hypothesis, which we have just begun to re-discover in the last two years. It is surprising how accurate this thirty year old description is, considering there was no awareness of AMPK, TOR, PGC-1alpha or the vast array of intermediate connections in this regulatory pathway, at that time. However, even today, our new knowledge still boils down to the control of redox, energy charge and metabolites, which could be monitored even, at that time, in the absence of this modern regulatory pathway knowledge. This was done by constructing metabolic flow charts under different drive states and deducing where control links must exist, even if they were, as yet, unknown.
Just as metformin can bypass SESN by directly up regulating AMPK and rapamycin can bypass AMPK by directly down regulating TOR, T3 thyroxine in its non-shivering thermogenesis mode, can mostly bypass TOR by up regulating PGC-1alpha. In addition to ignoring the TOR anabolic/catabolic toggle, this can help illustrate the temporal duality of PGC-1alpha function.
A single dose of T3 thyroxine binds to nuclear DNA upstream of the mitochondrial biogenesis activator master control system and the PGC-1alpha binding co-activator, and begins transcription. Within five hours, activated PGC-1alpha causes more than 1,000 nuclear genes that are specific to the building of new respiration impoverished mitochondria to begin transcription. These very long mRNAs contain the code for their respective gene products as well as the leader sequences for their respective mitochondrial targets. These mRNAs are exported from the nucleus to the cytoplasm to form translational polysomes where mitochondrial outer membranes become confluent with endoplasmic reticulum. Depending on their signal sequences, these mitochondrial proteins are ferried to their mitochondrial home compartments to take up functional residence. After about 48 hours the thyroxine and PGC-1alpha signal system decays and a late set of nuclear and mitochondrial genes specifying the components of the respiratory chain are activated, causing these poorly coupled neogenic mitochondria to become efficient ATP producing regenic mitochondria. In chronic hyperthyroidism, the neogenic phase is powerfully up regulated relative to the regenic phase and the resultant ROS damage is severe enough to dramatically shorten life. A common term for early hyperthyroidism termination is ‘burnout', because unlike TOR and its anabolic activated neogenesis function, the thyroxine activation is catabolic.
In the thyroxine activated neogenic phase, there are also a set of uncoupling proteins (UCP) that are produced that allow NADH protons to ‘leakback' into the mitochondrial matrix without their chemiosmotic potential being captured and stored as high chemical energy ATP. Although this an over simplified description, the net result is that the uncaptured energy becomes manifest as heat, which is easy to measure. Thyroxine also supports catabolism by shifting fuel sources from low energy per carbon sugar to high energy per carbon lipid, and if need be, protein. However, when PGC-1alpha is up regulated by TOR, anabolism is supported and glucose is the preferred fuel. This difference becomes not only important, but highly magnified when we consider the cancer metabotype, later. Chronic up regulation of PGC-1alpha, whether anabolically driven by growth hormone stimulation of TOR or catabolically driven by direct stimulation of thyroxine as in hyperthyroidism, results in an incomplete mitochondrial biogenesis stuck in a high ROS producing neogenic state which can induce cancer and shorten life span via ROS produced genotoxicity and stochastic randomization of proteins compounded by the absence of phagocytic housekeeping functions and DNA repair systems. Chronic neogenesis in the absence of regenesis is not only a cancer cell metabotype inducer but a cancer cell metabotype maintainer, as well.
Another way to uncouple NADH from ATP production is for mitochondria to export NADH to the cytoplasm via the NADH/NAD shuttle system. In growing and dividing cells, the redox and energy charge states always lag, so this system is employed more heavily. Also, in non dividing quiescent cells, citrate in excess of krebs cycle needs can inhibit the ‘committing' enzyme phospho fructo kinase (PFK) at the headwaters of glycolysis. Fetal PFK is often elevated in cancer cells. Although it is an inefficient ATP and NADH producer, glycolysis can run at explosively fast rates when stimulated. For the sake of brevity, we will not distinguish between the two uncoupling forms in this document.
The above described AMPK to TOR to PGC-1alpha portion of the closed unidirectional loop are the inputs to the mitochondrial neogenesis/regenesis system. The ROS to SESN portion represent the ROS output feedback loop to AMPK. Although the exact mechanism of the mitochondrial output of ROS to SESN is still to be articulated, its requisite path and net results are unambiguous. Increases in ROS eventually leads to activation of SESN, which in turn, activate AMPK to inhibit TOR to down regulate PGC-1alpha to institute mitochondrial regenesis to reduce ROS. SESN gene knockout drosophila die prematurely of age related disorders, and the anti-oxidant vitamin E protects life length function in SESN gene knockouts.
The system, as so far described is more elucidative of life extension than it is of the generation and maintenance of the cancer metabotype, soon to be discussed. Basically, life extension via the CR upregulation of AMPK occurs, mostly due to the reduction of ROS caused by mitochondrial regenesis of efficient ATP producing mitochondria. This essentially puts the adult organism in an extended holding pattern until nutrient energy supplies can support fecundity and other energy intensive functions such as immune surveillance, wound healing and muscle building.
Here is how resveratrol probably fits into the picture. In dietary quantities, free resveratrol enters interstitial cells in too low a quantity to mimic caloric restriction by more than a very modest degree. In these quantities, it up regulates mitochondrial neogenesis more so than regenesis by a moderate but significant up regulation of thyroxine. The purported mechanism is via its mimicry of beta-estradiol activation of hypothalamic stimulation of thyroxine stimulating hormone releasing hormone. But, resveratrol is also a powerful anti-oxidant. In this mixed effect, it acts as a caloric restriction meta-mimetic rather than an actual AMPK stimulating mimetic. It does not significantly up regulate AMPK, but it activates PGC-1alpha without up regulating TOR, so it is not acting like growth hormone, either. This is a huge difference because, like CR elevation of AMPK, it is definitely not anabolic and it sports its own catabolic influence. On the other hand, it is unlike thyroxine stimulation in that it scavenges ROS, evoking a regenesis rather than a neogenesis result, another net outcome of CR. Regardless, resveratrol is more neogenic than regenic in these quantities. How much its mixed CR mimetic function plays into this tortuous scenario, is anybody's guess, and its numerical impact on the ROS load is unknown. The largest evidence supporting this scenario is that dietary resveratrol's cancer killing and life extension functions, as seen at in vitro concentrations, some ten times higher, are not significantly manifest. At the dietary levels it would be prudent to force a neogenic default to regenesis just to hedge the bet toward a definitive CR like outcome. Vigorous endurance exercise after an over night fast would probably turn the trick via creating a sugar depletion oxygen debt. In humans, resveratrol followed by exercise, even without fasting, converts glycolytic fast twitch white muscle fibers into aerobic red slow twitch fibers, and increases mitochondrial cell volume from about5% to 30%, with regenic characteristics. Similar results occur in fasting runners in the absence of resveratrol. The experiments we need are rather obvious.
The in vitro life extension and cancer apoptotic effects of resveratrol in the 20-50 uM range are so enticing that this dietary bioavailability deficiency should soon be overcome. Already, free resveratrol serum levels well above the 20-50 uM target range are being reported, industrially. Also, synergistic molecules like quercetin and co enzyme Q with antioxidants are in the mix. Still, TOR down regulation and mitochondrial regenesis are requirements for full CR impact. We explore these issues in the practical applications section, later. But, for now, our metabolic feedback loop attentions divert their focus onto the cancer metabotype.
From a genetic perspective, cancer cells appear insane. Between the chromosomal inversions, insertions and uneven cell divisions that render cells into a heterogenous mix of hundreds to thousands of genes in polyploidy or haploidy, add to this, the changed protein complement and its post translational miss modifications, and the result becomes a bewildering array of changes from any given cancer's not quite fully differentiated stem cell progenitors. Although each cancer cell type retains many of the characteristics of its parent cell type, shot gun analysis, such as 2D electrophoresis and tryptic digest multi-gradient HPLC (high performance liquid chromatography) and MALDI-TOF (matrix assisted laser desorption ionization-time of flight) mass spectrometry, demonstrate that no two cancers are alike and that a given cancer is not even like itself. A cancer tumor seems as if it is composed of a heterogenous thematic of a precursor cell type engaged in a hyper-Darwinian selection for survival in an organism that is desperately trying, but failing, to kill it.
Fortunately, even cancer cells must obey the laws of thermodynamics, and they must do so within the constraints of the metabolic tool kit of sugar, amino acid, lipid and nucleotide apportionments and redox (NADH/NAD) and energy carriers (AMP/ADP/ATP) that permit the cell to grow and divide, so as to be able to grow and divide, and so on. Note here, that the sugar and carbohydrates are the cheapest energy source in the earth's biotic food web. Lipid is a bit pricier, but proteins and nucleotides are very expensive because phosphate and redoxable nitrogen are nutrient limiting, pretty much, planet wide. Thus, sugar is the preferred fuel during cell growth and division (especially during hypoxia), while lipids, proteins and nucleotides are preserved as building materials. These nutrient limitations and metabolic requirements were fixed in stone a billion years before the first multicellular organism existed. In addition, cancer cells share a lot of features with fetal cells. Very importantly, they are always outrunning their fuel and oxygen supply needs, so they take on a hypoxia metabotype that induces blood vessels to grow toward them. This blood vessel growth is called angiogenesis. They also dramatically increase their glycolytic rate, in some cases well over 1000%. Most importantly of all, this changes the glycolytic to mitochondrial ATP production ratio by even a greater percentage, due to mitochondrial paucity and/or inefficiency. Like fetal cells, they become glucose junkies as they parasitize the sugar making hepatic gluconeogenic processes of their host, but unlike fetal cells, they cannot turn glycolysis off.
Because of this hypoxia and its anabolic requirements, cancer cell growth is always neogenically out pacing its regenic function. Many books have been and still will be written about fetal and enviromental bioenergetics and its evolutionary and organismal growth condition implications, and especially now, even more so, that the primary elements of the CR pathway have been clarified, and implicate cancer and other diseases of aging. But, for now, the main points, described above, will suffice.
How all this CR based AMPK feedback loop stuff fits together to arrive at cancer cell intermediary metabolism is an astonishing wonderment and a stunning new achievement. We grant many laudits and heaps of praise for the scientists who slogged through years and hundreds of thousands or even millions of man hours to elucidate the particulars of the regulatory loop and its myriad of attendant pathways. Even though cancer research and CR authors (as well as diabetes and cardiovascular researchers) may not yet know it, their results show that the cancer metabotype and the CR pathway are the exact same pathway, albeit operating in basically opposite directions and under different conditions, with the AMPK loop and mitochondrial neogenesis vs. regenesis as core control elements in both cases, and with cancer cell glycolysis providing its own caveat. The fact that type II diabetes and cardiovascular hyperplasia and cardiac hypertrophy are also outcomes of this pattern, is even more amazing. Readers of this document would easily understand and be pleasantly surprised by the basic cancer connection if they read (and this is a must read) New Scientist, 5/15/2010 p.6, a brief outline, of which, is below, after the Warburg correction discussion.
In the last two years, cancer researchers have proven that the particulars of glycolytic and aerobic metabolism in cancer cells are precisely as previously described in 1980. At that time the hypothesis corrected a flaw in the Warburg aerobic glycolysis hypothesis by postulating that cancer cell mitochondria suffered from an ATP production shortfall resulting in an anaerobic to aerobic ATP differential as opposed to Warburg's mitochondrial oxygen consumption deficiency concept. This is an important difference because it changes the NADH/NAD, ATP/ADP and substrate flows in the cell. It was also described, in detail, how this shortfall was integrated with glycolytic fetal enzyme activation to force the system to amplify the, as then poorly understood, anabolic command system, to operate in an irreversible state of cell growth and division, we previously have coined as the cancer metabotype. Interesting methods of attack designed to kill or renormalize cancer cells were envisioned at that time. With our new found knowledge, we might wish to revisit some of these strategies, in a search for synergies. It is remarkably serendipitous how the ‘rediscovery' of this forgotten system during the last two years is so similarly identical in such a wide array of particulars. In all cases, whether as old discoveries, rediscoveries or new discoveries, the results unambiguously show that the cancer metabotype is obligately and inextricably intertwined with the CR pathway, and with mitochondrial over neogenesis with a paucity of regenesis. It is this synthesis that is the really new stuff.
As an overview, from a metabolic standpoint, most cancer cells are stuck in mutationally up regulated fetal enzyme induced hyper glycolysis supported by down regulated AMPK to TOR etc. driven mitochondrial neogenic ATP production deficiency, in ways that the cell cannot recover from, as it can in fetal cells, at least in normal in vivo circumstances, short of artificial intervention. Under the influence of increased mitogen drivers and decreased or dysfunctional cell growth suppressors, the cell is forced into irrepressible and irreversible rounds of growth and division. We ignore metastasis and other issues, here, as we are focused on the ancient metabolic drive states of cancer cell induction and maintenance as opposed to progression.
What the researchers in the New Scientist review article found was that blocking fetal pyruvate kinase enzyme driven glycolysis with dichloroacetate ‘reawakened' (their words) mitochondrial regenesis (our words), re-establishing normal glycolytic to mitochondrial ATP production ratios and metabolite flow, and brought cancer cell growth to a virtual halt in brain glioblastomas. Furthermore, previous hospital records showed that up regulation of AMPK with metformin in diabetic lung cancer victims increased survival times. This is the first time, in humans, for it to be shown that CR and anti-cancer therapies share the exact same AMPK control circuit, and with an anti-diabetes drug, to boot. We must also note that the system has been shown to work in numerous mouse cancers, and this is one time in cancer research that mice and men really share an ancient and attackable metabolic control pathway. This is just the early ‘sledgehammer' phase of the human work. More sophisticated assaults are envisioned with excited expectancy. Let us hope that we don't have to find too many fetal enzyme blockers, because even thirty years ago, we knew of other such fetal enzyme supporting changes in glycolysis and its attendant anabolic NADPH providing pentose phosphate shunt, in different cancers.
Reducing hyperglycolysis and increasing mitochondrial efficiency are the two key elements in slowing the impact of age related like cancer, type II diabetes and cardiovascular dysfunction. For instance, in the aging adult, cardiovascular ROS damage institutes mitogenic and hyperplasic thickening in the intima of the vascular tree, and ventricular hypertrophy concomitant with mitochondrial decline and a steady state shift from efficient high energy lipid catabolism to low efficiency glucose catabolism. Contrast this to hypoxic fetal conditions, when birth provides abundant pulmonary oxygen followed by full cardiac mitochondrial biogenesis, a rapid shift from carbohydrate to lipid catabolism, a conversion from parasitic high affinity fetal hemoglobin F to free living lower affinity adult hemoglobin A and a decrease in ROS production. The first is a stop-gap response to ROS induced genetic damage, while the second is a finely tuned genetic system response to an energy opportunity. Both are mediated by the AMPK, TOR etc. feedback loop, and judicious stimulation of this loop via CR or its mimetics are shown to yield significant inhibitory impacts on these exact forms of cardiovascular decline. Type II diabetes is a similar whole body response to the same type if insults found in cardiovascular decay, and can be staved off by direct metformin activation of AMPK that lowers insulin resistance and creates cellular housecleaning and mitochondrial regenesis. Metformin has been in use from long before we were even aware of such things as the sestrin feedback loop, mitochondrial neogenesis, regenesis and its relation to fetal hyperglycolysis!
Both neogenesis and regenesis are critical to retaining a juvenile youth state in adult cells. By analogy,
