Circadian Rhythm Connections, Part 2: Weight Loss and Meal Timing

There are five key elements to weight loss from a circadian point of view: Timing of Meals; Light Exposure; Sleep; What to Eat, When; and Genetic Variants.  All of these can come together in our modern world to give you a propensity to gain weight – and all can be hacked to help you lose weight.


#1: Timing of Meals

Timing is everything when it comes to our bodies.

Midnight snacks, a bowl of cereal before bed, or even ‘saving’ desert until 9 or 10 pm. All of these are fairly normal behaviors these days. Just open up the fridge and pop something in the microwave to heat it up, anytime day or night. Modern convenience at its best; not something our ancestors would have been able to do.

This penchant for eating at any time, day or night, is one factor driving the obesity epidemic.

It is always interesting to look at animal models and agriculture to understand weight gain. Financially it makes the most sense to have animals gain weight quickly for food production, so a lot of research has gone into this topic. For example, farmers have known for decades that low doses of antibiotics increase weight in cattle. When it comes to the timing of eating, it has been known for a long time also that the amount of weight gained for the same quantity of food depends on the time of day that the food is given. For example, a study from 1982 found that catfish gain more weight when fed at a specific time of night.[ref]  A more recent example is a mouse study from 2009 that found that mice fed during the time that they normally would be resting gained more fat although they were eating the same number of calories as mice fed during their active period.[ref][ref]

Let’s take a look at the research on people: 
A study of a Mediterranean population of 420 looked at weight loss over a 20-week diet. Those who ate earlier in the day (defined here as eating lunch before 3 pm) lost more weight than those who ate later in the day.[ref]

Another study found that “Eating late is associated with decreased resting-energy expenditure, decreased fasting carbohydrate oxidation, decreased glucose tolerance, blunted daily profile in free cortisol concentrations and decreased thermal effect of food..”[ref]

One more example from a 2017 clinical trial that looked at the timing of meals in healthy 18-22-year-olds: “These results provide evidence that the consumption of food during the circadian evening and/or night, independent of more traditional risk factors such as amount or content of food intake and activity level, plays an important role in body composition.”[ref]

Lifehacks:
The simple solution is to eat earlier in the day and to not snack at night. This is easier said than done, for some of us. So make a plan for your meals for a few days. Yes, actually sit down with a pencil and paper and come up with ideas for shifting your calories to the morning hours. If you are a habitual TV watcher at night (with a subsequent bowl of popcorn and a beer), plan out a couple of evening activities to get you out of the house for a few evenings while you break the snacking habit. Perhaps go for a walk, go see a movie and avoid the overpriced snacks, or dust off your bowling shoes for a quick game.

While this all may sound a bit cut-and-dried, we really are flexible creatures, able to withstand periodically eating at different times without drastic effects. The bigger picture is the chronic effects of eating at the wrong time, rather than just the one-off change up of our daily eating habits. So don’t beat yourself up if you nibble on something at an evening event. Just get back on track for the rest of the week.


#2: Light Exposure

Light is also important to weight gain.  While it seems strange to think about, again the research on this topic seems to point to an incontrovertible conclusion that light – both bright light exposure in the daytime and no light exposure at night – makes a significant difference to our weight.

Science-y Stuff about light and the Circadian Clock:
In Circadian Rhythm Connections, Part 1: Mood Disorders, I explained how light at a specific wavelength (~480nm, blue light) hits melanopsin containing photoreceptors in our eyes, signaling to our core circadian genes (CLOCK, BMAL1) in the brain that it is daytime.

Our body has both the strong central circadian clock in the suprachiasmatic nucleus in the brain as well as what are known as peripheral clocks in our organs. These peripheral clocks include the timing of functions in the liver, pancreas, etc.

The core clock genes are mainly entrained through the cycle of light and darkness, while the peripheral clock in the liver is more quickly reset, or entrained, by food intake. But the core clock genes do still affect the peripheral clocks.

The core circadian clock is located in a region of the hypothalamus called the suprachiasmatic nucleus (SCN).  The SCN signals to the adrenal system to increase adrenal glucocorticoids (e.g. cortisol is a glucocorticoid hormone) production just prior to waking. “This promotes arousal and alertness by enhancing liver gluconeogenesis (from amino acids and fatty acids), promoting release of liver glucose to the blood, and increasing its uptake in the brain and muscles. Adrenal glucocorticoids have been implicated as a peripheral humoral cue for the entrainment of oscillators such as the liver.” [ref]  The SCN also controls the circadian rhythm of the hormones insulin, glucagon, and adrenalin.

That may sound like science mumbo-jumbo, but it has practical implications. For people waking up at 3:30 or 4:00 am every night, this could be caused by the circadian spike in cortisol levels. Personally, I used to see 4:00 am on the clock quite often. Blocking blue light in the evenings, going to be at a reasonable hour, and cutting out snacking after dinner has eliminated the 4 am wake-up for me.

Weight gain and light at night:
Again, animal studies for efficiently producing more meat show us a lot. Chickens have been studied under different lighting conditions for many decades to determine the quickest way to have plump chickens. One study found that chickens exposed to specific wavelengths of light (450-630nm) pack on the pounds better when exposed to the light from 8 am until midnight. The study also notes that poultry workers are adversely affected by blue or green wavelengths of light at night and thus suggests using light in the yellow wavelengths is almost as effective for chicken fattening.[ref]

What does light at night do to people? Shift work is a very well-studied risk factor for obesity. One study of rotating shift workers (Canadian men) found a 57% increase in the risk of obesity.[ref] Another study of shift workers (Korean women) found a 63% increased risk of obesity.[ref] Numerous other studies have similar results.

You may be thinking that all those shift workers are eating bags of Doritos all night long. Perhaps. But even a dim light at night has been linked to weight gain in animal studies that control for the number of calories eaten.[ref] Another mouse study looked at the effects of dim light at night (5 to 15 lux – similar to a night light) and found that mice fed the same number of calories gained weight when exposed to either dim or bright light at night.[ref]

Dim light at night was shown in a study to affect human weight as well. A large study looked at the amount of light in a bedroom at night and correlated higher light amounts to higher BMIs.[ref] Other studies have repeatedly shown the same results.[ref]

Lifehacks:
Solving this problem is as simple as shutting off that night light, getting some blackout curtains, and eliminating all the glowing LEDs from chargers in your bedroom.

Not enough light during the daytime:
Our modern world of cubicles and working indoors also affects our waistlines. Studies show that more light during the day — specifically outdoor light during the morning hours — is linked to weight loss.[ref]  One study that tracked people’s light exposure concluded “having a majority of the average daily light exposure above 500 lux (MLiT500) earlier in the day was associated with a lower BMI.”[ref] A study of people in the northern latitudes during the winter found that bright light therapy in the morning increased weight loss and suppressed appetite. [ref]

Lifehacks:
Make getting outside during the morning a priority. Drink your coffee on the porch, walk or bike to work, take a morning break outside, and eat lunch outside if possible.


#3: Sleep

Sleep is something that every health guru out there puts on their lists of “Top 5 ways to improve blah, blah, blah.” But does it really affect our weight and metabolism that much? Is the benefit worth the trade-off – e.g. is it worth going to bed before 11:00 each night rather than staying up late, having fun with friends or working long hours? Quick answer: Yep. Research shows that it really does make a significant difference.

Fun facts: The average amount of sleep per night has decreased by about 1.5 hours over the last century.[ref] And the recommended amount of sleep for children has decreased by over an hour from 1897 to today.[ref]

Not-so-fun fact: A meta-study of 75,000+ people found that sleeping 5 hours per night or less increased the risk of having metabolic syndrome (e.g. high blood pressure, high blood sugar, overweight) by over 50%. To not have an increased risk of metabolic syndrome, participants had to be sleeping over seven hours a night.[ref]

A 15-day in-patient study looked at the effect of 5 days of insufficient sleep, mimicking the effects of not sleeping enough during the work week.  The study found that insufficient sleep caused greater energy expenditure, but that extra energy expenditure was offset with greater food intake. After the two week trial, participants had gained almost 2 lbs. Women were more likely to be affected by weight gain than men.  (Impact of insufficient sleep on total daily energy expenditure, food intake, and weight gain)  Another larger study had similar findings, with additional results showing that African Americans gained slightly more weight than Caucasians with sleep insufficiency.[ref]

Another study looked at sleep insufficiency (5 hours/night of sleep) and found that insulin sensitivity decreased and inflammatory markers increased.[ref] 

Sleep timing also matters.  A study looked at the average sleeping time (over a week-long time period) and BMI.  The results showed that those who were late sleepers (defined as the midpoint of sleep being after 5:30 am) had an average higher BMI and a greater percentage of calories eaten after 8 pm.[ref]

So that was just three studies; there are hundreds of more studies on this topic showing similar results. The science is clear and unambiguous on this topic.

Why sleep is important to our metabolism:
There are several players involve here, with melatonin being an important one.  Melatonin, a hormone that rises and peaks at night while we sleep, is important to our basal metabolism for a couple of reasons that I will go into below. Light at ~480nm (blue wavelength of light) hitting the retina of our eye stops melatonin production. It is surprisingly quick, with 15 seconds of light stopping melatonin production for over 30 minutes and two minutes of blue light suppressing melatonin for more than 45 minutes.[ref] Thus, turning on the bathroom light in the middle of the night means it will take a long time to fall back to sleep.

Thyroid and basal metabolic rate:
What is melatonin doing at night while we sleep? Among other things (like acting as an antioxidant), melatonin modulates the secretion of leptin, the hunger hormone.  There are also melatonin receptors that regulate the synthesis and secretion of thyroid hormones. “During long photoperiods, higher levels of TSHβ and DIO2 favors the conversion of thyroxin (T4) to triiodothyronine (T3), increasing energy expenditure and basal metabolic rate. Lower, short-photoperiod levels of TSHβ promote dominant DIO3 activity, which convert T4 to both inactive reverse T3 and diiodothyronine T2, increasing food intake and adipose deposits” [ref]

Glucose metabolism and insulin resistance:
First, let’s take a look at a 2003 study that just kind of makes logical sense.  The study looked at medical students who were ‘nocturnal’ – e.g. staying up until 1:30 am and sleeping in until 8:30 am – vs. those who were ‘diurnal’, which would be going to bed well before midnight and getting up when it is light.  The nocturnal med students skipped breakfast and ate more of their calories later at night. This caused glucose impairment as well as decreased melatonin and leptin secretion.

It has been known for decades that people are more insulin sensitive in the morning (again why we shouldn’t eat a big meal at night).[ref] Another study states: “Multiple studies have shown that in healthy humans, both insulin sensitivity and beta-cell responsivity to glucose are lower at dinner than at breakfast”. It goes on to explain that mouse models show that deleting one of the core clock genes (BMAL1) in the pancreas causes insulin resistance.[Multiple studies have shown that in healthy humans, both insulin sensitivity and beta-cell responsivity to glucose are lower at dinner than at breakfast] Circadian disruption is intimately coupled with poor glucose metabolism and insulin resistance.

Lifehacks:
Blue light at night effectively shuts down melatonin production, so you need to block all blue wavelengths for a couple of hours before bed.  You may be thinking… “ha! I don’t need to wear silly looking blue-blocking glasses because I have night shift enabled on my phone/tablet.”  Well, it turns out that researchers studied the night shift mode at a couple of different settings, and it did very little to prevent melatonin production from being suppressed.  So either (shock face!) put away electronic devices a couple hours before bed or get a pair of blue-blocking glasses.

It takes a couple of weeks to get your body’s melatonin production up to optimal after you start blocking blue light at night.  In the meantime, you could increase your consumption of foods that contain melatonin. Foods high in melatonin include tart cherries, grapes, and almonds. Interestingly, melatonin levels fluctuate in plants as well, so the time of harvest, season, and other environmental conditions may affect the levels found in plants.

Why not take a melatonin pill instead of blocking blue light at night? Well, your body’s production of melatonin (without unnatural light) is a bell-shaped curve. Taking a pill gives you a big dose immediately that then gets metabolized and eliminated. Most people are better off with increasing their natural production of melatonin.


#4: What to eat, when

The liver coordinates our metabolism through the synthesis of lipids from carbohydrates and storage of both fats and carbs as glycogen.  The liver’s peripheral circadian clock is powered by both the SCN (core clock) and by feeding timing. CLOCK and BMAL1 genes are thus involved in the rhythm of glucose metabolism and release.

What does this mean? Our body is primed to break things down (metabolize) better at different times of the day. This applies to everything coming into the liver – from foods that we eat to toxins we are exposed to. Here are a couple of studies on food as examples:

A study of 93 overweight women looked at the effects of either a higher calorie breakfast or a higher calorie dinner over a 12-week diet plan.  The results showed that those eating the higher calories at breakfast lost 2.5 times the amount of weight as the high dinner group.  The higher calorie breakfast group also had a decrease in triglycerides by 33% compared with the high-calorie dinner group which had an increase in triglycerides.

A mouse study found that mice given glucose during their rest period gained more weight than mice given the same amount of glucose during their active period. [ref]

Generally, we can sum it up as glucose metabolism is best in the morning.[ref] It makes sense, then, if you are eating a mixed diet of carbs, proteins, and fats to shift your carb intake towards the morning hours and eat fewer carbs at your evening meal. This is even more evident in studies of people who already have impaired glucose tolerance. One study looked at the differences between high fat in the morning and high carb in the evening or the reverse (high carb morning/high fat dinner). It found that the high fat morning/high carb dinner “shows an unfavourable effect on glycaemic control” especially in those with already impaired glucose tolerance. “Consequently, large, carbohydrate-rich dinners should be avoided, primarily by subjects with impaired glucose metabolism.”[ref]

What about time-restricted eating?
Time restricted eating (TRE) is a concept whereby people eat all of their daily calories within a specific window of time.  There have been several good animal studies showing that eating the same number of calories during a restricted feeding window (8 hrs to 10 hrs) causes mice to weigh less than the control groups that are eating the same number of calories spread throughout the 24 hour day.  It can also reverse the progression of metabolic diseases such as type-2 diabetes.[ref][ref]

What time of the day should you do TRE?
A time-restricted feeding study for an 8 week period had participants eating their normal amount of calories during a 4-hour window in the evening (5 – 9 pm). Participants did lose a little weight, but they also had increased fasting blood glucose levels and impaired glucose tolerance.[ref] This seems to indicate that a time restricted feeding plan at any time does work to reduce weight, but the feeding window needs to be earlier in the day so as to not impair glucose tolerance.

TRE doesn’t have to be nearly as strict as a four-hour eating window to be effective.  A study of overweight individuals who normally had a 14-hour eating window found that reducing their eating window to 10-11 hours caused them to lose about 7lbs over 16 weeks. This was maintained over the next 12 months.[ref]

A cross-over study had participants eat their first meal of the day either a half hour after waking or 5.5 hours after waking. One of the findings was that PER2 expression was delayed by about an hour when the people shifted their mealtime later in the day. Another finding was that glucose levels remained high in those eating late.[ref]

Lifehacks:
The research really is good on the effectiveness of a time-restricted eating program. If you are the type of person likes experimenting and who needs to set some rules for yourself, try a TRE program. Example: eat a good breakfast at 7:30 before heading out the door to work; lunch around noon; and then finish up with a light meal around 6:30 pm. This gives you an 11-hour eating window. Simple. And shown to be effective.


#5: Genetics

Of course, I have to talk about genetics here. We are all different, and our genes play a role in our natural circadian rhythm. I’ve written other articles on this topic as well, so I won’t go too in depth here.

The most obvious example of genes affecting our circadian rhythm and our propensity to gain weight is the aptly named CLOCK (Circadian Locomotor Output Cycles Kaput) gene. This is one of our core circadian genes, setting the daily rhythms for the rest of our body.

One well-studied variant of the CLOCK gene is known as 3111T/C or rs1801260. Those who carry the TT (AA for 23andMe orientation) genotype have the normal type, while those who carry a C (G for 23andMe orientation) allele (CC or CT) are thought to have higher expression of the CLOCK gene and of PER2. Those with CC or CT are more likely to be obese, and in a clinical trial, they lost 23% less weight than those with TT on the same type of diet. [ref]

A small trial with 40 middle-aged women (half were TT, half were CT or CC) found that those who carried the C allele lost less weight (about 7lbs less) and also woke up ~30 minutes later in the morning.  They also ate breakfast about an hour later than those with TT.   Additionally, the study looked at heart rate variability and several markers of autonomic nervous system function.  It found that “As compared with TT carriers, risk allele C carriers had a reduction of 34–57% in the daily rhythm amplitude of parasympathetic activity…” The C allele carriers had reduced parasympathetic tone during the night and increased parasympathetic tone during the day.  Think of it as an overall flattened sine wave.  The study also found that those with a higher amplitude (think taller sine wave graph) of parasympathetic tone had greater weight loss during the 30-week study.[ref]

Overall, the CLOCK gene variant leads to an ‘evening’ chronotype. Bipolar patients carrying the C allele are, on average, likely to stay up 79 minutes later at night and sleep less on average as well.[ref]  Bariatric surgery patients who carry the variant are more likely to be evening types and also to lose less weight than those without the variant. [ref]

Another study of this variant showed that morning gastric motility may be slower in C allele carriers. Variant carriers also had somewhat lower morning diastolic blood pressure.[ref] This may play a role in timing for breakfast, with C allele carriers perhaps wanting to eat breakfast an hour or two later.

Lifehacks:
Around 30 – 40 percent of the population carries this CLOCK gene variant. For these people, it may be even more important to watch your blue-light exposure at night so that you aren’t fighting a lack of melatonin alongside your natural propensity for staying up a little later. Get into a good routine for getting to bed at a reasonable hour, and, if possible, shift your morning work schedule a little later to allow you to get enough sleep. Yes, I know that is easier said than done. While you may not be the person who wants to get up at 6:30 am, this variant is more of an hour or two shift rather than an ‘I should sleep in until noon’ excuse.

 

More to read:

 

 

 

Genetics of Seasonal Affective Disorder

The Winter Blues… described as a low feeling, generally apathetic, blah, usually accompanied by changes in sleep.  It is fairly common in northern latitudes, affecting almost 10% of some populations.

Seasonal Affective Disorder (SAD) is characterized by a recurrent depression with a change in the season usually in fall/winter for most. Scientists think this is possibly due to an aberrant response to light – either not enough brightness to the sunlight or not enough hours of light.

SAD is considered to be “heritable” with twin studies indicating that about 50% of the risk factors are genetic.

Genes that have been found in studies to be tied to the risk of seasonal affective disorder are mainly circadian rhythm genes that function to control our 24-hour rhythmic cycle. Our circadian rhythm is controlled by genes that are set by light hitting the retina of our eyes. Interestingly, some of the genes associated with SAD also overlap with genetic variants that increase susceptibility to bipolar disorder and schizophrenia but not depressive disorders.[ref]

You may be wondering, but what about serotonin?  Everyone thinks of serotonin for depression due to the popularity of SSRI’s as an antidepressant. Several studies for seasonal affective disorder have looked into the link to serotonin. Most of the studies didn’t find a big link to serotonin genes, but the way serotonin is used by the brain may play a role in SAD.[ref] [ref] [ref] And how people react to SAD, for example, by overeating, may be related to serotonin.[ref]

While genes do play a major role in increasing the risk of SAD, there is not one specific gene mutation that causes seasonal affective disorder. Rather, there are multiple genetic variants that add to the risk, along with latitude, length of daylight, and possibly dietary factors.


Genes involved in the risk for Seasonal Affective Disorder

PER3 Gene
The PER3 gene has been tied to the seasonal effect from shorter daylight hours in a number of studies. All of the PER (Period) genes (PER1, PER2, and PER3) play a central role in our body’s circadian rhythm. PER1 and PER2 genetic variants may cause disruptions in sleep and a shift in circadian rhythm. PER3 genetic variants have been linked specifically to mood changes due to shorter daylight hours in the winter. The slight shift in circadian rhythm from the PER3 genetic variant coupled with the change in daylight may be what causes SAD for some people.[ref][ref] [ref] [ref][ref]

Check your 23andMe results for rs139315125 P415A (v.5 only):
AA: normal
AG: less PER3, higher risk of SAD
GG: decreased PER3, higher risk of SAD, delayed sleep phase disorder [ref]
Check your 23andMe results for rs150812083 H417R (v.5 only):
CC: normal
CG: less PER3, higher risk of SAD
GG: decreased PER3, higher risk of SAD, delayed sleep phase disorder [ref]
Check your 23andMe results for rs228697 (v4, v5):
CC: normal
CG: linked to evening preference; higher risk of anxiety disorders, SAD
CG: linked to evening preference; higher risk of anxiety disorders, SAD [ref][ref][ref]

OPN4 – melanopsin gene
Melanopsin is the non-visual photopigment in your retina that sets the circadian clock. It is thought that lower levels of melanopsin may contribute to the risk of SAD because of the lower light levels in the winter.
Melanopsin is the photopigment involved in photoentrainment, negative masking, and pupillary light reflex.

Check your 23andMe results for rs2675703 (v5 only) P10L:
CC: normal
TT:  5.6x more likely to have SAD; heightened responsivity to daylength.[ref] [ref]

CLOCK Gene
The Circadian Locomotion Output Kaput (CLOCK) gene is one of the core genes that set our daily rhythms.

Check your 23andMe results for rs1801260 (v. 4, v5)
AA: normal
GG: decreased risk of SAD; a higher level of activity in evening. [ref] [ref]

Lifehacks

If you can’t get outside for enough sunlight during the daylight hours for whatever reason (working, living too far north, etc), there are full spectrum lights made specifically for SAD. Studies have found 30 minutes of 10000 lux in the early morning to be effective.

New studies show that narrow spectrum blue light (100 lux) may be as effective as bright full wavelength light (10,000 lux).

Putting a blue light in your ear may sound a bit ‘out there’, but there are a few studies that indicate this might just be something worth trying. A clinical trial of transcranial blue light through the ear canal reduced depression by half in more than 75% of participants. (I’m not sure how great this clinical trial is, though, since there is no sham or control group, just comparisons of different strengths of light.)  Transcranial light isn’t as crazy as it seems. Animal studies have shown that extra-ocular light (i.e. through the ear canal) has an effect on the brain. Birds are known to have photoreceptors in their brain that regulate seasonal reproduction.  Sunlight through the skull induces GABA release in rats.

A mouse study looking at the effect of dim light at night found that for mice lacking in PER3 (similar to above genetic variants), dim light at night caused an anhedonia-like effect. Anhedonia is the loss of pleasure or interest in things, feeling blah. Night-time light exposure had become a huge problem around the world, with far-reaching health effects on people and animals. If you have PER3 genetic variants (or even if you don’t!), blocking light at night is important for healthy sleep. Blackout curtains are not that expensive, and you can block all the little LED lights from chargers, etc by just putting a piece of dark tape over them.

A gingko extract reversed depression in light-deprived mice.

A recent study found that vegetarians in the Netherlands and in Finland are 3 to 4 times more likely to have seasonal affective disorder.  I’m not sure if this means that vegetarians are more susceptible to SAD, or if people who have SAD are more likely to be vegetarian.

Another study found that SAD is more likely to affect people with lower total cholesterol levels (<230 mg/dl) than with higher cholesterol levels (>230 mg/dl).  Not sure that this is really a ‘lifehack’ but it is another reason that higher cholesterol may not be as bad as the statin-producers make it sound like.

Several studies found that commonly suggested supplements, such as melatonin and fish oil, may not have much benefit for SAD. Keep in mind that these studies are looking at a general population and individual results could vary. (In other words, if fish oil or melatonin makes your SAD go away, keep taking it :-)
A review that looked at studies of melatonin for mood disorders (including SAD) found no benefit to melatonin supplementation. Another review looked at omega-3 supplements for seasonal affective disorder and found no evidence of clinical efficacy.

More to read:

Will Norway Ever Beat the Winter Blues?

 

Color TV has made us fat: melatonin, genetics, and light at night

Color TV has made us fat!

Nope, not just because of the commercials advertising Taco Bell at night nor the fact that we are laying on our couches watching those commercials.  The flickering blue light that can be seen each evening pouring out of almost every window in the neighborhood is fundamentally changing our biology.

So my argument goes as follows:  obesity started to rise right around 1980 in the US, which coincides with color TV’s being in the majority of homes in the US.  

Every good argument needs data to back it up, so here is a nice chart from the National Institute of Health webpage showing the increase in obesity and extreme obesity starting just before 1980 in the US:

NIH_Obesity_Statistics

Yes, I am being a bit sarcastic here with my broad, sweeping statements and reckless use of a chart.  (I really dislike the health websites that over-hype things and then throw in a random chart to prove their point!)

More seriously:  Blue light at night negatively affects health. 

When you start looking at the increasingly strong evidence that blue light at night is messing us up, it starts to make sense that color television sets pouring blue light into our living rooms each night would affect the population as a whole.  Currently, people are exposed to more blue light at night than ever before from phones, tablets, and CFL or LED lights.

There is actually quite a lot of evidence that light in the evening and at night, especially in the blue wavelengths, causes a disruption to our body’s natural circadian cycles.  This disruption can cause weight gain as well as more serious metabolic issues.   Here are just a few studies from the past couple of years:

There has always been light at night from moonlight, candles, fire, or even incandescent light bulbs.  But those light sources all have very little of the short wavelengths of blue light.

The blue wavelengths stop the production of melatonin for up to 2 hours, so exposure in the evening/night from TV’s, tablets, and smartphones delays the onset of melatonin production. [study]  It on takes a surprisingly short amount of exposure (15 seconds!) to bright light to delay the onset of melatonin production.

So what does melatonin do in the body?

Wondering why it is a big deal for melatonin production to be delayed or decreased by light at night?  It turns out that melatonin plays a role in several systems in the body.

Melatonin was first isolated from pineal glands in the late 1950’s.  Eventually, studies were done that associated it with sleep, and synthetic melatonin was first patented and produced as a sleep aid in 1995. Melatonin production is part of our body’s natural circadian rhythm: the level rises at bedtime, peaks around 3 am for most people, and then drops off sharply around 6 am.

Although most often thought of as the sleep hormone, melatonin has many more roles than “just” a good night’s sleep.

  • It acts as an antioxidant: “It achieves this action via a variety of means: direct detoxification of reactive oxygen and reactive nitrogen species and indirectly by stimulating antioxidant enzymes while suppressing the activity of pro-oxidant enzymes”.
  • Melatonin also chelates transition metals such as iron.
  • Melatonin plays a role in the circadian rhythms of insulin secretion.  The pancreas has melatonin receptors, and insulin is down-regulated by melatonin at night.  [study]

A recent review sums it up “The reduction in melatonin production, as during aging, shift-work or illuminated environments during the night, induces insulin resistance, glucose intolerance, sleep disturbance, and metabolic circadian disorganization characterizing a state of chronodisruption leading to obesity.”

How is melatonin made?

Melatonin Biosynthesis (public domain, Wikimedia Commons)
Melatonin Biosynthesis (public domain, Wikimedia Commons)

Melatonin is synthesized in the body in a four-step process.  It starts with the amino acid l-tryptophan, which we can get from a variety of foods.  (This is where we get the idea that Thanksgiving turkey (high in tryptophan) makes you sleepy.) The tryptophan goes through a couple of steps to become serotonin.  Serotonin then can be used as a neurotransmitter, or it can be methylated to become melatonin.

So there are quite a few processes in the body that can play a role in your melatonin levels including eating adequate protein (tryptophan), producing the right amount of enzymes needed in the synthesis, and having adequate methyl groups available for the final step.  When all of the processes are working optimally, the final role in melatonin production is set by the lack of light at night.

Genes involved in melatonin levels:

Some people may be more affected by blue light in the evenings or low levels of light at night — depending on their genes. There is both a genetic component to the amount of melatonin created as well as the interaction with the environmental cues from light.

 Period 2 (PER2) and PER3 gene:

A small recent study looked at haplotypes (groups of variants) for the PER2 gene and found that the ancestral haplotype had less suppression of melatonin when exposed to bright light at night.  For this study, most of the variants in the haplotype aren’t ones that are included in 23andMe data.  But it is interesting that only those with variants different than the ancestral type were affected by the bright light.

Another study looked at the PER3 gene and found a similar effect.  Those with a longer version of the gene (PER3 5/5) had a significantly greater suppression of melatonin from blue light, while those without the insertion had less of an effect.  Those with the PER3 5/5 genotype also were more likely to be morning-types. Again, this variation isn’t covered in the 23andme data.

One PER3 variation that is covered in 23andMe data is rs228697.  The G allele is tied to evening preference and the C allele is associated with morning preference.  While you might speculate that the C allele here is similar to the PER3 5/5 (morning type, greater suppression of melatonin by blue light at night), there haven’t been any studies that I can find to confirm that.

Check your 23andMe results for rs228697 (v.4 and v.5):

  • GG: may prefer to stay up late [study][ref]
  • CG: may prefer to stay up late
  • CC: may be more of a morning person

Methylation cycle genes:

The final step in melatonin synthesis involves methylating serotonin.  MTHFR plays a big role in the methylation cycle and the production of methyl groups. Check your MTHFR variants here.

Melatonin Receptor (MTNR1B):

Melatonin signals through its receptors to downregulate insulin production at night, so it makes sense that a genetic variation in the melatonin receptor would be linked to the risk of insulin-related problems.

rs10830963 (G is the risk allele) linked to higher risk of type 2 diabetes, gestational diabetes, and fasting glucose levels.  A study published in Cell Metabolism explains that this variant confers “increased expression of MTNR1B mRNA in human islets”.   There is an excellent article on this variant at Dan’s Plan blog.  One study notes: ” it is intriguing that we and others have found that a variant of the MTNR1B gene is associated with elevated plasma glucose levels, a reduction of the early insulin response to both oral and intravenous glucose, a faster deterioration of insulin secretion over time, and increased future risk of T2D”

A recent randomized, cross-over trial found that “The concurrence of meal timing with elevated endogenous melatonin concentrations resulted in impaired glucose tolerance. This effect was stronger in MTNR1B risk-carriers than in non-carriers. Furthermore, eating late significantly impaired glucose tolerance only in risk-carriers and not in the non-risk carriers.”

Another recent study that looked at different types of diets (high fat/low carb, low fat, high protein, etc) found that for those in the low-fat group, carriers of the rs10830963 G allele had a greater total reduction of cholesterol (LDL) levels.

Check your 23andMe results for rs10830963 (v.4 and v.5):

  • GG: linked to higher risk of diabetes, increased fasting glucose – don’t eat dinner late
  • CG: linked to higher risk of diabetes, increased fasting glucose – don’t eat dinner late
  • CC: normal

 

AANAT gene:

The alkylamine N-acetyltransferase (AANAT) gene controls the rhythmic production of melatonin by the pineal gland.

rs28936679 (A is the risk allele) -A rare variant that causes delayed phase sleep disorder (Japanese study)

Check your 23andMe results for rs28936679 (v. 4 only):

  • AG: may cause delayed phase sleep disorder
  • GG: normal

 

Diet, supplements, and lifestyle:

Blocking blue light at night through the use of blue-blocker glasses for several hours before bedtime increased melatonin production by over 50% in just two weeks in a recent study.

I am now wearing some really cool looking orange safety glasses at night. For around $10 on Amazon, you too can look like a dork and sleep like a baby! Of course, sleeping like a baby is just one benefit of increasing melatonin, the reduction in risk of chronic diseases such as type 2 diabetes, breast cancer, prostate cancer, heart disease, and mood disorders is the real driving factor for me.

Put up some black-out curtains in your bedroom to eliminate light coming in from street lights, cars, etc. I was surprised at the difference it made for me. An easy way to experiment and see the difference for yourself would be to simply hang dark sheets or black trash bags over your windows for a couple of nights.

F.lux software will turn down the blue light at night on your laptop and tablet.

Bright light in the morning may help balance the effects of blue light at night.  Get outside first thing in the morning and exposure yourself to real sunlight.

There are some food sources that contain a little melatonin.  Tart cherry juice was shown to increase melatonin levels.

What about just taking a melatonin pill?  A study in older adults looked at supplementing with either .4mg or 4 mg of melatonin.  Both dosages raised melatonin levels, but the higher dose (4mg) stayed high longer into the day which could interfere with insulin levels.

More to read:

Learn more:

 

Genetics of Grinding Your Teeth

The Genetic Polymorphisms involved in Teeth Grinding (Bruxism)
The Genetic Polymorphisms involved in Teeth Grinding (Bruxism)

It never fails to amaze me how many of our quirks and traits have a genetic basis.  A study that came out last week caught my eye. Bruxism, teeth grinding, is linked to a genetic variant.

The study, Genetic polymorphisms in the serotoninergic system are associated with circadian manifestations of Bruxism, looked into several polymorphisms in neurotransmitters such as serotonin.  For some people, SSRI’s are effective in helping  control teeth grinding.

The September 2016 study found that a variant in the HTR2A gene, which codes for a 5-HT2 serotonin receptor, is associated with bruxism.  Those with a C allele in rs2770304  were found to have twice the normal risk for bruxism.[ref]

Another study from 2012 of bruxism in a Japanese population found a different variant in HTR2A to be significant.  In that study, a G allele for rs6313 gave a 4 times greater risk for grinding your teeth in your sleep.  [ref]

Both variants are very common and have many other studies associated with them. [ref]

Check your 23andMe results for rs2770304

  • CC: 2X increased risk of bruxism (teeth grinding)
  • CT: increased risk of bruxism
  • TT: wildtype/normal

 

Check your 23andMe results for rs6313

  • GG: 4X increased risk of bruxism
  • AG: increased risk of bruxism
  • AA: wildtype/normal

 

So what can you do with this information? Logically, if you are grinding your teeth and have these variants, you could look into the serotonin system.   Be cautious and read up on serotonin before starting supplements that could affect your neurotransmitter levels.  Honestly, it is not clear to me whether it would be better to try to stimulate more serotonin or to try to decrease serotonin for bruxism.  Tryptophan is an amino acid that may increase serotonin, as well as 5-HTP. [ref]  So talk with your doctor and get your serotonin levels checked.

Genetics of Sleep Disturbances

Sleep DisordersA good night’s sleep is invaluable, literally priceless — but so many people know the frustration of not being able to regularly sleep well.

There are many factors involved in sleeping well, and genetics plays a role in some sleep disorders.

Looking at the genetic basis of your sleep disorder may give you ideas on which path to take to fix the problem. Read on to find out how to check your 23andMe data for your sleep genes…

Circadian Rhythm
One of the first genes that I learned about when I started looked at genetics was the CLOCK (circadian locomotor output cycles kaput) gene. I found it fascinating that some people really are genetic ‘night owls’.

Our natural circadian clock is run by several core genes that rise and fall over a 24 hour period, setting the rhythm for all of our body’s functions. Sunlight hitting the retina in the morning resets the circadian clock. Circadian rhythm disruptions have been tied to obesity, difficulty in losing weight, diabetes, Parkinson’s, Alzheimer’s, heart disease, and ADHD symptoms.


CLOCK gene:

Check your 23andMe results for rs1801260:

  • GG: higher activity levels in the evening, delayed sleep onset. [ref][ref]
  • AG: somewhat delayed sleep
  • AA: normal

AANAT gene:
AANAT (arylalkylamine N-acetyltransferase) controls the production of melatonin in the pineal gland. AANAT enzyme activity is high at night and tied to a person’s circadian rhythm. Polymorphisms in AANAT are more common in those with Delayed Sleep Phase Disorder (Japanese Study).[ref]

Check your 23andMe results for rs28936679:

  • AG: higher risk of Delayed Sleep Phase Disorder (Japanese)
  • GG: normal

PER3 gene:
There are several SNPs and repeats in the PER3 gene that are connected to Delayed Sleep Phase Disorder, but the data isn’t available for 23andMe users.

Restless Leg Syndrome and Periodic Limb Movement Disorder
Restless Leg Syndrome (RLS) is a fairly common disorder affecting about 10% of the US population. Periodic Limb Movement Disorder -PLMD (also called Periodic Limb Movements In Sleep – PLMS) is often lumped together with RLS in studies. The two often go together with about 80%-90% of RLS suffers also having PLMD.[ref] About 40% – 60% of people with RLS have a family history of it, suggesting a strong genetic component. People with a family history of RLS tend to get it at a younger age.[ref]  In general, RLS is more likely to be found in women, in older people, and in those with iron storage issues. [ref]

MEIS1 gene:
The MEIS1 gene has been studied for restless leg syndrome.  MEIS1 encodes a homeobox protein that is involved in normal development, and it has been studied for its role in leukemia. (Homeobox genes are involved in forming organs and limbs in embryonic development.) There are several MEIS1 SNPs that have been linked to an increased risk of RLS and PLMD.

Check your 23andMe results for rs2300478:

  • GG: greater than 1.7x risk of RLS
  • GT: 1.7x risk of RLS
  • TT: normal risk of RLS

BTBD9 gene:

Check your 23andMe results for rs3923809:

  • AA: approx. 50% with this genotype will have RLS, 1.9x risk of PLMD without RLS, serum ferritin levels decreased  26%  [ref]
  • AG: higher risk of RLS and PLMD, serum ferritin levels decreased 13%
  • GG: normal risk of RLS

Check your 23andMe results for rs9357271:

  • CC: lower risk (<0.63) of RLS  [ref]
  • CT: slightly lower risk of RLS
  • TT: normal risk of RLS

PTPRD gene:

Check your 23andMe results for rs1975197:

  • AA: increased (1.8x) risk of RLS  [ref]
  • AG: increased risk of RLS
  • GG: normal risk of RLS

 

There are several other SNPs that have been studied in relation to RLS/PLMD that are not included in 23andMe data, as well as several that slightly reduce the risk of RLS. If either RLS or PLMD is a problem for you, searching through the PubMed studies would be a good idea.

Narcolepsy
Narcolepsy, or excessive daytime sleepiness, is found in about 1 in every 2,000 people in the US.  It is now thought to be an autoimmune disease and is associated with HLA-DRB1*1501 and HLA-DQB1*0602. HLA-DRB1*1501 is highly correlated with rs3135388 and found to influence the risk of several autoimmune diseases including MS, lupus, and narcolepsy. HLA-DQB1*0602 is found in 90% of people who have narcolepsy, but it can’t be determined by a single SNP that I have found.

Check your 23andMe results for rs3135388 (HLA-DRB1*1501):

  • AA: increased risk of narcolepsy, MS  [ref]
  • AG: increased risk of narcolepsy
  • GG: normal risk

 

Check your 23andMe results for rs1154155:

  • GG: increased risk of narcolepsy (2.5x increased risk) [ref]
  • GT: increased risk of narcolepsy
  • TT: normal

Lifehacks

One small thing that will make a HUGE difference in sleep and circadian rhythm function is to block blue light at night. Our modern environment is full of light at night and especially in the blue wavelengths from LED bulbs, TV’s, and phones. The blue wavelength (~480nm) is the exact wavelength that resets our circadian genes each morning.

Other than changing all your light bulbs to red lights or going back to candlelight, you can block the blue wavelengths with glasses. There are inexpensive options like the UVEX safety glasses or more stylish options like these Swannies.

More to read:

Circadian Rhythms: Genes at the Core of Our Internal Clocks

Circadian Rhythms: Of Owls, Larks, and Alarm Clocks

Narcolepsy, the Sleep Disorder, Linked to Immune System Problem