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“To kill an error is as good a service as, and sometimes even better than, the establishing of a new truth or fact”
~ Charles Darwin (it's evolutionary baybeee!)

Thursday, March 29, 2012

An elegans argument in insulin's favor

No, that's not a typo in the post title.  I'm referring to the nematode (aka worm) known as Caenorhabditis elegans, or C. elegans  for short.   More recently the topic of longevity has been introduced into discussions regarding diet and health, and when one looks into aging research, they will inevitably be inundated with studies involving these worms.  The caption of the picture at right is "adult and two juveniles".  Apparently there are some similarities between some genes in this worm and insulin receptor genes in humans.  I'm always intrigued when the "I am not a mouse (or rat)" crowd starts citing worm longevity research to support their theories on metabolism and endocrinology.  Surely they see that where there are differences in rodent and human physiology, these differences are dwarfed many times over when one tries to extrapolate worm physiology to humans!   


And yet from time to time, studies on these worms looking at the effect of not only calorie restriction but introduction of glucose/carbohydrate effecting longevity are used to make the case that insulin = bad.  So first let's learn a bit about our squiggly brethren, shall we?

Here is a nice, lay-friendly description of them:  A Short History of C. elegans Research, and another source:  C. elegans II

Some highlights:  
  • These worms are really, really tiny!  They are roughly 1mm in length, for those unfamiliar with the metric system, there are a little more than 25 millimeters to an inch.  
  • As a cold-blooded animal, C. elegans has a limited temperature range (~12−26°C) at which it is viable and fertile.
  • There are two sexes, hermaphrodites and males.  Hermaphrodites can self-fertilize or mate with males but cannot fertilize other worms.  
  • The wild type worms all have 959 cells,  cell number and position remains constant.
  • They are transparent.
  • There are a number of genetic mutants to experiment with.
  • They live only 2-3 weeks under normal circumstances.
  • They can enter an alternate state called the dauer state when resources are scarce.  This is essentially a hibernation where the worms sleep until resources become available and the worms emerge from the state.
Depicted at right is the life cycle of the C. elegans.     Do tell me more about this "dauer" pathway!  Look!  The larva skips from L2 to L4 stage.  Whassup with that?
When starved, young C. elegans larvae can enter into a dormant state called the dauer larva. Although dauer larvae are capable of moving, they are characterized by a unique morphology and enter a period of dormancy with reduced activity and metabolic rate. Dauer worms can survive for months in this state and the time spent as dauer larvae is additive to their total longevity.
So basically in the worm equivalent of infancy, a starved worm can go through this alternative state of arrested development.  From:  C. elegans dauer formation and the molecular basis of plasticity
Notably, in favorable environments, C. elegans will develop rapidly to reproductive maturity, but in unfavorable environments, animals will arrest at the dauer diapause, a larval stage geared for survival.
In this paper we learn that food restriction and, oddly enough warmer than normal temperatures, lead to dauer formation.  We also have the following description of the metabolic state of these worms:
Dauer formation entails vast coordinate changes throughout the body, suggestive of an endocrine mechanism. Prior to the dauer molt, they feed and store fat and carbohydrate. During morphogenesis, they suppress food intake, undergo radial constriction, and remodel various tissues of the body. Once in diapause, they are nonfeeding and spend down their reserves, converting fat to glucose through the glyoxylate cycle. Aerobic respiration is suppressed in favor of glycolysis and fermentative metabolism.
Sounds almost human to me ... not!   In the longevity literature, there are several mutants of this worm that are frequently referenced, and the focus is on the insulin receptors.  These seem to imply that low insulin levels are conducive to longevity in worms.  From the introduction of this study (I've decluttered the references, see full text link if interested)
In C. elegans, mutations in several genes, such as daf-2 and tph-1, cause an extension in life span and also result in an increased fat content in the intestine [the main fat storage organ in these worms]  speculated that these mutants shift from fat-metabolizing to fat-storing adults. Additionally, mutations in these genes result in an increase in TG content. We asked whether tub-1 mutants that have a higher TG content also show a change in life span ... in addition to increased fat storage, mutations in tub-1 lead to a 20% extension of life span. 
So there you have it folks.  Three mutations in a worm -- mostly all involving insulin/insulin receptor disruptions -- lead to increased lifespan but FATTIER worms.  I have many more C. elegans papers that say much the same thing.  When I get around to it one day I'll post them up at least in the library.  They all point to the longer living worms depositing more fat.   

Now, I don't know about you, but here I thought the purpose of carbohydrate restriction for us humans was to reduce body fat and become fat-burning machines.  As this abstract indicates, the daf-2 mutant is the low carbers dream worm to bolster the case for keeping your insulin levels as far down in the toilet as you can to live longer:  
A C. elegans neurosecretory signaling system regulates whether animals enter the reproductive life cycle or arrest development at the long-lived dauer diapause stage. daf-2, a key gene in the genetic pathway that mediates this endocrine signaling, encodes an insulin receptor family member. Decreases in DAF-2 signaling induce metabolic and developmental changes, as in mammalian metabolic control by the insulin receptor. Decreased DAF-2 signaling also causes an increase in life-span. Life-span regulation by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction, suggesting a general link between metabolism, diapause, and longevity.
Well, folks can't have it both ways.  A reduced insulin state may make me live longer, but if humans are like these worms, that would mean that it would also increase fat storage and decrease fat metabolism.  The exact opposite of what TWICHOOB's keep telling us is the result of lowering insulin levels.  I suppose some might look at these worms and see evidence of a beneficial insulin-resistant-like state.  However I suggest that the C.elegans makes a better argument for robust insulin signaling in humans who cannot enter into anything remotely resembling a dauer state.    Especially if the humans have an interest in being lean or leaner.  Because the worm data is unmistakeable:  restriction => slowed metabolism and increased fat storage.

So I guess we humans have an intelligent decision to make.  Do we just want to live longer no matter the effects on our mental well-being, or do we want to optimize the life we're living.  Are the fatty longer living worms as fully functional as their wild-type counterparts?  I suggest reading:  Fitness cost of extended lifespan in Caenorhabditis elegans.
An insulin/IGF-I-like signalling pathway determines the rate of aging of the adult nematode, Caenorhabditis elegans. Mutations in genes encoding this pathway can result in a doubling of lifespan. While such mutations may appear to have little effect on development or fertility, evolutionary theory predicts that large increases in lifespan will not be optimal for fitness. We demonstrate by laboratory natural selection that partial loss of function of the insulin receptor-like protein DAF-2 results in dramatically reduced fitness even under laboratory conditions. Despite long-lived mutants appearing healthy, they exhibit a heavy fitness cost consistent with an evolutionary theory of aging.
Folks like Rosedale & Kruse will tell you that longevity is not paleo, yet at least the latter is telling us we need to look to evolution for keys to our longevity.  I look at this a different way because I see no reason for living just for the sake of being alive -- isn't it also about form and more importantly function?  I don't care what anyone tells me on that front ... I know the answer for myself.  If lower insulin makes for a fattier me who lives another 10 years but must rely on others for basic tasks, I want no part of it.  If, on the other hand, my insulin signaling can remain intact for the long haul it should preserve both my lean (functional) mass, and the metabolic integrity of the adipose tissue I do have.  I believe these worms do, in the end, make a rather elegant argument in favor of robust insulin signaling consistent with metabolic health and well-being.  So be it if longevity perhaps suffers.

12 comments:

Alex said...

Clearly, you don't understand the science. The objection, correctly stated, is that rodents are not furry little humans. Since neither those worms nor humans are furry like rodents, it is obvious that worm studies can be extrapolated to humans while rodent studies can not. You're welcome.

Evelyn aka CarbSane said...

Thank you Alex! I think I get it now. If a human is not a mouse, and a worm is not a mouse, clearly then a human is a worm. (Or some humans are - grin)

Tonus said...

"The objection, correctly stated, is that rodents are not furry little humans."

Am I the only person who saw that documentary about that Stuart Little guy????

Karen said...

Well a man can be a mouse or a worm but what does that mean for a woman? LOL

IcedCoffee said...

Not to sound argumentative, but how does any of this matter to a human (non-worm). This is not the way human physiology works, so it doesn't have any bearing on our food choices. Or am I missing something?

Lesley Scott said...

"Folks like Rosedale & Kruse will tell you that longevity is not paleo, yet at least the latter is telling us we need to look to evolution for keys to our longevity." Yes, I think you've put your finger directly on this state of ambivalence that seems to be taking over what Joe Q Public sees as "paleo". The cherry-picking that goes on in the PaleoAncestralLowCarb blogosphere reminds me of the more radical fringes of the environmental movement, which then unfortunately gets everyone tarred with the same brush. As KGH commented about the Gateking interview: the fallout is that PaleoAncestralLowCarb will be perceived as some fringe insulin-phobic mashup of Atkins & Deepak Chopra (or should I say ChOPrah, Sanjeev) rather than a template with some actual science backing it up that helps people better understand their biochemistry a bit so they can eat, live & move in ways more in tuned with how they were designed & that help them improve their health (and weight). Sad.

Evelyn aka CarbSane said...

Bwa ha ha!

Evelyn aka CarbSane said...

Welcome to the Asylum IcedCoffee! You raise a very good point which was sort-of the point of the first part of my post. We share physiology with these worms. Yet when the safe starches debate began, Rosedale was a big name coming back on the scene. Rosedale is into the longevity angle and basically believes we're all some degree of diabetic and blood glucose kills us thus should be kept as low as possible all the time and that low T3 and body temperatures favor longevity. Quack Frost (Jack Kruse) is now recommending ice baths to lower body temperature, and says if you feel cold on his diet that's a good thing, for much the same reason, and calorie restriction is part of his "Holy Trinity". The CR stuff comes from longevity studies on these worms and mice and there are humans doing CR in the hopes of living longer. Nevermind that when CR is instituted later in life, and not consistently throughout the life of these organisms, there is limited if any benefit on lifespan. The temperature effect on lifespan stuff comes mostly from research on these cold-blooded worms. They live longer in colder environments than warmer. I've got a post in the works regarding Quack Frost's latest thing and how it is misguided wrt warm-blooded humans.

Evelyn aka CarbSane said...

Third sentence should read "We share LITTLE physiology with these worms."

Evelyn aka CarbSane said...

Rosedale has posted a bit over at PaleoHacks. He is clearly NOT paleo, but he's a newbie on the paleo circuit all of a sudden (he was at that PaleoFX recently). So I guess the usury (yes I know that's not the correct use of that term) works two ways these days -- Rosedale is happy to revive his business with the exposure, and the organizers of events bearing a "paleo" label are happy to have his name recognition and that MD after his name. Sad indeed Lesley :(

Lesley Scott said...

"Quack Frost (Jack Kruse) is now recommending ice baths to lower body temperature, and says if you feel cold on his diet that's a good thing" - I remember from Mat Lalonde's interview (w/ Sean Croxton? w/ Ignatius...starting to b/c a big blur) he said that doing this ice bath thing would actually lead to an adaptive response of us building up an additional layer of bodyfat as a result. Which I know I don't want more of.

Sue said...

You can learn more from Quack Frost if you go on his new forum. There are 3 levels - the free one, the $48 per month or the $248 per month!

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