Scientific Nutrition Update 29: Calorie Restriction and Longevity

Today’s episode is a deep dive into the science of living longer, specifically whether significantly cutting calories may help with living a longer life.  There is one of my longest and most in depth episodes so buckle up and let’s go.

Script (Remember I ad-lib and go off script):

For today’s episode we are going to talk about living longer.  Just a warning this is a slightly longer and more in depth podcast than normal, but this mostly new research for me so I had to dive deep to really understand it.  I mean the slogan for this website; live long, live healthy, and live happy does have live long in it so I figured we should discuss it. There has for a pretty good amount of time been evidence that calorie restriction may help increase your lifespan.  

 

The issue here is that this is a really complicated issue to pick apart.  We can’t assign humans to cut their calorie consumption for the rest of their lives, so we need to rely on a combination of short term human experiments, epidemiological human studies, and well-supported animal models, which as we know makes me nervous.  Especially since many of these effects are seen in very short lived organisms like mice and rodents, and we are still waiting for results from nonhuman primates. So I’m going to do my best, but there will be no strong conclusion or advice that will come from this episode.  Be aware of that.

 

Being a biochemist by training in order for me to truly grok any of these health effects I need to get a handle on the underlying biochemistry, and that is very difficult with this because there have been so many proposed mechanisms.  The first and the one that initially made sense to me was a general metabolic slowing, which reduced the formation of ROS’s or Reactive Oxygen Species, which have a habit of oxidizing. These are a natural byproduct of cellular respiration and so if you could reduce them it could help.  However, upon review this effect did not seem to hold up, at least in mice there seemed that there was not a significant reduction in the number of species formed, and since they were living longer a greater number of total ROS’s resulted. However, there do seem to be some changes to the mitochondrial membrane, which may reduce its vulnerability to the oxidative damage, so that is not conclusively disproven.  Returning to the literature there are a couple of other interesting pathways which get brought in, the two I am going to look at briefly here are SIRT1 and SIR2. The SIR2 pathway is responsible for interacting with cellular respiration and can change the NAD/NADH ratio which seemed promising as NAD is important in many metabolic reactions. This pathway seemed important for regulation of metabolism in many organism including flies, worms, and so the analogue in mammals became the topic of speculation.  This would be the SIRT1 pathway. What differentiates SIRT1 from SIR2 is that besides the histones which are the substrate for SIR2 it also has several regulatory transcription factors as substrates, it is also expressed throughout the organism and as such is a promising candidate. Now the full proposed mechanism gets even more complicated and I’m not 100% confident I’ve fully grasped it, so if you know this better than me please send me an email and help me out. Okay so the majority of fat in the body is what is called White Adipose Tissue, now in the past this was often seen as just energy storage, but it is actually an important endocrine organ that helps regulate the levels of several different hormones.  So the proposed mechanism is that calorie restriction activates SIRT1 which then induces the white adipose tissue to release some of the fat into the bloodstream, along with hormonal changes that may help regulate the ageing process. Woo, that was a lot of heavy science, but we aren’t done yet. Try to stick with me for just a minute more.

 

There is another mechanism that is super fascinating to me that involves insulin resistance.  Basically there is a proposed mechanism that suggests this calorie restriction is able to increase insulin sensitivity, which due to interactions with several other pathways may also help contribute to the longevity improvements.  However, I am keeping this mechanism at arm’s distance, because despite my obsession with insulin mechanisms, I also know just how contentious much of the science surrounding them is. There is still a lot of debate about downstream effects from changes in insulin dependent pathways, so I’m just mentioning it to be thorough.

 

Okay so time to start looking at our animal models and see what clues they might give us.  Going back to 1985 and looking at a Journal of Nutrition article and there were several different levels and types of restrictions.  What they found is that a 25% reduction in calories significantly increased lifespan, however a 65% reduction resulted in the greatest lifespan, and the longest lived of their mice, seemed to live longer than had ever been documented before for any strain of these mice.  This suggested that there was some mechanism related to severe calorie restriction that was responsible for significantly lengthening the lives of these mice.

 

Now we need to look at humans, there was a study published in JAMA that looked at several different protocols of calorie restriction in humans for six months and measured a couple different biomarkers to determine if there was an effect.  There was a couple of interesting effects I want to take a minute to discuss. Every single intervention group ended up with a lower fasting insulin which we would expect, however, there were also some interesting metabolic change sin those who did the calorie restriction.  Namely we see a reduction in body temperature, suggesting a reduction in metabolic rate and there was also a reduction in dna damage. This suggests to me that there may be a slowing of the metabolism that could in theory increase longevity. This seems corroborated by the fact that measured metabolic rates slowed by greater than expected based on weight loss.  This suggests to me that long term calorie restriction does slow the metabolism, which may contribute to a longer life, but could also help contribute to eventual weight regain. This might end up being our double edged sword here, where living long is going to require a significant amount of discipline.

 

Now it is not a universally held opinion that calorie restriction is going to benefit humans in the same way that it benefits rodents.  There was a piece published in the journal Biogenterology which actually tries to make the argument that it is unlikely to increase lifespan in humans.  This argument centers on a model of resource allocation. Where basically these benefits are seen in mice because there is an evolutionary benefit happening here wherein they benefit in periods of famine more by putting their resources into maintenance in lieu of reproduction.  The authors claim that this strategy is less likely to be present in humans for several reasons, namely the cost of reproduction is not as high basically humans can maintain pregnancy and lactation in conditions that mice cannot, our body supplies so fat and glycogen and all of that also provides us a much longer window of survivability than it does for short lived species like mice, and finally that the absolute time of food shortage would be similar for short and long lived species, but the relative time would be much different.  Meaning that in terms of percentage of life our food shortage is likely to be much shorter, so we do not need the same adaptations. This part does seem interesting to me, and at the very least suggests to me that we would see smaller results in human than in mice, but does not completely discount the possibility of a smaller effect in humans. They also then point out that a wide variety of species react in different ways to stress, and suggesting that humans respond in a similar manner to mice is likely too strong of a claim to be making.

 

So where does all of this leave of us, well in my opinion calorie restriction is probably a good thing.  It is unlikely that we would see the same magnitude of effect in humans as we would in mice, however, the similarity between the SIR2 and the SIRT1 pathway does suggest to me that there is likely something to this.  Especially since I have seen proposals that deal with endocrine issues with obesity that also focus on hormonal changes in the white adipose tissue. So basically my conclusion is we need a whole bunch more research, both short term studies in humans, and longer studies in nonhuman primates, but it is way too early to conclude anything.  That’s all I have for today, thanks for sticking with me through this longer and pretty dense episode. There was a lot of learning in here for me.

Studies:

https://jamanetwork.com/journals/jama/fullarticle/1108368

http://fundaysdiet.com/wp-content/uploads/2017/09/4_Study_1.pdf

https://cpb-us-e1.wpmucdn.com/blogs.uoregon.edu/dist/f/5492/files/2014/04/mice-cr-1a727ci.pdf

http://science.sciencemag.org/content/289/5487/2126.full?casa_token=QR3CNFkNLWAAAAAA:oxQIDm-6LXUYD7leN3rnzY64fHV2ihsUShhNxi1Y3zKGG0v-7rlCONnudFL0u67uyrbNlZhAQwiprg

https://www.sciencedirect.com/science/article/pii/S1357272502000389

http://genesdev.cshlp.org/content/17/3/313.full.html

https://www.sciencedirect.com/science/article/pii/S0092867405001030

http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.335.3708&rep=rep1&type=pdf

https://academic.oup.com/ajcn/article/78/3/361/4689958?__hstc=171738815.e835c34ab7bf88e972fdd7a7debc8575.1478563200086.1478563200087.1478563200088.1&__hssc=171738815.1.1478563200089&__hsfp=528229161

https://link.springer.com/content/pdf/10.1007/s10522-006-9006-1.pdf

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