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The quality of the video is bad because of his end and the audio was bad on my end.  I’m working on making future interviews will be better on both fronts, but there’s some good nuggets here.

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I’m bringing another scientist on board today, Dr. Diego Golombek. Dr. Golombek won the Ig Nobel Prize in 2007, a parody of the Nobel Prize honoring achievements that “make people laugh, and make people think,” for discovering that viagra aids jet lag in hamsters. The research can be found in this study.

About Dr. Diego Golombek

Dr. Diego Golombek is an Argentine biologist, communicator, popularizer of science and an experienced researcher in chronobiology. He is currently a professor at the National University of Quilmes and researcher at CONICET, and is an author of several books about biology and related topics.

What We Cover in This Interview:

  • Percentage of genes controlled by the circadian rhythm
  • Why you should sleep in a cool environment
  • PDE5 inhibitors and the best way to correct your circadian rhythm during travel
  • How nitric oxide can help with circadian entrainment
  • How much light exposure is needed during the day
  • Eating at night and why this interferes with our circadian rhythms
  • The effects of drugs on the circadian rhythm
  • The connection between jet lag, metabolic disorders, weight gain, and cancer

% of Circadian Rhythm Genes

Sleeping

Q: My first question is what percentage of the genes are influenced by circadian biology, or are circadian rhythm genes?

A: It’s assumed about a third of the genome is under circadian control. But we actually still don’t know, because the techniques for doing that are very different. For instance you can do genomics and look at gene expression, but then you have to validate all that by informatics, microarrays status with other kinds of techniques, and not all of the genes that have been found to be cycling by either informatics or microarrays studies have been validated by other techniques, so we’re not completely sure. The other thing is that we might know that a gene is cycling, but for many of those genes we don’t know what’s going on in the proteins. So it’s an expanding field, of cyclic genes, and then you want to see how many are expressed in the liver, heart, lungs, brain, and that’s another part of the story that several people are looking at, but we have a long ways to know what’s going on.

Q: That’s really interesting. In your opinion do you think we’re going to have an expansion of genes, thinking there’s a higher percentage or lower percentage as time goes on?

A: I would say that it’s a larger percentage because probably circadian rhythms are imprinted in all of the genome. Of course not structural genes, I wouldn’t find a reason why structural genes would be cycling throughout the day, maybe they are, but any kind of functional genes, enzymes, channels, things like that. These actually need to be rhythmic in a sense because they need to anticipate all of the changes having on the environment, both the body and the outside environment. The problem here is that we might have a sensitivity challenge. If you have a gene that cycles in a way that the day night difference is 2 fold 3 fold 5 fold, it’s very easy, but what if it’s a .5 fold, or .3 fold change between the day and the night, which might be very relevant in terms of physiology or in terms of microbiology. But the techniques might not be sensitive enough to find them. Once we refine the techniques I guess it will be much higher than 1/3.

Circadian Amplitude

Q: Oh wow, very interesting. Now the research speaks about the amplitude of the circadian rhythm and the period. What I think I’ve come to learn is that the higher the amplitude, which is the higher the genes go up and down, the healthier it is for the human body. Because then this means in the morning you’ll be more awake, you’ll process glucose, your insulin will work better, and at night you’ll be more tired. Is that true?

A: I guess it’s a little bit exaggerated. What’s really true is having a rhythmic body physiology in terms of physiology and behavior, that means health. But I wouldn’t push it that far as to say having rhythmic individual genes is to be healthy. Becuase each of these physiological variables depends not on 1 but on myriads probably 10s or 100s of genes. So what we really should look for is the rhythm in the result of the activity of all these genes. I wouldn’t take a look at 1, 2 or 10 genes and if the amplitude of those genes is high, say you’re healthy. I would look at the output, meaning behavior physiology, maybe cellular biology, cognition, that’s what you need to be real rhythmic, and in that sense you’ll be a good sleeper, alert in the morning, your temperature will go up and down, your cognition will change periodically, which is something healthy as well, but that depends on the activity of many genes some of which might not be rhythmic.

Temperature: a Marker of Circadian Rhythms

Q: So you mention a few things. Let’s say temperature will go up and down. Now if somebody’s sleep is fragmented, if somebody’s temperature doesn’t fluctuate as well, does that indicate a problem with the circadian rhythm?

A: I would say so, yea. Actually temperature is a very good marker of circadian rhythms. You might be able to predict the sleep phase of an individual based upon it’s temperate rhythm. Also it’s cognitive behavior depends also on temperature. S0 if it’s not a very robust rhythm of temperature or sleep, that means that the whole circadian rhythm is faulty in some ways. And that might be a diagnostic tool as well of several illnesses, general illnesses, metabolic problems, or cardiac problems, and it might also be that one of the early symptoms is that the rhythm is not robust. So if somebody is at risk of acquiring or falling back into some kind of illness, you should take a close look into their sleep wake cycle, rest cycle, temperature cycle, melatonin cycle, which are markers that something is not going really well in their circadian clock.

Cool Temperature and Sleep

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Q: Very interesting. You just described how you see the product of a whole bunch of genes, and you see what’s happening if the temperature or something that is really controlled by the circadian rhythm isn’t working, then this obviously signifies a problem. We know that these things are also zeitgebers, that they go the opposite way. You want to be cooler at night, I always tell my girlfriend to not have such thick covers at night, that she should be cooler. Does it go the other way, if she wears really thick covers, it will disturb her circadian rhythm in some ways?

A: That’s a lost battle, let’s start with that. You cannot convince a woman that she has to sleep without socks, without lots of covers.

ME: I have experience, you’re right about that.

A: The best thing if you want to be really warm is to use several sheets, not a thick blanket. Because the idea here is the same as why you have hairs on your skin, even if you have microscopic hairs. The idea is if you need to keep yourself warm, your hairs will go straight up, and that will maintain a small surface of warm air between yourself and the cold air outside, which is the same thing that would happen if you used a lot of sheets, or when let’s say motorcycle people have to go out when it’s very cold. Sometimes they put newspapers between their bodies and the clothes because that allows them to keep a lot of warm air barriers between them and the outside. Going back to your question, yes definitely. If you are too hot during the night, you won’t have a very good sleep process because you won’t let the body undergo its normal cycle, and the same would happen if you’re very cold during the day.

Q: Now I want to ask you about DHA and the circadian rhythm. I haven’t actually seen any research on this but, we know that DHA is loaded in the eyes. It’s the most concentrated place, and we know that the eyes are important to connect to the suprachiasmatic nucleus, which is the core center of your circadian rhythm. Do you think that DHA is important for the circadian rhythm?

A: I haven’t seen any research on that and it’s a very good question. The eyes are full of surprises in terms of the circadian system, like what was found maybe 10-15 years ago, that used specialized photic pathways for entrainment and maybe the eyes still have more surprises to go with. I haven’t seen any studies at all on DHA and circadian entrainment so it’s a good research question.

Nitric Oxide and Reentrainment

Q: You’ve published a lot of research on PDE5 inhibitors and circadian entrainment, and that you can do it quicker with something like viagra. There’s some natural PDE5 inhibitors such as icariin, you’re familiar with that. I’ve actually experimented with things like Icariin. What I’m wondering is, can you get that same benefit from, or similar benefit from the sun? We know UVA increases nitric oxide and nitric oxide stimulates cyclic GMP. That would be the same mechanism by which the PDE5 inhibitors are working as well. Is that too far of a stretch? I’m thinking that’s maybe nature’s way to help us entrain circadian rhythms.

A: We do have a whole line of research regarding nitric oxide and circadian entrainment. If you administer NO donors (nitric oxide donors) to the SCN, then you will get an increase of entrainment. We have a paper that was published last year with a specific NO donor, nitroso melatonin, which is a melatonin in which they have added NO. At the PH of the brain it releases NO. You also have melatonin at the base. You have both effects, and what we found with that compound with that nitroso melatonin is that you get about a 50-60% increase in light-induced phase shifts, and that also you accelerate re-entrainment after a change in the light-dark cycle. Other people have used other NO donors and have found exactly the same. Also applied to the SCN, not necessarily to the eyes, I’m not sure if somebody has looked at NO donors and the eyes in entrainment, but it’s going strong and the rationale is quite straight-forward. If you are increasing the cyclic AMP pathway by means of activating one of the cycles by nitric oxide, then you should get the same kind of effect that you get with PDE5 inhibitors.

Q: So you’re saying any way you’re gong to increase nitric oxide you’re going to help re-entrainment?

A: Yes.

Best Time for taking PDE5, or Increasing Nitric Oxide

Q: When is the best time to take a PDE5 inhibitor, or get an increase in nitric oxide? Is that in the morning?

A: It depends on what you want. If your rhythms are ok, if you’re a relatively young adult and the amplitude of the rhythms is ok and the entrainment is ok, then I would do nothing, I wouldn’t increase normality – that’s for sure. But if you do need to entrain or accelerate entrainment, then it depends on what kind of phase entrainment that you need, whether you need a phase delay or phase advance. We are diurnal specieis, meaning that early in the morning would induce a phase advance, and late in the afternoon would increase a phase delay.

Our research suggests that the cyclic GMP-related pathway is only active for increasing phase advances, meaning that you should take either PD5 inhibitors or NO donors, these kinds of drugs, in the morning, and together with light.

They do not act by themselves, they just increase the effect of light. You have to think carefully for example if you are traveling from America to Europe and if you want to start your entrainment before your traveling then you have to think about your morning at the destiny, not home. That’s when you should take the viagara or an NO donor or whatever together with the light. Then when you arrive at destiny, let’s say Europe, then you can continue exposing yourself to light early morning. And you can do it with just the light of course, or you can go and take a walk at dawn or close to dawn, and it may be even healthier.

Light Dose

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Q: How much light exactly do you actually need. And does the dosage of light make a difference? I know there’s bright-light therapy, but does the dosage of light help increase the photo entrainment even more?

A: Definitely there is a dose-response curve for light entrainment, both for laboratory animals which is what we are working with, and also humans. Classic papers researched dose response curves for light pulses, and you do have a threshold, which is very low actually. Very little light is able to affect the clock, which is something like 1 lux (basically nothing), and it gets very saturated with very high doses of light, which is something like 10,000 lux (this would be something like being exposed to light in the middle of a summer day). So getting more than that is useless because you will get the same effect. When I say 1 lux… if you give out very low dose for acquiring large phase shifts, but if you give out very low dose light pulse in the middle of the night, then you will certainly decrease the melatonin peak, which is also related to entrainment.

Blocking Light at Night

Q: So are you concerned about having spectrums or intensity of light that will stop melatonin production, which will harm your circadian rhythm? There’s a lot of research out there. I’m assuming you aren’t concerned about blocking out light at night?

A: I am, but again not to be exaggerated. What I strongly advise is that you don’t sleep with computers, TVs etc. because they are all based on blue LEDs, which we know are the ones that affect the clock most. Once you go to bed you should go to bed.

We’ve been sleeping in the dark for some time, and it doesn’t harm that much but I would be concerned with the current fashion of having the TV set in the bedroom, or taking the computer or iPod to bed, and spending long hours that way. What is that telling the clock? Not only through melatonin inhibition but also through direct action on the SCN it’s telling the clock that it should delay, because that’s what light exposure does.

This means that sleep onset will be harder to acquire, meaning that you will sleep later, and you will probably have to wake up early for work, school, etc. and you will be acquiring a sleep debt. Then you will certainly paid for it, being sleepy, annoyed, and more susceptible to different kinds of illnesses. I think that kind of sleep hygiene certainly works. I wouldn’t push it that much as to having no light at all until midnight or until you go to sleep. It might help, but it’s probably not worth all that trouble.

Q: I hear that, but if people are having sleep troubles, or if there is some problems with their circadian rhythms, then they want to pay attention, try it out and see how they feel from it.

A: That’s for sure. Not only light at night, but you need light during the day.

Daytime Light Exposure

Q: Is it important to get light throughout the day, or is it important just during the morning to reset it and that’s good enough?

A: There is a dead zone of the PRC (phase response curve) that occurs around the middle of the day. So it doesn’t matter that much your light exposure mid-day, noon, or so, but light has other effects. Not only the effect on the clock, but it also has an effect on alertness in general, on how you feel, and in that sense if you can get as much light as possible during the day it will be certainly better. If you work in a basement or any kind of extreme situation where you’re not getting any light, you should get some light baths every now and then, meaning artificial and natural light every hour or so, because the clock will know.

Q: That’s really interesting. Now here’s what I found really interesting with the SCN. If I read correctly, it directly connects to the adrenal glands. How does it affect various cells throughout the whole body from that tiny point in your hypothalamus?

A: It’s not a direct pathway, it’s a multi synaptic pathway.

The SCN has two main ways of talking to the body, one is a neural pathway, for example the control of melatonin is a neutral pathway, going from the SCN to the PVN, to the nuclei of the autonomic nervous system, and to the pineal gland. So it’s all neural.

Also, the SCN controls the release of different neural hormones or neural peptides that might be released to the third ventricle, it’s very close to the third ventricle, from there it goes to the other parts of the brain.

But the main communication pathway of the SCN is through the autonomic nervous system, and from there you get to control or moderate the adrenal glands and almost every gland in the body. The relatively modern notion of peripheral oscillators is very related to this because what the SCN does probably is not directly controlling the activities of the adrenal glands, like controlling the release of adrenaline, but it does put into synchrony the peripheral oscillator located in the adrenal glands.

The analogy is that the SCN may be considered as an orchestra director, and there are different little directors or musicians that need to be in place. If the SCN isn’t there for a very long time, each of the musicians will tick at their own place, and that’s not very good for the body because it’s not a very good economical situation. You need all of the body to be synchronized, and that’s the role of the SCN, not controlling the adrenaline release or heart rate rhythm, but moderating all of the peripheral oscillators that seem to be everywhere in the organism.

Eating at Night

Q: Now what about eating at night? Do you take care of that, trying not to eat at night? Because there’s a whole bunch of metabolic effects when you eat at night and we weren’t primed for eating after a certain time. Do you take care of not eating after a certain time?

A: No. What you should take more care of, is to separate evening eating times with sleep, which is hard because it depends on culture.

You should not have dinner and then go to bed. That’s for sure because your sleep will not be as good as if you could take a few hours before sleep after dinner time.

And it’s a cultural problem. Here in Argentina in South America in general, or Spain, we eat very late at night, and we don’t wait a few hours before bed because that would mean going to bed at 2am. So we have to compromise between our culture and what you assume is good for the clock which is having dinner relatively early, and then waiting awhile to go to bed….If your sleep cycle is healthy….

But if it’s not that good and you are having sleep problems and you wake up at night, there are a few things you definitely shouldn’t do: you shouldn’t turn on the light, if at all possible, and go to get a snack. Most people wake up at night, turn on the lights, and go get a snack or glass of milk, and mess up with their whole phisiology in that way. If possible they should try to go back to sleep in the most quiet way possible.

Q: Is that something you try to do yourself?

A: Lately I’m so tired, I’m not waking up at all during the night. But if I do wake up at night, I try not to turn the lights on and I try to go back to sleep as smoothly as possible. Sometimes it works and sometimes it doesn’t.

Shorter/Longer Circadian Rhythms

Q: Ok, interesting. Now, what are the drawbacks of having a longer or shorter rhythm? I read that naturally, the rhythm is somewhat shorter than 24 hours, but since we reset it that’s what keeps it on track. Are there any drawbacks to having a shorter or longer rhythm?

A: That’s a species-specific trait. On average, each species has a very specific sleeping period.

In the case of humans, the average circadian period if you don’t have any zeitgebers around, is a bit longer than 24 hours. First, it was believed it was much longer. Now people believe it’s something between 24.1 and 24.5 hours, which seems to be pretty close to 24 hours.

But even if it’s a .1 hour difference, that means that you drift away from 24 hours 6 minutes a day.  Which means that in 10 days you will drift an hour, in 100 days it will drift 10 hours, and that then you would cease being a diurnal species.

So that very little difference between your circadian period and the 24 hour cycle, needs to be reset every day by light. If you’re very far away from 24 hours it will be very hard, because you will have to delay or advance your clock a lot. Most animals have a circadian period that is very close to 24 hours. What we study that deviates from 24 hours are usually mutants that have some kind of mutation of a clock gene, and then you have a 26 hour period, or 20, and then it’s harder to go back to 24 hours.

The thing is that if your circadian period is able to be entrained by light to an exact 24 hour period, then natural selection does not see that there is a difference. So there’s no problem at all of having a 23. something, 24. something period, because nature doesn’t see it. You’re entrained every day to 24 hours and that’s what you need. You don’t need anything else. If your circadian period is much further away from 24 hours, say 30 hours, then it would be much harder to entrain and you might be at risk of not being adapted to a 24 hour day.

Q: Now, there’s a whole bunch of research on mice, rats, and flies. We know that rats and mice are nocturnal animals, and everything is switched. So how much does that research apply to humans?

A: That’s a great question. The real answer is that we don’t know. It’s not only for circadian research but most research has been done in rodents and then we extrapolate that to humans and it might not be the case.

There are some people around the world trying to find good diurnal models for circadian rhythms, even rodents, that are diurnal not nocturnal, but it’s yet not that advanced. There are also some people working on some monkeys, but that’s so expensive to work with, and we don’t know much about primate rhythms in the field or in the lab. So it’s actually a leap of faith to go to a result from a result in a nocturnal rodent and a diurnal human. Things seem to be pretty well maintained, similar between the two, their night is very similar to our day, but you can’t extrapolate from one to the other, and may need to consider that there may be some fundamental differences that aren’t being taken into account.

Drugs and the Circadian Rhythm

Q: There’s a whole bunch of drugs that interact with the circadian rhythm, and since the circadian rhythm itself so complex, we don’t even study it so much. The only one that we study is let’s say lithium. Can you explain number one how lithium is interacting with the circadian rhythm, if you’re aware of that, and number two what’s your opinion in general of pharmaceutical drugs and how they interact with the circadian rhythm? Is that something we should look into more.

A: Certainly. Lithium affects the kinase GSK3 that is somewhere in the circadian molecular loop. It’s a modulator of CLOCK proteins, so it does affect rhythms. It changes the period if you take lithium throughout the day, but the main indication for lithium is for a completely different kind of person which is the bipolar, manic depressive illness, and we still don’t know why it stabilizes the changes between being manic and being depressed.

We all have changes in our mood between being in a good spirit and being a little bit melancholic, so probably the bipolar depression is an exaggeration of a natural trait. And lithium, for reasons I don’t know, and I’m not sure that it’s well known either, kind of stabilizes those abrupt changes between those big mood affections.

Most drugs that have some kind of psychotropic effect, meaning they affect something in the brain, will probably mess up rhythms. In some cases, we know that some drugs increase alertness, and very few of those cases doctors are aware that they also have to warn their patients of putative circadian effects.

Chronobiology, in general, has not yet entered the mainstream of clinical medicine. I think we’ll get there. Also, there is a specific kind of drug called chronobiotics, meaning that they change the hands of the circadian clock. That’s an active field of research and development in pharmaceutical companies. We have these means of doing a screening of drugs, and you can test thousands of drugs in a day.

Doctor Delay

Q: Why do you think, I mean you’ve been doing research on the circadian rhythm for many years, and so have many other researchers, if you look at the amount of data that’s been obtained, and then you see what’s being translated into clinical medicine, you see an extremely slow shift or no shift really? The current breed of doctors doesn’t know that the PDE5 inhibitors are going to be good for jet lag for another 15 years. Why do you think that’s the case?

A: For one reason, doing circadian research, especially translated into medicine is quite expensive. This is because you need to record variables for a very long time in many patients and many subjects. Since pharmaceutical companies not only want to find good drugs, but also a good cost-benefit relationship, maybe it’s not worth it for them to pursue the circadian effects of drugs unless it’s very specific. Also, the purely circadian disruptions are not that massive. People that have sleep delay phase syndrome, compared to those that just cannot sleep or have difficulty in sleep onset is very small. So I’m not sure that there is a big interest of pharma in going into drugs for this very specific circadian sleep disorders.

Q: If someone has a sleep problem it’s not like a mainstream diagnosis disease that pharma can cure or treat.

A: If it’s a sleep problem in general terms, then yes pharma is there for anxiolytics, but if it’s a circadian problem, meaning you have an abnormal sleep period or abnormal sleep phase onset, then it’s not such a big problem for pharma to be aware of. Although there are several companies doing like melatonin medics or compounds specifically for those kinds of problems, and they’re doing quite well.

Q: I have a belief and opinion that anyone who is having a sleep problem is having a circadian problem on one level or another. Is that a wrong notion?

A: No, it’s not a wrong notion.

Most of the people who have a sleep problem will have an amplitude problem, meaning they are sleepy during the day, and/or are too alert during the night.

We circadian biologists do not give that much credit to amplitude, in terms of phase and period without the other two components of circadian rhythms because the amplitude is so heterogeneous it varies so much within individuals and between individuals, that it’s not our favorite.

Since most people that have sleep problems will have an amplitude problem, it’s relative to say whether it’s a real circadian problem. But I agree, down to the bottom of it, it is a circadian problem.

Q: Last question, bright light sensitivity. I’m trying to research what that’s from. I’m looking at cyclic GMP and things like that. What do you think of bright light sensitivity? The reason I’m asking is because a lot of people who have circadian problems have bright light sensitivities. What do you think that’s from?

A: I have no idea actually. Bright light sensitivity is usually a symptom of something else. When you have a headache or migraine, that’s when it’s the worse, when you cannot look at the bright light. I’m not sure whether it’s a retinal problem or a visual cortex problem, or something in between. You mention that people with circadian problems also have bright light sensitivity. Is that a fact, is that something you’ve looked into?

Q: It’s more my subjective experience. Various cytokines interrupt the circadian rhythm, like BMAL1, those clock genes. A big core driver why people are getting circadian rhythm problems is if they have chronic inflammation. It could be the common theme is that the inflammation of the optic nerve is causing a bright light sensitivity via some mechanism I’m not 100% sure of in a precise way. It is a correlation, like half of people with CFS have bright light sensitivity.

A: Well, that’s a testable hypothesis. You could induce inflammation in mice or rats and look at the optic nerve.

ME: The reason why I asked you also is because PDE5 inhibitors also cause bright light sensitivity as well in some people. I thought it had something to do with cyclic GMP. I know it has a lot to do with how the light processes visual inflammation and things like that, combined with the fact that viagra and these PDE5 inhibitors cause bright light sensitivity sometimes. Something’s going on there that I’m not quite sure of right now.

A: Yes yes could be.

Q: So this has been really fascinating. What are the future directions for your research?

A: We still keep a line of research regarding nitric oxide and cyclic GMP, but we just have one person working on that. We’ve mostly been dealing with rodents and inflammation actually. Also we have developed a chronic jeg lag model in the mouse, meaning we make the mouse fly the equivalent of 6 time zones every two days, and we’re looking at the consequences of that. The latest we’ve found is that there’s very severe metabolic consequences.

The animals get fat, although they note that they do not eat more, meaning that it’s a real metabolic variable, it’s not something related to eating. They’re also more susceptible to cancer, which is something that was known but we are pursuing that as well. We still don’t know much about inflammation in those chronic jet lagged animals, but I’m sure there’s something going on. Then we are also doing some second to minute subjective time estimation, and the relationship between that and the circadian clock. Like if I asked you to estimate 30 seconds now, or tomorrow in the morning, you would certainly do different estimation. We want to know where is the length between the two time frequencies.

ME: That’s really interesting, because I was actually reading that with drugs like marijuana, they interact with the SCN, and that’s why you have this time distortion effect. So that’s what you’re studying, how different times of the day effect this. I really appreciate this, thank you so much!

A: Great questions!

Q: Where can people find your work?

A: We do have a lab webpage but it’s outdated so it’s fine!

ME: Ok, thank you so much have a great night.

A: You too, bye.

Links:

Epimedium (IHERB) for a PDE 5 inhibitor.

Dr. Diego Golombek’s TEDxMontevideo 2012 for those of you who speak Spanish

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2 COMMENTS

  • astroff

    interesting.

  • Kyle

    What are your thoughts on viagra verses icariin? do you think one is safer? more effective?

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