Response to Jim Watson’s wager challenge

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This blog entry is in response to the wager challenge in Jim Watson’s post Aging science wager challenges and prizes open to readers of 8 April, 2013.  As you will recall, $2.00 is the total at stake.

Normally, Jim and I see quite eye-to-eye when it comes to the science issues covered in this blog, as you can discern from previous blog entries co-authored with Jim. However, when it comes to these two wager issues, I think Jim is egregiously off base.  He is off-base in a very fundamental sense, that is in the very way he poses the wager issues. It is too strong to assert that his tricky formulations of these issues are just sheer baloney. Perhaps creamed pastrami or corned beef spam is a more appropriate metaphor.

Wording of Jim’s original challenge is shown in ordinary text and my responses are in italics.

“Vince: As I get to know you better, I now feel comfortable enough to create some “intellectual hormesis” between us.  Just like physical stressors are good for our bodies, I think that intellectual debate is good for our minds.  A fun way of creating debate is to do what Stephen Hawkings famously does with his astrophysics friends…..they make a wager.

I would like to propose that we make bets for a large sum of money…..one dollar per bet.  I would like to propose that we wager on the following controversies which I will “stir up” as follows:

I accepted Jim’s wager offer and promised this response.

1. Wager #1 – What is the most important signal?  ROS, nutritional substrates, or hypoxia?  [i.e.ROS signaling (via Nrf2) vs Nutritional & Hypoxic Signaling (via HIF-1a and SIRTs)] (I, Vince, think this refers to anti-aging interventions)

Based on what I have read of your writings, I believe that you are convinced that the key to understanding aging and doing something about it lies in the Nrf2 transcription factor.  Am I correct?  You are arguing that all efforts to do something about aging must increase the cytoplasmic-to-nuclear translocation of Nrf2 where it can bind to of the anti-oxidant response elements (AREs) at promoter sites.

Based on everything I have read, I disagree with the above fundamental premise and will “debate” with you that “ROS signaling” is not the most important signal. My premise is that low nutrients (i.e. redox signaling due to low glucose, fatty acids, and amino acid substrates) and low oxygen (hypoxia) are the most important “signaling mechanisms” that turns on longevity mechanisms.

Proposal:   I propose that we make an “intellectual wager” for the lump sum of one dollar.  To allow time for the debate, the winner will be “paid up” at end of 2013.  The “wager” is on which is the most important “signaling mechanism” for longevity – “ROS signaling” or “Nutrient/Oxygen signaling.”

I know Jim well enough to shy away from taking on his formidable intellect directly. So I am going to argue that “ROS signaling” and “Nutrient/Oxygen signaling, along with a number of other signaling mechanisms are equally important for longevity. In other words, the question itself is dumb.  Therefore I am proposing that the outcome of this wager be a tie. My argument hinges on what is meant by “importance,” and I can best start out with an analogous question.  “What is most important for the long-term trouble-free operation of an automobile, the engine, the transmission, or the wheels? It is tempting to answer “the engine”but in fact the automobile will not operate without any one of these components. The same is true for the question at hand. The body will not operate and die without both ROS signaling and Nutrient/Oxygen signaling.   Longevity, in fact the continuance of life of an organism, depends on multiple pathways, these two along with many others.

Perhaps the gist of Jim’s point is to ask which pathway is most important from the viewpoint of enhancing health and longevity.  That is, if we want to create practical health and longevity intervention, is it better to go after the ROS signaling or the Nutrient/Oxygen signaling pathway.  There, I would submit the answer is probably both, and that it is unclear whether one is more likely to prove amenable to effective interventions than the other

It is true that I have been an exponent of the importance of ROS signaling, but in fact so also have you been so, Jim. The arguments for the importance of ROS signaling have been laid out in multiple past blog entries and in my other writings and presentations starting with three often mentioned entries: The pivotal role of Nrf2. Part 1 – a new view on the control of oxidative damage and generation of hormetic effects, The pivotal role of Nrf2. Part 2 – foods, phyto-substances and other substances that turn on Nrf2, and  The pivotal role of Nrf2. Part 3– Is promotion of Nrf2 expression a viable strategy for human human healthspan and lifespan extension? The latter two blog entries are among those which suggest that this pathway offers significant opportunities for health–generating and possibly longevity enhancing interventions. I think Jim will agree that ROS signaling and the NRF2 pathway are key to several health and possibly longevity inducing processes of hormesis.  This, too, is pointed out in multiple blog entries such as in Multifactorial Hormesis – the theory and practice of maintaining health and longevity and in the PowerPoint presentations contained in the blog entry Multifactorial hormesis II. A nice thing about this pathway is that there are numerous interventions that can kick it off including eating a number of plant-based substances, radiation of various kinds, and taking very small doses of a number of toxic substances.

I think that the same importance, both for survival of an organism and for health and longevity inducing interventions, can be made for Nutrient/Oxygen signaling so I am not in a position to claim outright victory in this wager. Without doubt, low oxygen turns on hormetic hypoxia signaling as pointed out in the same blog entries related to hormesis.  And the hypoxia-induced hormesis can be health-inducing and possibly longevity-inducing. Interventions that can produce health effects related to glucose include calorie restriction(ref), exercise, alternative day fasting(ref), taking Resveratrol to stimulate SIRT(ref), and climbing mountains to achieve hypoxia.    

Personally I practice interventions in both categories, related to ROS production and to Nutrient/Oxygen signaling.  Some interventions such as vigorous exercise relate to both pathways.  Also, a new favorite set of interventionsof mine is utilizing cold shock, such as induced by leaving windows open in the winter here in New England while naked. Some day, when we “get the hormetic stressor dose right”, we might indeed discover that activating one particular set of stress pathways is clearly the best single way to go.  For now I am betting on both of our candidates and all others I can easily activate.

Wager #2 – What is the most important cellular adaptation mechanism? (i.e. hormetic response).  (i.e. anti-oxidant response element upregulation, unfolded protein response, mitochondrial biogenesis, DNA repair mechansims, autophagy, etc.)

Based on what I have read of your writings, I believe that you are convinced that up regulating the anti-oxidant enzymes is the most important cellular adaptation mechanism.  Am I correct?  According to you the most important “hormetic mechanism” is the up regulation of the anti-oxidant enzymes in response to low doses of “ROS” or through administer of phyosubstances that interact with the cysteine side chains of Keap1 (and Nrf2) and thereby effectively act as “ROS mimetics” to up regulate the AREs.

Based on everything I have read, I disagree with the above fundamental premise and will “debate” with you that up regulating the anti-oxidant enzymes is NOT the most important cellular adaptation mechanism.  For the sake of an intellectual debate and a one dollar wager, I will propose that activating autophagy is the most important cellular adaptation mechanism for longevity, not anti-oxidant enzymes.  Specifically, I am talking about “getting rid of bad mitochondria” by mitophagy, rather than trying to “mop up” all of the excess baseline ROS produced by these “leaky mitochondria”. I don’t think you can make enough anti-oxidant enzymes or ingest enough “exogenous antioxidants” to make a dent in the baseline ROS levels.  Both exogenous antioxidant use and endogenous antioxidant up regulation are futile.  Getting rid of bad mitochondria (the source of the excess baseline ROS) is NOT FUTILE. This is why I want to have a debate with you over the next year on this.

Proposal:   I propose that we make an “intellectual wager” for the lump sum of one dollar.  The question is what is the most important cellular adaptation mechanism? (i.e. hormetic response) that promotes health and longevity.  (i.e. anti-oxidant response element upregulation, unfolded protein response, mitochondrial biogenesis, DNA repair mechanisms, autophagy, etc.)  You say it is upregulating the AREs and I say it is upregulating autophagy.

My first line of response to this bet is that all the pathways Jim mentions are there for a reason, a very good reason —  we would soon die without any one of them.  They are all equally important for survival.  So I also declare this bet is a tie. This was also a dumb question.  

 True, I have written and thought more about the ARE’s than the other pathways.  I like them because they are so easy to upregulate using dietary substances, for example.  I also deeply respect your candidate, autophagy, as reflected in our recent blog entry Autophagy – the housekeeper in every cell that fights aging, and I quite agree that without autophagy our cells would soon die due to accumulated internal junk.  And, as declared in that blog entry “Recent discoveries have shown that almost every genetic, dietary, and pharmacologic manipulation proven to extend lifespan activates autophagy as part of its mechanism of action.”  Also, “There are many practical ways to activate Autophagy like consuming green tea and caffeine, and some less-practical ones.”  But wait a minute now, our two candidate pathways are not in fact independent.  In fact, Section 14 of the autophagy blog is devoted to “Autophagy is a key step in activating the Nrf2 pathway.  And Nrf2 expression can in turn(negatively) regulate autophagy.” And of course it is the Nrf2 pathway that activates the AREs.  So if you win the bet, I win too and if I win the bet you win too

As to your point regarding the importance of getting rid of “bad”mitochondria via autophagy:  sure I agree.  That’s essential.  But it is essential for us  to keep our mitochondria  from going bad in the first place  They are hot little beasts containing electron chain energy engines that can easily get somewhat dysregulated and start producing excess ROS.  A mechanism is essential to detect such ROS, picking it up as a signal, and activate the AREs to prevent the ROS from doing serious damage – including any damage that makes the mitochondria go bad.  Remember our blog entries Mitochondria in health and aging, and possibilities for life prolongation – Part 1:basics and Mitochondria Part 2: mitochondrial pathways, diseases and aging.  We require mechanisms both to get rid of “bad” mitochoindria and to keep them from going bad.  So I declare here too we have a tie.

As to the other stress-response pathways you mention: the UPR, the mtUPR, mitochondrial biogenesis, DNA repair mechanisms – they are all there for excellent reasons and we could not survive without any of them either.  Evolution is extremely economical and does not bother putting elaborate mechanisms in us without excellent reasons.

To allow time for the debate, the winner will be also “paid up” at end of 2013.

Of course Jim, you might want to come back with a rebuttal and seek to destroy what I have said and we can keep going on this argument.  However, at least as of now, I suggest that at the end of the year we both write each other a check for $2.00.  Also, I continue to invite readers to weigh in and take the prizes away from both of us.  Actually, I suggest that if a third party wins the wager, both Jim and I pay up our $2.00 losses making the total stakes $4.00 – doubling the stakes for that astute individual.