Chill out, live longer? How do VLC & caloric restriction factor in?

I've been working on a related post when I came across an interesting study that I thought was worth a blog  post on by its own and was more timely for other studies I've been looking at more recently. A sidebar of looking into the claims of L.Ron Rosedale is that he's really all about longevity and believes his diet will deliver on that promise.  What I'm about to say may shock  some of you, but, there's some evidence out there that he might just be right!   The Catch 22, however, is that where he's correct it flies in direct conflict to the claims and theories espoused by the other ardent evangelists of carbohydrate restriction.  

Any research into aging and longevity these days inevitably lands one into a sea of studies on teeny tiny worms known as C. elegans.   I have some stuff in the pike on these worms, but basically, two ways of  "naturally" extending the lifespans of wild type C. elegans are (1) growing them under lower temperature conditions, and (2) forcing the worms through a dauer state (essentially dormant) developmental phase as larva through "starvation".  Both of these manipulations have the effect of producing adult worms with reduced metabolic rate.  (Worms are not intended to be the topic of this post, but here is one review on metabolic rate and longevity for those interested).  The other popular species for longevity experiments is mice.  Caloric restriction in mice has resulted in extended lifespan coupled with a reduced metabolic rate.  At first glance, run hotter/faster, burn out, run cooler/slower ... fade away?

In any case, with worms, the body temperature is easily controlled by manipulating the environmental temperature.  But what of warm blooded animals?  You put a warm blooded animal in a cold environment and their metabolism increases.  In the case of small animals like mice, they are blessed with relatively (to total fat and body mass) large amounts of brown fat (BAT) which is the thermogenic fat in such animals.  As an aside, the original uncoupling protein (UCP1) is that which generates heat in BAT.  Warm blooded animals have a vested interest in keeping their body temperatures within a relatively narrow operating range.  So ... you put a worm in a cold climate and it's metabolism goes down, you put a mouse in one, and it goes up.  A transgenic mouse to the rescue!

Transgenic Mice with a Reduced Core Body Temperature Have an Increased Life Span 

Temperature homeostasis in mammals is regulated centrally by neurons located in the preoptic area (POA) of the hypothalamus, a region that includes the medial and lateral part of the preoptic nucleus, the anterior hypothalamus, and the nearby regions of the septum. This region is believed to contain the central thermostat, which keeps core body temperature (CBT) within a very narrow range even when the animal is exposed to a wide range of ambient temperatures.

Apparently the neurons of the POA sense temperature and regulate metabolism accordingly.  What they did was create transgenic mice with increased UCP2 activity in a neighboring region of the brain.  This increased uncoupling essentially locally heats the POA of these mice.  Sensing the mouse is warm, the POA dials down metabolism -- it's like aiming a space heater at your thermostat, it won't sense the cooler temperature of the room it's in and turn the furnace on.

This worked!  By messing with the thermostat, the core temperatures of the transgenic mice were reduced by 0.3-0.5 °C, and as predicted, lifespans were increased. A summary of the findings:

• Fed ad libitum, dietary intake was similar between transgenic and wild type mice -- they ate the same amount.
• Median lifespan was increased 12% in males and 20% in females
• Body weight did not differ for females, but beginning at 20 weeks transgenic males gained more weight than wild types, a difference reaching 10% greater bodyweight at 35 weeks.
• Transgenic mice lost less weight with 27 hr. food deprivation than wild types indicating reduced metabolic rate that did not differ between genders.

The authors describe the results of the food deprivation experiment as evidence of "increased energy efficiency".  What I'm seeing on an increasingly regular basis is a diametrically opposed split in the VLC world.  From  the weight loss camp, we are regaled with tales of the super charged fat burning metabolism, the ability to lose and maintain weight eating far more fat than carb calories, and the promise that lowering insulin levels disfavors fat accumulation.  The MADdest of hatters (Eades) in his most recent book that fat excesses will be blown off by futile cycles and/or uncoupling.  From the health and longevity camp, the metabolism becomes super efficient with the premise that idling more slowly extends lifespan by minimizing wear and tear.  A lean phenotype is the purported result of such a metabolic state, but it's not about losing weight. In his 2005 book, from Google books, Rosedale states:

The fourth and sixth bullet points are in direct opposition to the claims of eating thousands of calories, running hot and basically feeling all warm and fuzzy all over eating low carb.  Many, many who undertake LC diets already have compromised thyroids and feel cold all the time.  Whether either of these reponses actually occurs to significant degree on a low carb diet, one thing is true:  They cannot both occur! 

Since we're talking longevity, let's focus the remainder of this discussion on Rosedale's fifth bullet point:  Calorie restricted animals have a lower percent body fat (as demonstrated in nearly every study).   Let's look at one such CR study:  Mild Calorie Restriction Induces Fat Accumulation in Female C57BL/6J Mice .  Now, this wasn't a longevity study, it lasted only 3-4 weeks in 8-10 week old mice ... but the bottom line was that caloric restriction during a period of substantial growth for a mouse resulted in slightly smaller (if at all) mice who were decidedly fattIer -- e.g. they had a higher percentage of body fat because they gained almost 70% more fat mass than the ad libitum group.  This finding was attributable to a 20% reduction in resting metabolic rate.  As I'll be discussing in the coming weeks, those worms too are notably fattier than their shorter lived cousins.  It is important to note that the longevity models (whether environmental or genetic) are not generally "fat" as in being larger/heavier/etc. than their wild type cousins, but they do tend to be fattier.  

So ... if, as an adult, you change your diet to something VLC, what metabolic magic can you expect?  Will it extend your lifespan and favor partitioning of fuel into fat stores while lowering your metabolism?  Or will it turn you into lean, mean, steam blowing, fat burning phenom?  It can't be both ways.  

(image link to view larger)

Remember Mighty Metabolism Mouse?  In this study, two of the interventions compared were CR (to 60% ad libitum cals) and ketogenic diet (KD).  Although the KD mice ate as much as the normal ad libitum fed mice (A), they achieved reduced bodyweights similar to the CR mice (B).  Ahh but look at (C) on the bottom there  This was body heat and the comparison between KD and CR is rather significant.  The KD mice in this study are running hotter and faster than the CR mice.

I think it would be fair to say that these mice on  a Rosedale-style diet  do not share the longevity profile of the calorie restricted mice.  

Here is another mouse study looking at energy expenditure (aka metabolic rate) for KD vs normal chow fed mice.  In this study, the mice were 15% lighter attributable to a 17% increase in energy expenditure.  We have some additional information here on body composition of the mice.  The ketogenic diet clearly produced a fattier mouse despite higher energy expenditure and reduced overall body weight.   (And, despite having insulin levels half those of the regular chow fed mice!!)  It is worth noting that in this study they measured hepatic (liver) insulin sensitivity and the KD mice exhibited "severe hepatic insulin resistance" associated with a 3.5X increase in hepatic diacylglycerol (DAG) -- intermediate fatty acid metabolites -- content, a hallmark of non-alcoholic fatty liver disease, NAFLD.   This needs further attention!

So ...  the longevity in calorie restricted mice seems associated with (a) reduced energy expenditure and (b) body temp at the expense, apparently, of (c) higher body fat percentages but  (d) normal to lower body weights.  Does a VLC diet get us to that exalted state?  The studies cited here seem to imply that VLC would produce the desired body weight and composition outcomes (c&d) characteristic of longevity, but the opposite of the metabolic outcomes (a&b) characteristic of same.

For me, reading these studies is  rather unsettling, as I imagine they might be for some others achieving success with VLC/HF diets.  Does exercise help mitigate the fat accumulation?  Clearly fat accumulation in and of itself is not detrimental to lifespan -- for worms and mice at least.   How about the body temp stuff.  Is the activity of these mice merely compensatory for feeling cold, or are they happy critters feelin' groovy?  How functional on physical tests are these long living worms and mice ... can we even do such tests?  (there are some for mice, but 1mm worms?).  If I attain a longevity-promoting metabolic state, will I be able to carry my groceries and kitty litter into the house in one trip, and if not will I have the energy to make two or three?  Will I freeze to death because I can't do my wood-workouts anymore?  Is all skinny fat the same?  The list could go on.  Far more questions than answers, I'm afraid, and doubtful we'll have actionable answers in my lifetime.  But for me, what we do know tends to argue against severe carbohydrate restriction for the long term.  Your mileage may vary on the interpretation.