Show #2684
p1 DIALOGUE edit
Why Working The Night-Shift May Lead to Cancer 
with guest, Dr. Hans Van Dongen, Ph.D. - Dr. Jason McDermott, PH.D. - Dr. Shobhan Gaddameedhi, Ph.D. - Patrick Johnson

SHR_Show_2684_E

Carl Lanore: [00:00:00]
Today we're covering a topic that's been discussed on this show over the past 15 plus years numerous times: The link between cancer and interrupted sleep. The study was titled Shift Workers, but don't lose the real message here - if you're somebody who stays up late all the time, this is important to you as well. It's estimated that according to current cancer statistics in the United States, one in two women and one in three men develop cancer in their lifetime. That's startling to me. That's a lot of people. And there are things that seem to increase the risk of cancer.

We're going to get into that today and maybe even some possible takeaways to help protect you.

Welcome my guests to the show:
Dr. Jason McDermott from Pacific Northwest National Labs
Dr. Hans van Dongen from Washington State University
Dr. Shobhan Gaddameedhi from North Carolina State University

Why this study? What research had been done before this that made you look to answer some unanswered questions?

Dr. Hans Van Dongen, Ph.D.: [00:03:36]
It's been known for quite some time that shift workers and other people that stay up at night and do work in the early hours of the day are at an increased risk for a variety of medical disorders ranging from metabolic disorders and obesity to mental health problems, to cardiovascular disease and also cancer. The increased risk for cancer in shift workers particularly has been an enigma. We understand that working against the biological clock causes all kinds of problems and we have a good handle on why that is, but the increased cancer risk has been challenging to understand.
It wasn't until I started working with Dr. Gaddameedhi and Dr. McDermott that we had a team that was poised to crack this issue, was poised to figure out what was really going on. We'll talk more about that I'm sure, but that was really the reason our study happened. There was a problem that we didn't understand which affects lots of people. About 20 to 25% of the population at any given time is involved in some form of shift work. Knowing there was something important that we did not completely understand - we wanted to make sure that we figured it ou and this was our opportunity. 

Carl Lanore: [00:05:03]
How was the study designed or was this a review of existing studies? Did you do a meta analysis or how did you approach this?

Dr. Jason McDermott, PH.D.: [00:05:22]
This was a study that was designed with volunteers who were exposed to two different regimens. One was a standard day shift, waking up at the same time in the morning that they normally would go to bed, at the same time for three days. The other regimen was a simulated night shift. Volunteers normally on day shift were scheduled off by about 12 hours. So now they’re going to sleep when they would be waking up and waking up when they would be going to sleep. At the end of that three day introduction period, the subjects were kept at a constant light for 24 hours. And so they're basically in reclining chairs. They had small snacks, so at the same time, to keep all of the external environment the same. It was a very controlled experiment. Then we assessed their gene expression during that time.

Carl Lanore: [00:06:33]
When you say you checked their gene expression, what were you looking for? Specific known markers or end points? Or do you just look at it as a whole and see what changed?

Dr. Shobhan Gaddameedhi, Ph.D.: [00:06:49]
There was already meta analysis, epidemiological studies, but the goal was to understand why the shift workers are prone to increased risk for cancer, especially breast cancers in women and prostate cancers in men. What are the mechanisms which are associated with cancer. Cancer involves at least 10 different biological pathways in which a disruption of any of those pathways lead to cancer. Of the genes in those pathways, we pulled those gene expressions using the samples, especially white blood cells, collected from our day shift controls and night shift simulator subjects. That's where we found the mechanisms associated with the cancer risks in night shift control subjects.

Carl Lanore: [00:07:59]
Interesting. There is some debate whether rotating shift workers in and out from night shift to day shift could mitigate some of this. There's other research out there that appears to say rotating them in and out is not a good idea because once they become acclimated to working in this shift, changing it all again isn’t a good idea. Was that a consideration when you were looking at your research?

Dr. Hans Van Dongen, Ph.D.: [00:08:36]
We knew this question was important to begin with, but what we saw in our data changed the way we looked at that. In the experiment and also in most shift workers, the master biological clock in the brain does not actually change all that much. It's rather resistant to change. So one of the problems that you have with shift work is your biological clock doesn't adapt very quickly. You can stay on a night shift schedule for a long period of time and eventually it will catch up with that new schedule but very few people work more than a week or so in a schedule like that, and then when the weekend comes and you go back to a normal schedule to meet up with family and friends and do things that people need to do, then you have a problem; just as the biological clock was just about to be adapted, you change. There's this idea out there that if you rotate your schedule, that you don't give your biological clock a chance to adapt, and that you might be better off. What we found (more generically) in this research, that the tissues and the rest of the body are much more responsive, much more quick to adapt to the changes associated with shift work than what the biological clock in your brain is doing. So your biological clock in the brain is not catching up. You're in this internal state of dis-synchrony. 

Carl Lanore: [00:11:00]
Talking about peripheral clocks, which you're talking about right now, the organs have their own clock and we have all these peripheral clocks and coordinating the peripheral with the super cosmetic nuclei, which is the master clock, if you will. We know that eating and movement help the peripheral clocks to choose their time. This speaks not only to shift workers who probably just have a certain meal time but to the person sitting home in their recliner, watching nighttime TV and getting up and snacking constantly at night. How much does that snacking and the signals coming from food intake, maybe even promote cancer to a greater degree than the guy or gal who has that one meal at their 2:00 AM lunchtime, and then goes home and goes to sleep at 10:00 AM? What role does this have in this whole process of cancer?

Dr. Shobhan Gaddameedhi, Ph.D.: [00:12:27]
So the peripheral clocks are very much impacted by the time of the day we take the food, especially during the nighttime. Our biological clock is not only disrupted by the light at night, because we are supposed to sleep during nighttime. We are supposed to be active during the daytime. Having the constant uptake of the food, during nighttime disrupts our biological clock which influences and causes disruption in our baseline and that misalignment could be more profound than just performing the night shift.

Carl Lanore: [00:13:20]
We're all fascinated by time restricted feeding. Does it sound like, for the shift worker, that restricting their eating during the night and holding off till they get off their shift or they've just awoken has any benefit? 

Dr. Jason McDermott, PH.D.: [00:14:00]
I don’t know, our research didn't speak directly to that. I know that there's a good body of other research that's available here, but I would defer to Hans for that discussion because I'm not as familiar with that research.

Dr. Hans Van Dongen, Ph.D.: [00:14:17]
Happy to chime in. You're absolutely right Carl that the sleep restriction as a tool to mitigate some of these health consequences is an important way to go. For a long time we believed that the time that you eat has something to do with the calories that you pack. Another good reason to think that is because there's hormones that coordinate your hunger and your association that when you feel that you've had enough and when you are in the shift work situation or jet lag or otherwise misaligned with the time of the light-dark cycle, then those hormones get out of sync with each other and it turns out that you then start craving food at the wrong time of day.
Typically fatty greasy foods that you start craving. It's been believed for a long time that just the act of eating and taking those calories in at the wrong time is how you would pack those calories, how you would actually accumulate that energy that you don't really need. That's how you would then develop obesity over time and metabolic disorders and ultimately leading to type two diabetes, for instance.
But based on data from the same experiment, in another aspect of it having to do with digestion, we have learned that what actually happens when you eat at night is you start to shift the biological clock in the tissues associated with digestion. So you start to shift the peripheral clocks in the gut, in the liver, in the pancreas. Those are concerned with making sure that your food is processed properly, and that you have a proper response to glucose, for instance. We think people should minimize their food intake at night, if they can.

Carl Lanore: [00:16:39]
One of my frustrations with the medical orthodoxy and how they report the hierarchy of death in America. They say the number one killer is heart disease and number three is cancer. I say that's a lie because those are all end points of insulin resistance. We know from numerous studies, one that I point out most often was done with Olympic athletes, where all they did was short sleep them for five hours a night for two nights, and they had trouble managing blood sugar akin to that of seven-year-olds literally in just two nights. There are studies that show when physicians move into residency and they have to stay up for 48 hours that thyroid function and blood sugar management goes out the window.
But we know that sleep deprivation, even fragmented sleep, leads to insulin resistance, dementia, poor memory consolidation. Cancer can be traced back to insulin resistance. Dr. Thomas Siegfried was on my show two times. He wrote a fantastic book called Cancer as a Metabolic Disorder. He says it doesn't happen genetically first; the mitochondria shift. Dr. Warburg didn't discover how to find tumors, he found how to feed tumors. If we stop ignoring things that make us insulin resistant, maybe we'll start to see these cancer trends come down. Is that too broad of a statement? Who wants to correct me?

Dr. Shobhan Gaddameedhi, Ph.D.: [00:19:10]
I would like to point out that there is a strong connection with obesity, disruption of the metabolic system and the increase of cancer. Also the biological clock plays a large role in metabolism. There is a lot of data from a basic scientific perspective and also from epidemiological studies on humans,including the shift worker. There are metabolic disorders and increased cancer risk and cardiovascular disorders. So indeed it is well known in cancer biology that a disrupted metabolic function, is one of the hallmarks of cancer.

Carl Lanore: [00:20:16]
Interesting. Did you look at the effects of artificial light in any way or does that confound things for you? Having a person awake at night under fluorescent lights, incandescent lights, and now LED lights is not the same thing as having them out in daylight. Does that play a role in any of this discussion at all?

Dr. Hans Van Dongen, Ph.D.: [00:22:00]
In this particular study, we did not really focus on light but it's an absolutely relevant part of the story. Everything that has the potential to disrupt the circadian rhythms, whether it's the central pacemaker in the brain or in the peripheral tissues in the body, is going to play a role in the story. There’s at least 10 pathways that we need to be concerned with. We have started to learn that each of those pathways in one way or another are susceptible to circadian disruption, to dis-regulation, from the factors when your biological rhythms are out of sync with the light-dark cycle. Of course, if you start to play with the light-dark cycle itself, by adding light to the environment, as we tend to do when we work at night, then that complicates the story further. What keeps coming to me as interesting, and actually sort of baffling is how little responsive the master clock in the brain is to some things. We can definitely see the effect of artificial light on the central pacemaker in the brain.

Carl Lanore: [00:24:37]
Are there any takeaways from your research that indicate any steps that can be taken? I'm old enough to remember businesses being closed on Sundays, TV stations going off the air at midnight, and no such thing as a night shift worker, unless you were a security guard in a factory. There are a lot of people out there who are probably filled with angst knowing this. Is there anything that your research points to that could help perhaps mitigate the risk in any way, shape, or form? 

Dr. Jason McDermott, PH.D.: [00:25:24]
I don’t think our research points directly to any of that but I think there are some indications. Our research certainly points out and highlights the importance of and impact on health of shift workers.

Carl Lanore: [00:25:51]
How about supplementing with melatonin since melatonin is interrupted for shift workers? Is melatonin suitable for therapy?

Dr. Hans Van Dongen, Ph.D.: [00:26:08]
Melatonin is a free radical scavenger. It cleans up free radicals in the system. There's an interesting story that Dr. Gaddameedhi can tell on why that would matter here. 

Carl Lanore: [00:26:23]
Okay. Take it away Dr. Gaddameedhi.

Dr. Shobhan Gaddameedhi, Ph.D.: [00:26:26]
Our studies suggest a shift work schedule potentially compromises your genome integrity, which is imparted for protection against mutations and genomic instability, which is one of the hallmarks of cancer. Melatonin works as a free radical scavenger antioxidant. Potentially melatonin could help in bringing down the oxidative stress which is the DNA damage, which is influenced potentially through oxidative stress as well, which we could have been experiencing because of the shift work condition. Also there are several studies on melatonin, especially on the basic science perspective, and animal studies, such as that supplementing melatonin, especially after artificial light on the rat models, it potentially helps in decreasing the breast cancer outcome, but most studies were not validated.

Carl Lanore: [00:28:13]
Fascinating. Thinking that there's just one thing is an insult to the complexity of the human body. There's a lot more to the picture. From this research do you feel there are any things that we can say safely to the people out there who are working shift work, pay attention to this, or pay attention to that?

Dr. Hans Van Dongen, Ph.D.: [00:29:19]
First and foremost, shift work does come with additional risks and people should be aware of those, but at the same time many shift workers do not develop disorders or diseases, and have very fulfilling and very important jobs. Not all that there is to say about shift work is necessarily bad, we just need to be aware of the possible consequences that shift work can have. It can have increased risk of cardiovascular disease, metabolic disorder, cancer, mental health disorders and a variety of other things, immune problems come to mind and we should be aware of those. What that really means is that if you're in a shift work scenario, pay extra attention to your health, have yourself checked regularly because prevention and mitigation early on are always the safer options.

Dr. Jason McDermott, PH.D.: [00:31:54]
I do some cancer research at the molecular level and one of the things that is really interesting is that there's a large number of studies looking at profiles of tumors, for instance, and trying to identify mechanisms. In general, the role of circadian rhythms isn't taken into account in these studies. I don't know that it is necessarily a confounding factor in a large number of studies because everybody's basically day shift, but I think it needs to be taken into greater consideration when we're doing human studies. There's an emerging area of research about timing of drug treatment.

Carl Lanore: [00:33:02]
So I have an n=2 scenario. I have two friends, they're both pilots. One of them flies for a commercial carrier. The other one flies for a shipping company. The one who flies for the commercial carrier for most of his career, has flown overnight. He's aging extremely well. All the phenotypical signs of aging, he doesn't have them. That is counter-intuitive to me because he's up all night, all the time. On his days off, his wife complains that he stays up all night and he stays in his shift, which makes it difficult for her to stay up with him. Or she stays up with him and she's exhausted the next day because she's a day shift person. I've said to him on numerous occasions, you are aging amazingly. He has almost no gray hair and he's close to 60, he doesn't have a weight problem. He doesn't have dementia, he doesn't have any of the things that you would expect that somebody for the past 25 years has been up every night to have. He says when he comes home on his days off, he used to stay up all night and then go to sleep at normal time and stay in his schedule.
On the flip side, I have a friend who works for a package company at a delivery service. He flies nighttime also, but on his days off, he doesn't stay up. He goes to sleep at night.He's constantly going back and forth between tissue time synchronization. He is very overweight. He has hard times. He's been told to lose weight if he wants to keep this job. I have a feeling that people who work the night shift need to stay in that lane until they're taken off the night shift and then they can regroup and try to get back into a day shift kind of a time zone. Any comments on that? Any eye rolling or anything like that?

Dr. Hans Van Dongen, Ph.D.: [00:35:45]
You make an excellent point. If you can do that, it's great to stay aligned to the schedule because once your work schedule and your sleep schedule and your biological clock and the rhythms are in alignment, you don't really have any of these circadian mediated problems. You don't really have that internal dis-synchrony that seems to be the precursor and the cause for many of these problems and playing out in various different ways. The hard part is that the rest of society is not particularly forgiving as far as living a schedule that's different from everybody else.

Carl Lanore: [00:37:32]
I just want to hit a couple of listener questions:  Tommy D who is an avid fan of the show says he's been struggling with fragmented sleep for over 18 years now. He is a firefighter and paramedic. He works a 24 hour shift. Even on his days off his sleep suffers. Perhaps elevated cortisol levels at night but I think it's just so much more when you dis-regulate your sleep, would you agree with that?

Dr. Hans Van Dongen, Ph.D.: [00:38:30]
Yes absolutely. Cortisol is just one of many, many things that get out of alignment when you have schedules like that. We hear over and over again if people were actually scheduled for a long time, there was something about their body and their brain that adopts that as as a new status quo and makes changes to try to minimize the damage that that can potentially occur. Those are the mechanisms that kick in to make sure that in the face of sleep loss and in the face of circadian misalignment, if you do this continually you will be able to sustain living under those circumstances. There's a good analogy with blood pressure. If you're constantly stressed, we know that your blood pressure will go up, and that’s a bad thing, but it initially starts as a good thing. Having higher blood pressure, you can deal with the stress better. You can also maintain your ability to stay upright and live because of that. But high blood pressure becomes a risk factor in the long run, and leads to cardiovascular disease. If you have chronic exposure to that circumstance in the long run it becomes a bad thing, and we believe that with shift work and with schedules that are outside the norm, a similar thing happens where your brain and your body find ways to cope with that challenge. That's initially a good thing but over time, there's wear and tear involved. And some point that load becomes a risk factor, it becomes a problem. We don’t actually know how to get rid of that allostatic load, to reduce that response or to rewind how you ended up there

Carl Lanore: [00:40:51]
My last question to you is this: industry depends on night work. Competition depends on night work. Should the companies that rely on large night shift workers be sensitive to the higher health risks of these employees? And if so, what should they do to support them?  Just keep in mind that when you answer this question, you're going to piss a lot of big CEOs off.

Dr. Shobhan Gaddameedhi, Ph.D.: [00:42:28]
I don't know what particular advice I could give, but in Denmark they do compensate for night shift workers, especially the healthcare workers, frontline workers, compared to the day shift workers. If you can identify the employees within the organization by their chronotype and assign them based on their that, for example, early chronotypes work day shifts and late chrototypes work late hours. There are studies that suggest if you assign the early chronotype the early shift work, their risk, especially for cancer, is low. 

Carl Lanore: [00:43:42]
This makes perfect sense. I’m very familiar with chronotypes and I've actually started to think that maybe there were some nocturnal humans in our past and that's why we have these different chronotypes. Maybe some polymorphism in them that they were nocturnal humans which carried on transgenerationally.

Dr. Hans Van Dongen, Ph.D.: [00:44:51]
Many of these companies actually already try to do the right thing. Some of the carriers have provisions where night workers have an ability to get some sleep in between parts of their duty so that they can get enough sleep at night and supplement that with daytime napping, which is also, in many instances, paid time. I think there is a lot more awareness of these issues that we sometimes give companies credit for.

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p2 DIALOGUE edit
Does Light Therapy Really Work?
with guest, Patrick Johnson

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