Changing Your Circadian Gene Expression with Polyphenols

This is a bit of a departure from my usual article. It is a paper that I recently wrote for a class that I’m taking for my Master’s in biology.  Thought I would share it in case anyone is interested…

Overview:
Resveratrol, EGCG, grape seed extract, passion flower, and other polyphenol supplements can increase the amplitude of core circadian genes — depending on the time of day that you take them.  Timing may be everything when it comes to the benefits from polyphenols.

 

 Introduction
All living things have core biological rhythms, which are set around the 24-hour period of dark and light. Life on Earth has evolved over the last 3.5 billion year with one constant: a 24-hour cycle of day and night.

Rhythms based on the 24-hour day are called circadian from the Latin word circa (about) and diem (day). (McClung 2006) Circadian rhythms are found in both plants and animals. Plant circadian examples include photosynthesis during the daylight hours, the opening and closing of flowers such as morning glories, and seasonal variations that respond to light and temperature. (Song, Ito, and Imaizumi 2010) Examples of animal circadian rhythms include sleep/wake cycles, body temperature fluctuations over the day, and blood pressure naturally rising in the early morning hours. (Thosar et al. 2018)

Plant Compounds Impact Our Human Circadian Rhythms
Recently, research has shown that many plant compounds interact with human circadian clock genes and can impact the amplitude or period of the transcription of the genes. Compiling the data from recent studies on polyphenols and circadian gene expression will show that the benefits of polyphenol consumption are derived, in part, from their impact on our circadian clock.

Plant Circadian Rhythms
Circadian rhythms, both in plants and animals, are endogenous and self-sustaining in stable environmental conditions where light and temperature remain fairly consistent. Even without the daily re-setting, or entrainment, of that rhythm, most organisms maintain an endogenous circadian period that is approximately, but usually not exactly, 24 hours. In the early 1900’s experiments showed that the leaf movements of plants kept in the dark varied just a little from being 24-hour cycles. The concept that endogenous cycles are not always exactly 24-hours is known as the organisms free-running time and applies to both plants an animals. (McClung 2006) Light, as a zeitgeber (German for time giver), entrains the core circadian rhythm each day, resetting a slightly longer or shorter free-running time back to 24-hours.

Plant circadian rhythms have been studied for hundreds of years. Charles Darwin wrote a book on plant movement in 1880.  In it, he postulates that heredity (genetics) is involved in the movement of plants. Some of the observations he made include the inherited movement of the hypocotyl arching and breaking through the ground as certain plants germinate. (Darwin 1880)

Groundbreaking genetic discoveries in the 1970’s and 80’s paved the way for understanding the genes that drive circadian rhythm.  While the first circadian gene to be cloned was the Per (period) gene from the Drosophila melanogaster, a fruit fly (Bargiello and Young 1984), the genetic basis for plant circadian function was not completely elucidated until the 1980’s. The circadian function of the Cab-1 gene was discovered in 1985 in peas and replicated in 1988 in wheat. (Nagy et al., 1988) A series of experiments in the ‘90’s and early 2000’s showed that there are three interlocking feedback loops in most plant circadian rhythms with the genes TOC1, CCA1, and LHY playing integral roles. (McClung 2006)

Human Circadian Rhythm
The human core circadian clock is governed by the feedback loop of the transcription of CLOCK and ARNTL (Bmal1) genes that rise during the day and are then repressed during the night by rising levels of the PER (period family) and CRY (cryptochrome family) of genes. When CRY and PER levels reach a certain level they inhibit their own transcription, forming the basis of the 24-hour oscillation of our molecular circadian pacemaker.  The region of the brain that controls the core circadian rhythm is called the suprachiasmatic nucleus (SCN) and is located in the hypothalamus. Light, specifically in the ~480nm blue wavelengths, hits the melanopsin-containing non-image forming photoreceptors in the retina, signaling to the SCN that it is daylight. This entrains the core clock genes each day to the 24-hour rhythm, and it also stops the production of melatonin, an antioxidant and signaling molecule that rises during the dark.(Xu and Lu 2018)

Research is increasingly showing how intertwined our circadian rhythm is with our health. Circadian dysfunction has been implicated in many chronic diseases including depression, bipolar disorder, heart disease (Thosar et al. 2018), certain cancers, Alzheimer’s disease, and other dementias. (Xu and Lu 2018)

Disruptions to our natural circadian rhythm are ubiquitous in modern life.  Artificial lighting at night, especially in the short blue wavelengths, disrupts the core circadian clock through activating melanopsin and signaling to the SCN that it is still daytime. Blue light in the evenings or at night from TVs, cell phones, computers, and CFL/LED bulbs creates havoc within our circadian system.

Our 24/7 society demands shift work, and we now have food readily available in any season and any time of the day. These two things come together in modern times to increase the risk of many chronic diseases that are dependent on metabolism. Feeding and fasting times regulate circadian metabolism, and mouse studies have shown that time of eating influences adiposity regardless of caloric intake. (Potter, Gregory D. M. et al. 2016) Not only does the time of day impact metabolism, but the overall number of hours in the feeding window, or time from the first food of the day to the last, also impacts metabolism. This was clearly shown by Hatori, et al. in a mouse study that restricted the mice to eat only during an 8-hour window during their normal active time at night. The time restricted feeding mice ate the same number of calories as the mice allowed to eat ad libitum, but they gained less fat and were protected from getting hyperinsulinemia and fatty liver. (Hatori I 2012)

While the body’s core circadian rhythm is governed by the oscillation of CLOCK, BMAL1 and PER, CRY in the SCN, there are also peripheral clocks governing circadian patterns in organs such as the liver, pancreas, and adipose tissue.  Twenty percent of proteins in the liver are under circadian control, varying in the time of day that they are expressed. (Ribas-Latre, Aleix, et al. 2015b.)

Polyphenols
While the term polyphenol is often used in health and nutrition articles, the formal definition of the term has been debated and changed over the years. Polyphenols are generally defined as phenolic molecules that contain one or more benzene rings linked to a hydroxyl group. Plants produce polyphenols in response to either UV radiation or as a defense against various different pathogens. (Beckman 2000, 101-110) Historically, polyphenol was a general term given to plant compounds capable of tanning (a tannin).

Large, epidemiological studies link the consumption of higher amounts of polyphenols to various health benefits including reduced risk of cardiovascular disease, cancer, and neurodegenerative diseases. Food sources that are high in polyphenols include tea, red wine, olive oil, and most fruits and vegetables. Tea is one of the most widely consumed sources of polyphenols, and drinking three or more cups a day has been found to reduce the risk of cardiovascular disease by 11%. (Vauzour et al. 2010)

Polyphenols can be categorized into several main types including flavonoids, phenolic acids, and phenolic amides.  Flavonoids, which often act as antioxidants, have a standard ring structure of C6-C3-C6 with the two C6 rings being phenols. They can be further categorized base on different ways of bonding with the ring structure, with subcategories including proanthocyanidins, flavonoids, flavones, and flavonols. (Tsao 2010, 1231-1246)

The category of flavonoids called proanthocyanidins includes several compounds that have been found to favorably affect human health. Proanthocyanidins, which are polymers of flavonols, include catechins, (Tsao 2010) epigallocatechin (e.g. EGCG from green tea), and grape seed extract. The most common sources of proanthocyanidins in the US diet are apples, chocolate, and grapes, with the 2 – 4-year-old age group eating the most proanthocyanidins.  (Gu et al. 2004)

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol known as a stilbenoid, which is produced by certain plants when they are attacked by fungus or another pathogen.  High levels are found in knotweed, grape skins, pine trees, berries such as blueberries, raspberries, cranberries, mulberries. (Tsao 2010) Resveratrol is a phytoalexin, which is a compound formed by a plant when under stress due to attack by pathogens such as fungus.  Red wine is known for its high resveratrol content, with resveratrol concentrated in the skin of grapes as a way of fighting off the fungus. The grape variety Vitis vinifera is well known for its high concentrations. (Jeandet, Bessis, and Gautheron 1991) Specific cultivars of grapes are higher in resveratrol and thus have a greater natural capacity to resist fungal infections. (Dercks and Creasy 1989)

Effects of Polyphenols on Circadian Rhythm
When looking at how polyphenols affect the expression of core circadian genes either in the SCN or in peripheral systems, there are two elements at play: the effect of the compounds and the timing of the compounds. A compound that causes a rise in one arm of the circadian clock could possibly be a negative at certain times and positive at other times.

Resveratrol
Oike and Kobori in 2008 found that 100um of resveratrol increased the expression of Per1, Per2, and Bmal1 genes. Although a cell study using rat cells, this was one of the first to show that gene expression can be altered by resveratrol. (Oike and Kobori, 2008)  In 2011, Pifferi, et al. used a primate model to determine the effects of resveratrol on circadian period.  The mouse lemurs were kept in the constant dark for two weeks, with a control group and a group fed resveratrol.  The resveratrol group had a shorter circadian free-running period and a lower body temperature compared to the control group. (Pifferi et al. 2011)

Miranda, et al. compared a rat model of obesity (given high-fat diet chow) with a group fed resveratrol plus the high-fat diet (HFD). They found that resveratrol targeted the clock related gene Rev-Erba in adipose tissue and it reversed the changes normally induced by HFD. (Miranda et al. 2013)

A mouse study by Sun, et al. in 2015 found that adding resveratrol to the obesity-inducing HFD attenuated the weight gain. The mice fed a high-fat diet with resveratrol (11-week study) had weight gain about halfway in between the regular high-fat diet group and the control mice. The high-fat diet obese mice had nearly flat daily circadian rhythms of Per2, Clock, and Bmal1; adding resveratrol to the HFD restored the circadian rhythm to that of mice in the control group on a normal chow diet. (Sun et al. 2015)

The timing of resveratrol consumption may be important to reap positive health effects.  Mouse study on resveratrol measured antioxidant effects based on time of day of dosing.  Resveratrol given during the active period (dark for mice) acted as a fairly strong antioxidant in a dose-dependent manner.  Doses ranged from 0.8 to 5 mg/kg, which converts to a physiological dose for humans.  Conversely, when resveratrol was given during the inactive period (light for mice) it actually became a pro-oxidant, increasing oxidative stress in a dose-dependent manner. (Gadacha et al. 2009)

Tea Polyphenols and EGCG
Mi, et al. examined the effects of EGCG, a phenolic component of green tea, on circadian rhythm in mice.  The study used a high-fat, high fructose diet (HFFD), which disrupts normal circadian rhythm by dampening or decreasing the amplitude of Clock, Bmal1, Cry1, Per2, and Per3 gene expression as well as increases triglycerides and total cholesterol.  Adding EGCG to the HFFD diet during the active phase (at night for mice) reversed the changes in lipid metabolism and clock gene expression that was found in HFFD only mice.  The EGCG was added at the beginning and middle of the active period.  Additionally, the group fed HFFD plus EGCG gained less weight than the HFFD group with similar food intake and calorie intake.

In 2017, Qi, et al. studied the effects of tea polyphenols on circadian disruption using a mouse model kept in constant darkness. The constant darkness group had higher insulin levels at certain time points, similar to other studies on circadian rhythm disruption and diabetes. In the group that was given tea polyphenols, there was a suppression of the dysregulation of insulin levels. When comparing the circadian gene expression of the group in constant darkness versus the group in constant dark plus tea polyphenol, the group without added polyphenols had decreased Clock and Bmal1 levels while the group kept in the dark but given polyphenols had circadian gene expression similar to that of the control group kept in a regular light / dark cycle.(Qi et al. 2017)

Passionflower Extract
Passionflower extract (passiflora incarnata) is an herbal folk remedy often used for anxiety and insomnia. Passionflower is a woody, climbing vine that that is native to the southeastern United States. A placebo-controlled study found that passionflower extract was as effective as oxazepam, a benzodiazepine, for the treatment of generalized anxiety disorder. (Akhondzadeh et al. 2001)

Toda et al. found that passionflower extract increases the amplitude of Per1, Per2, and Cry1 about 12 hours after treatment. Treatment at 0 hr showed that it affected the circadian genes over next 20 hours as well as changing the corticosterone rhythm. For the study, the floral parts of passionflower were extracted from dried flowers from France.  The flavonoids in the plants included isovitexin, isovitexin 2″-O-glucoside, schaftoside, isoschaftoside, and homoorientin. Homoorientin specifically was found to separately increase Per2 the most, although the other compounds added to the effect. (Toda et al. 2017)

Proanthocyanidins
Grape seeds are high in proanthocyanidins, and grape seed extract has been used to study the effects of proanthocyanidins on circadian gene expression.  A mouse study by Ribas-Latre, et al. looked at the effect of chronic consumption of grape seed proanthocyanidin extract (GSPE). The results showed increases in the gene expression of CLOCK and PER2 at a dosage of 25 and 50 mg/kg/day in both the liver and in white adipose tissue. Additionally, Nampt was also increased at those doses in white adipose tissue. Nampt expression correlates with nicotinamide adenine dinucleotide (NAD) levels, which activates Sirt1 and affects the expression of Bmal1. (Ribas-Latre 2015a)

A second study by Ribas-Latre, et al. looked at the timing of GSPE administration.  The rats were fed GCPE either at ZT0 (when the lights come on) or at ZT12 (lights off).  The protein expression in the liver was recorded, and it was found that grape seed extract given at ZT0 decreased the expression of Nampt. When given at ZT12, grape seed extract increased the expression of Nampt, which correlates to NAD levels.  NAD activates Sirt1, which is a sirtuin that acetylates Bmal1, thus affecting the expression of Bmal1.  Bmal1 forms a heterodimer with CLOCK, so increasing Bmal1 is only important if there is CLOCK available also. (Ribas-Latre et al. 2015b)  

A final study by Ribas-Latre, et al. examined the effect of GSPE on circadian gene expression using liver cells.  The liver is both under the influence of the core circadian clock genes in the SCN as well as maintaining a peripheral clock influenced by the timing of meals and diet composition. The study found that GSPE altered the expression of BMAL1, increasing the expression at 1 hour and 15 hours after application in comparison to control.  The study also examined the impact of melatonin on BMAL1 as well. The results showed that melatonin at 10umol/L had a very similar impact on BMAL1 expression as GSPE. The researchers further looked at the impact of blocking the melatonin receptor, MT1, and found that GSPE is not acting through the melatonin receptor. (Ribas-Latre et al. 2015)  

Nobiletin
Nobiletin is a polymethoxylated flavonoid found in citrus fruit rinds.  In 2016, He, et al. found that nobiletin increases the amplitude of core clock genes and decreases the effects of metabolic syndrome in a circadian-related manner.  The study found that nobiletin is acting on ROR to enhanced PER2 amplitude in peripheral tissue systems but not in the SCN.  In a mouse model of diabetes and diet-induced obesity (db/db mice fed HFD), nobiletin was effective in blocking the weight gain through decreasing the size of the fat mass and the size of the adipocytes. The nobiletin was administered at 8-10 ZT 200mg/kg every other day.  This blocking of weight gain was accomplished even though the amount of food the mice ate was the same as the obese mice. A second arm of the study looked at the effect of nobiletin vs. a diet-induced obesity model strain of mice that were bred to be deficient in the Clock gene.  The nobiletin group with deleted Clock gene had the same weight gain as the HFD obese mice, reinforcing the circadian rhythm impact of this flavonoid. (He et al. 2016)

Discussion
Plant polyphenols can have a remarkable effect on animal metabolism; part of their benefit may come from their ability to modulate circadian rhythm.  The studies on polyphenols in mice, rats, and primates clearly show that the compounds affect both metabolism and circadian function. More studies are needed to elucidate the role of plant polyphenols on human circadian function. Future studies of polyphenols should include the timing of consumption as well as the daily circadian cycle of the study participants.

The importance to human health of a robust circadian rhythm is becoming abundantly clear with the many studies linking circadian dysfunction with chronic health problems such as mood disorders, cancer, obesity, type 2 diabetes, and dementia. As it is doubtful that our society will go back to a time of only firelight at night, the ability to manipulate circadian gene function with natural polyphenols could have a large impact on the health of the whole human population.

The polyphenols discussed here, with the exception of nobiletin, are readily available as supplements. The timing of taking those supplements may affect the health benefits received from them. For example, passionflower extract, which increases the amplitude of PER1, PER2, and CRY1, should be timed to maximize the expression of the genes that rise during the evening and night. In fact, one of the uses of passionflower in herbal teas is for promoting sleep. Resveratrol, well known as an antioxidant, was shown to actually exhibit pro-oxidant properties when administered during the inactive period. This leads to the idea that resveratrol may be better to take during the day rather than in the evening to reap the benefits as an antioxidant.

The changing effects of polyphenols based on the timing may also explain some of the differing results in studies on them. For example, resveratrol supplement studies may show different results depending on the time of day that the participants took the supplement. Further studies into the timing of supplemental polyphenols could strengthen their protective effects against metabolic disorders also associated with circadian rhythm disruption.

 

References

Bargiello, Thaddeus A., and Michael W. Young. 1984. Molecular genetics of a biological clock in Drosophila. Proc Natl Acad Sci USA 81, no. 7:2142.

Beckman, Carl H. 2000. Phenolic-storing cells: keys to programmed cell death and periderm formation in wilt disease resistance and in general defence responses in plants? Physiological and Molecular Plant Pathology 57, no. 3:101-110.

Darwin, Charles. 1880. The Power of Movement in Plants. London: John Murray.

Dercks, W., and L. L. Creasy. 1989. The significance of stilbene phytoalexins in the Plasmopara viticola-grapevine interaction. Physiological and Molecular Plant Pathology 34, no. 3:189-202.

Gadacha, Wafa, et al. 2009. Resveratrol opposite effects on rat tissue lipoperoxidation: pro-oxidant during day-time and antioxidant at night. Redox Report 14, no. 4:154-158.

Gu, Liwei, et al. 2004. Concentrations of Proanthocyanidins in Common Foods and Estimations of Normal Consumption. The Journal of nutrition 134, no. 3:613-617.

Hatori, Megumi, et al. 2012. Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet. Cell Metabolism 15, no. 6:848-860.

He, Baokun, et al. 2016. The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome. Cell Metabolism 23, no. 4:610-621.

Jeandet, Philippe, Roger Bessis, and Bernard Gautheron. 1991. The Production of Resveratrol (3,5,4′-trihydroxystilbene) by Grape Berries in Different Developmental Stages. American Journal of Enology and Viticulture 42, no. 1:41.

McClung, C. R. 2006. Plant Circadian Rhythms. Plant Cell 18, no. 4:792.

Mi, Yashi, et al. 2017. EGCG ameliorates diet-induced metabolic syndrome associating with the circadian clock. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 1863, no. 6:1575-1589.

Miranda, Jonatan, et al. 2013. Effects of resveratrol on changes induced by high-fat feeding on clock genes in rats. British Journal of Nutrition 110, no. 8:1421-1428.

Nagy, Ferenc, Stephen A. Kay, and Nam-Hai Chua. 1988. A circadian clock regulates transcription of the wheat Cab-1 gene. Genes & development 2, no. 4:376-382.

Pifferi, Fabien, et al. 2011. Resveratrol Dietary Supplementation Shortens the Free-Running Circadian Period and Decreases Body Temperature in a Prosimian Primate. Vol. 26.

Potter, Gregory D. M. et al. 2016. «Nutrition and the circadian system». British Journal of Nutrition 116 (3): 434–442. doi:10.1017/S0007114516002117.

Qi, Guoyuan, et al. 2017. Dietary tea polyphenols ameliorate metabolic syndrome and memory impairment via circadian clock related mechanisms. Journal of Functional Foods 34, 168-180.

Ribas-Latre, A., et al. 2015a. Chronic consumption of dietary proanthocyanidins modulates peripheral clocks in healthy and obese rats. The Journal of nutritional biochemistry 26, no. 2:112-119.

Ribas-Latre, Aleix, et al. 2015b. Dietary proanthocyanidins modulate BMAL1 acetylation, Nampt expression and NAD levels in rat liver. Scientific Reports 5, 10954.

Ribas-Latre, Aleix, et al. 2015. Dietary proanthocyanidins modulate the rhythm of BMAL1 expression and induce RORα transactivation in HepG2 cells. Journal of Functional Foods 13, 336-344.

Song, Young H., Shogo Ito, and Takato Imaizumi. 2010. Similarities in the circadian clock and photoperiodism in plants. Current opinion in plant biology 13, no. 5:594-603.

Sun, Linjie, et al. 2015. Resveratrol restores the circadian rhythmic disorder of lipid metabolism induced by high-fat diet in mice. Biochemical and biophysical research communications 458, no. 1:86-91.

Thosar, S. S., Butler, M. P., & Shea, S. A. (2018). Role of the circadian system in cardiovascular disease. Journal of Clinical Investigation, 128(6), 2157-2167.

Toda, Kazuya, et al. 2017. Passionflower Extract Induces High-amplitude Rhythms without Phase Shifts in the Expression of Several Circadian Clock Genes in Vitro and in Vivo. International Journal of Biomedical Science : IJBS 13, no. 2:84-92.

Tsao, Rong. 2010. Chemistry and Biochemistry of Dietary Polyphenols. Nutrients 2, no. 12:1231-1246.

Vauzour, David, et al. 2010. Polyphenols and Human Health: Prevention of Disease and Mechanisms of Action. Vol. 2.

Xu, Tao, and Baiyi Lu. 2018. The effects of phytochemicals on circadian rhythm and related diseases. Critical reviews in food science and nutrition1-30.

 

 

 

How light at night could double your risk of cancer.

The World Health Organization listed ‘light at night’ as a possible carcinogen in 2007. That is an eye-opening statement for something that affects almost all of us. From streetlights to the lamp in the living room, from accent garden lighting to the glow of TV’s and cell phone… artificial light at night is truly ubiquitous.

An often stated fact is that 80% of people in North America cannot see the milky way at night.  What was more surprising to me was that the Milky Way was supposed to be visible!  Who knew?  Oh, wait – people with no light pollution know…

So how can light possibly be a carcinogen? Will turning on the TV or a light in the living room after dinner suddenly cause cancer?  Let me start with two recent, contradictory studies, and then I’ll get into the science of why I think that artificial light at night is a fundamental health problem. 

Continue reading “How light at night could double your risk of cancer.”

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]

Finally, let’s sum this up with the first sentence from a study on circadian misalignment and glucose tolerance. “Glucose tolerance is lower in the evening and at night than in the morning.” Yes, the study goes on to quantify this as being 17% lower glucose tolerance at 8 pm vs 8 am.[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 the 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:

 

 

 

Circadian Rhythm Connections: Part 1 – Mood Disorders

Roosters crowing at the first crack of daylight. Morning glories unfurling their blooms as the sun rises in the sky. Lightning bugs flickering just as dusk falls.

Most people intuitively understand that plants respond to sunlight, using photosynthesis to produce energy and store sugar during daylight.  It is easy to also apply the thought of daily rhythms to animals, with nocturnal mice scurrying around at night and diurnal birds chirping in the morning.

What is often more difficult to understand is how deeply circadian rhythms are hardwired into us, humans. While evolutionary biologist may argue exactly how the circadian clocks evolved through different species, there is no argument that all animals and plants are governed by circadian rhythms, from blue-green algae preparing for sunrise to much more complex organisms with nocturnal and diurnal patterns.[ref]

Why is it so hard for us to understand that humans also are affected by light and dark?

Human hubris?  We are superior, beyond the animal rhythms of nature.  We craft tools for extending light into the night, and our society now functions 24 hours a day. Take back the night. Light it up; party all night.

But it seems that our chickens have come home to roost (pun intended).  This human determination to conquer the night, a 24-hour society of hustling and bustling, is probably at the root of so many diseases including mood disorders, cancers, heart disease, dementia, and diabetes.  In fact, over the course of this multi-part series of articles, I will make the case that research studies are showing that circadian disruption is at the heart of most of our chronic health problems.

Before you mentally check out and decide that this article doesn’t apply to you, I challenge you to read to the end and check out the overwhelming evidence for yourself.

This isn’t hippie-dippie, crackpot, wacko stuff. There is a true abundance of evidence that ignoring our circadian rhythm is fundamentally detrimental to our health.

This goes much deeper than just the standard, oft-repeated advice that you should sleep well. Everyone knows that they should sleep well – and most ignore it.  Sleep is involved, but I think I can make the case that good sleep is a byproduct of good circadian function.

The flow of science usually starts with observing a phenomenon. It is talked about, poked-and-prodded, and theories fly. But a true understanding of a phenomenon or a disease comes with understanding the mechanisms that cause it, reverse-engineering it. One way of reverse-engineering chronic diseases is to look at the genes that cause an increased risk for a disease. Modeling the disease state can then happen in an animal model using genetic manipulation, or knocking out a gene to see the effect.  It isn’t as neat and straightforward in biology as it is in engineering, but the principle remains the same.

My path into investigating the impact of circadian rhythms started with diving into genetics and a fascination with the genes that control our core circadian clocks. Humans (like all animals) have a few core genes that regulate our internal rhythms such as the rise and fall of our hormones, enzymes level fluctuation, cellular repair, body temperature, and the sleep/wake cycle.

Our core circadian rhythm is set by the rising levels of two proteins, CLOCK and BMAL1, that join together each day. Levels of CLOCK and BMAL1 rise over the daylight hours, eventually getting to a high enough level that they inhibit themselves, thus allowing the subsequent increase of the other half of our circadian genes: PER (period) and CRY (cryptochrome).  This feedback loop runs on approximately a 24-hour rhythm.

Notice the word approximately. Circadian comes from the Latin words circa (about) and dia (day). About a day. The daily fluctuations of our circadian rhythms usually take a little over 24 hours for humans kept in total darkness, and other animals may have slightly shorter than 24 hour periods. The CLOCK and BMAL1 timing needs to be regularly set and adjusted.

So what sets the beginning of our daily rhythm: morning sunlight.

The shorter wavelengths of sunlight in the 450-480nm wavelengths, what we perceive as blue light, are exciting a non-image forming photoreceptor in the retina of the eye that signals the beginning of the day. Like a lock and key, the specific wavelength of blue light causes the excitation of the molecule, triggering the signal for our circadian clock. (If you think back to plant biology, this same mechanism is at  work in photosynthesis with a specific wavelength of light exciting the chlorophyll pigment inside the chloroplast.)

If you are thinking back to high school biology and only rods and cones in the retina that form images, you may be surprised to find that there is a third type of photoreceptor in the eye known as intrinsically photosensitive retinal ganglion cells (ipRGC’s). The blue light-sensitive pigment in these cells is known as melanopsin, and it has only been known for less than 20 years.[ref]

So if our eyes are not supposed to be exposed to light at night, what about the fact that we have had light at night ever since our caveman ancestors first lit up a fire to keep their caves toasty at night? Good question. Firelight (and light from candles, oil lamps, etc) gives a nice warm glow; it is mainly light in the yellow and red end of the visible light spectrum without any of the shorter, blue wavelengths.

Over 100 years ago we conquered the night with electric lights, but these incandescent bulbs also cast a warm, yellowish light with only a little in the blue wavelength spectrum. Black and white TV’s came into living rooms in the ‘50’s, and by the 1980’s everyone had color TV’s pouring blue flickering light out into the night as we sat glued to the Duke of Hazard and The A-Team.

Fast forward thirty more years to our current era of ubiquitous devices such as cell phones, tablets, and laptops, all glowing with light in the shorter, blue wavelengths.  Add in the effects of LED and compact fluorescent light bulbs, which both have sharp peaks of blue wavelengths in their spectrum – the pure white light includes a lot of blue light in it. (Anyone else here see the irony of the government banning incandescent light bulb production in favor of the lights that are increasing our chronic health problems?)

We are now bombarding the receptors in our retinas at night with light in the exact wavelength (480nm) that signals to our brain that it is daytime.

All of this core circadian oscillation is taking place in a region of the brain called the suprachiasmatic nucleus (SCN).  Located in the hypothalamus the SCN is connected to the retina and receives the signal from the ipRGC’s. One interesting fact about the SCN is that when it is isolated from the rest of the brain, the cells still maintain electrical and molecular rhythms – the clock keeps on ticking.[ref]

It helps to visualize the rise and fall of the circadian genes like a sine wave, with the amplitude (height) of the wave being important as well as the phase (length of time) affecting us.

Let’s get into some of the scientific studies that investigate the importance of our circadian rhythm.

Mood Disorders:
In 2005, the NIH estimated that 9.5% of the adult population suffered from mood disorders.[ref] The 2016 statistics show that 18.3% of US adults suffer from a mental illness (which is a bit broader of a category than just mood disorder).[ref]  This topic is relevant to so many of us, and the science linking mood disorders to circadian dysfunction leads us to new solutions and alternatives to the psychiatric medications that so often come with side effects.

Seasonal Affective Disorder:
Let’s start with an easy and obvious example:  Seasonal Affective Disorder (SAD) is a well-known disorder that involves the onset of depressive symptoms with the changing amount of daylight in the fall or winter. SAD affects between 2 – 9% of the population, depending on the latitude. It is now thought that the decreased intensity or brightness of the light is what triggers SAD rather than a shorter period of daylight. One effective therapy for seasonal affective disorder is bright light therapy.[ref]  More to read: Genetics of Seasonal Affective Disorder

A study of diurnal (active during daylight) rats found that decreasing the intensity of light could effectively cause anxiety-like behavior. In other words, dim light was causal for mood disturbance. The researchers also found that the decreased light intensity caused a disruption to the HPA axis with increased corticosterone production.[ref]  Corticosterone in rodents is equivalent to cortisol production in humans.

Bipolar disorder:
The link between circadian disruption and bipolar disorder has been known since before the 1970’s. Bipolar patients with a shortened circadian period are the ones who respond to lithium carbonate[ref], which has recently been shown to inhibit GSK3beta, directly impacting the core clock genes. Lithium also causes an increase in the amplitude of the production core circadian protein PER2[ref]

The worldwide lifetime risk of bipolar disorder is a little over 2%, with onset most likely occurring between the ages of 17-27.  One mutation in the gene, CLOCK, causes people to be more likely to stay up a little later in the evenings (evening chronotype); it is also linked to a doubling of the risk of bipolar disease.  [ref]

Depression:
Major depressive disorder (MDD) has also been linked to circadian disruption. Our neurotransmitter levels of serotonin, norepinephrine, and dopamine all fluctuate with a circadian rhythm over the day. Moreover, MAOA (monoamine oxidase A), which terminates dopamine signaling, is a transcriptional target of the core circadian genes, BMAL1 and PER2.[ref]

It is interesting to look at how antidepressants work. Studies show that SSRI’s shorten or advanced the circadian period, and fluoxetine (Prozac) also causes phase advances.[ref] It is thought that SSRI’s are increasing serotonin in the SCN (suprachiasmatic nucleus), and part of the reason that it takes a little time for them to be effective is that they are changing the body’s circadian rhythm which takes a little while to adjust.[ref]

This brings us back to the chicken or the egg argument. Are mood disorders causing the changes in circadian rhythms or are alter circadian rhythms causing mood disorders?[ref] There seem to be arguments on both sides, and it could be that both sides are correct in that the interrelated feedback loops could keep driving the dysfunction.[ref]

One strong argument for circadian dysfunction causing mood disorders is that genetic variants in the core circadian genes are linked to increased risk of major depressive disorder, bipolar disorder, and anxiety. Another strong link is that altering the CLOCK gene in mice can produce a mouse model of depression. One specific strain, called CLOCKdelta19 mice, causes a longer circadian period with mania and anxiety during daylight and euthymia in darkness[ref] Knockdown of BMAL1 in the SCN of mice induced helplessness, behavioral despair, anxiety and weight gain.[ref]

But not all circadian gene mutations cause mood disorders. Per1 and Per2 mouse mutant strains have altered circadian rhythms without mood alterations. This has led some to hypothesize that light, rather than circadian rhythm, plays a causal role in mood disorders.[ref] While a genetic variant of the CLOCK gene may double the risk of bipolar disorder, obviously not everyone with the variant will become bipolar.[ref]

Looking at animal models of depression adds more fuel to both sides of the argument.  Chronic mild stress causes a dampening in the amplitude of circadian rhythms in mice. It also causes a damping of amplitudes of daily temperature variations and of corticosterone production.[ref]

What do human studies show?
Shift workers who alter their schedules for work are at an increased risk for depression.[ref] While the numbers vary depending on the study, a 2017 meta-analysis came up with a conservative estimate of a 43% increase in the risk of depression for those who work the night shift.[ref]

A number of human core clock genes are associated with the risk for MDD and seasonal affective disorder. Again, finding that circadian gene variants can cause mood disorders is a strong indicator that circadian disruption drives mood disorders.  Recently, it was shown that a PER3 mutation that causes Familial Advanced Sleep Phase Disorder (people who have this naturally want to go to sleep very early in the evening and get up extremely early in the morning) also is causal for seasonal affective disorder. The same study created a mouse model that decreased PER3 expression, which showed that not only were the mice depressed, but the severity of depression was worse with a shorter photoperiod. [ref]

A study of patients with depression looked at the gene expression at the time of death (you can’t do a lot of in vivo studies on gene expression in the brain with people who are living). The study found that compared to non-depressed, people with depression controls who had died at the same time of day showed a phase delay in gene expression, strongly linking circadian rhythm changes to depression.  [ref]

Sleep disturbance goes along with altered circadian rhythms, and sleep disturbances are a hallmark of both bipolar disorder and depression. It is theorized that dampened and shifted circadian rhythms can explain the sleep disturbances in mood disorders. Indeed, dampened temperature fluctuations (our body temperature is supposed to drop at night) and dampened hormonal rhythms are a big part of depression. In bipolar patients, it has been shown that circadian gene expression is phase advanced in manic states and delayed during periods of depression. [ref]

A recent study of blue-blocking glasses for bipolar patients had very positive results.  The study used two groups of patients, one group wearing blue-blocking glasses from 6 pm to 8 am for seven days, while the other group wore clear lenses. After seven days, the group wearing blue-blocking glasses had a drop in the Young Mania Rating Scale of 14.1 compared to the placebo group which had a drop of 1.7.[ref]  Simple, inexpensive, and effective – blocking blue light in the evenings had a significant impact after only a week.

Let me wrap this up by pointing out some things that may seem obvious now:

  • We are a society that is chronically somewhat stressed.
  • Most of us spend the majority of our day inside with low amounts of light (compared to sunlight).
  • We are constantly telling our body that it is morning instead of night by our use of electronic devices with blue light hitting our eyes at night.
  • All of this is having a deleterious effect on our circadian rhythm.

Lifehacks

Block the Blue Light at Night:  
Blue-blocking glasses (amber or orange colored lenses) in the evening for a couple of hours before bedtime.  This means wearing them constantly since less than a minute of blue light can delay melatonin onset for quite a while. One study found a 50% increase in melatonin production after just two weeks of wearing blue-blocking glasses. [ref] Be sure to look for ones that block 100% of the blue light wavelengths.

Alternatively, you could stop watching TV in the evenings, avoid reading from a lighted eReader, and refrain from looking at your cell phones, tablets, and laptops. Couple the avoidance of all electronics with low lighting in your house from bulbs that have a red hue and you are on the right track to resetting your circadian clock.

Bright Light During the Day:
Sunlight during the daytime is really important. There is just no way to get enough brightness from normal light bulbs during the day. Try eating your breakfast and lunch outside, or park farther from work and walk in the sunshine for a bit before your day begins. Just make it a priority to get some sunlight. A study shows that even sitting next to a window in your office can help. [ref]  Another study found that increasing morning light decreased depression and increased sleep quality. [ref]

Light therapy devices are becoming more and more prevalent, and the studies on them are showing efficacy for more than just seasonal affective disorder. One recent clinical trial found light therapy effective for postpartum depression [ref], and another in dementia patients also found bright light therapy effective.[ref] There are literally a couple thousand studies available on light therapy for depression, so I would encourage you to research the topic. Note that for most studies on depressed patients, the participants continue their current depression medication during the trial. If you are currently on medication, please don’t just throw out your bottle of pills and turn on a bright light—talk with your doctor and come up with a plan.

Darkness at Night:
Dark Therapy has been tried for some bipolar patients, with forced darkness for 10 hours per night leading to stabilization in mood.[ref] Along those same lines, all of us can benefit from blocking out all light sources in our bedrooms while we sleep. Get some blackout curtains (inexpensive on Amazon), and cover up all the little LED lights on chargers, etc.

Final thoughts:
Read and learn more,  pay attention to your circadian rhythm, and realize that the inconvenience of staying on a normal sleep/wake routine more than pays off in benefits for your long-term mental and physical health.

 

Lithium: A mineral that affects mood, Alzheimer’s disease, obesity, and telomeres

I’ve written before on the topic of supplemental lithium orotate for mood, anxiety, and irritability. (Read the previous article here: A little lithium and B12 makes the world a happier place — for some.)

What about the effects of lithium as a mineral supplement on other aspects of health?

In reading studies on a wide range of other topics over the past three years, several links to lithium have popped up. Topics such as circadian rhythm dysfunction, Alzheimer’s disease, telomere length, type 2 diabetes, and obesity… not the subjects that I expected to lead me back to lithium!

The rest of this article lays out the evidence that increasingly shows the importance of this mineral in our health and longevity. I think it is important to examine the research and look at the long-term effects and safety questions that always come to mind when talking about lithium. There is such a stigma, at least in my mind, around lithium that I’ve hesitated at times to talk with friends and family about it – a hesitation that no one seems to have in recommending other minerals such as magnesium or potassium.

Lithium orotate supplements compared to prescription lithium carbonate:
I want to clarify before getting into the studies on lithium what ranges of dosages the studies are talking about. The prescription medication that most people are familiar with for bipolar disorder is usually in the form of lithium carbonate.

Standard doses of lithium carbonate are around 900-1200mg/day, although this can vary based on the individual. For lithium carbonate, there is about 18.8 mg of elemental lithium per 100mg of lithium carbonate. So a 900mg dose would give about 170mg elemental lithium.[ref]

Lithium orotate usually comes as a 120mg supplement that gives about 5mg of elemental lithium.

The amount of lithium that we get in foods and drinking water varies based on the mineral content of the soil, with estimates of .5 to 3mg per day. A provisional RDA of 1mg/day has been recommended. [ref]  So a 120mg lithium orotate (5mg elemental lithium) supplement would average around twice the normal daily consumption from food and water, while the prescription dosages are closer to 80 to 100 times normal daily intake.

Alzheimer’s Disease:
A new study came out in November 2017 on Alzheimer’s rates and natural lithium levels in the drinking water in Texas. In an article about the study (which is easier to read than the research paper:-), the lead author of the study explains the findings. Water samples from almost all of the counties in Texas were tested for their natural levels of the mineral lithium, which varies depending on the concentration in rock and soil.

The researchers found that Texas counties with higher levels of lithium in their groundwater had less of an increase in Alzheimer’s rates compared with counties that had lower levels of lithium. This isn’t a total surprise since previous studies had linked lithium to a decreased risk of dementia, but it is a great confirmation at a large scale population level.  A lot of the initial studies were observations linking bipolar patients taking large doses of lithium carbonate and having lower rates of dementia.

A sampling of other recent studies on lithium and Alzheimer’s disease:

  • A 2015 review in the Journal of Alzheimer’s Disease analyzed the data from three randomized placebo-controlled clinical trials of lithium for treating patients who had already been diagnosed with Alzheimer’s disease. The trials found that lithium “significantly decreased cognitive decline as compared to placebo”.
  • An October 2017 article in JAMA Psychiatry details a nationwide study in Denmark on the exposure to lithium in drinking water and the incidences of dementia.  This was a large study, with 73,000+ dementia patients and 733,000+ people without dementia as the control. The study found that there was a decreased rate of dementia in those people exposed to naturally higher levels of lithium in their water (measured since 1986).
  • A March 2018 animal study looked into the mechanisms of how lithium chloride lowers the risk of Alzheimer’s. It found that lithium chloride caused an increase in soluble β-amyloid clearance from the brain. In mice genetically bred to be a model of human Alzheimer’s, lithium chloride restored the clearance of soluble β-amyloid to the levels of normal mice. One big thing to note from this study is that lithium chloride did not affect β-amyloid that had formed plaque already.
  • A study in 2015 looked at the effects of microdoses of lithium on a mouse model of Alzheimer’s disease. The study found that small doses of lithium carbonate in the drinking water of mice carrying the genes for Alzheimer’s disease caused “decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in cortex, when compared to non-treated transgenic mice.” This was a follow-up study to the human study in 2013 which showed that microdoses of lithium stopped the cognitive decline in Alzheimer’s patients.

You may be wondering at this point why all doctors aren’t handing out low doses of lithium to everyone at risk for Alzheimer’s. I think the quick answer is that it isn’t the ‘standard of care’ with enough clinical trials backing it up. The cynical side of me also notes that lithium orotate (and aspartate) are cheap, over-the-counter supplements without pharmaceutical companies sponsoring huge trials and pushing doctors to prescribe them. There seems to be a couple of ‘novel’ low-dose formulations in the works by pharmaceutical companies, though. [ref][ref][ref]

Telomeres and aging:
Telomeres are the sequences of DNA that are found at the ends of each chromosome. This sequence protects the ends of the chromosome from deterioration. The common example given is to think of telomeres like the plastic on the end of shoelaces that protects the shoelace from fraying. When cells undergo cellular reproduction (mitosis), a little bit of the telomere is lost, and thus telomere length is considered a biomarker of cellular aging. Shorter telomere length is associated with several age-related chronic diseases including Alzheimer’s.

A recent transgenic mouse study found that lithium carbonate treatment leads to longer telomere length in mice that are bred to have Alzheimer’s disease. Interestingly, the normal mice had no effect on telomere length from lithium.  A meta-analysis of 13 studies found that Alzheimer’s patients have shorter telomeres.

A human study looked at telomere length in patients with bipolar disorder. The study found that patients with bipolar disorder (not on lithium) and their relatives had shorter telomeres lengths than healthy, unrelated people. More interestingly, patients with bipolar disorder who were lithium-treated had longer telomere length than patients with bipolar disorder who were not taking lithium as well as relatives of bipolar patients.

Telomere length is a new field of investigation for researchers looking into so many different topics of aging, longevity, and disease. I don’t think the handful of studies on telomere lengthening from lithium really lead to a conclusion yet; I look forward to seeing what future studies tell us on the topic.

Anti-Inflammatory action of lithium:
Lithium exerts some anti-inflammatory effects on the body as well as pro-inflammatory effects under some conditions. It has been known since the 1970’s that lithium inhibits prostaglandin synthesis and COX2 in some parts of the brain. While there is some debate on the topic, the majority of studies also point to lithium decreasing the production of TNF-α, a pro-inflammatory cytokine.[ref]

A recent cell study looked at the potential of lithium plus caffeine, theobromine, and catechin on the innate immune system and inflammation.  The results showed that stacking lithium with caffeine, theobromine, and catechin was more effective as an anti-inflammatory than using them separately.

Another recent study looked at the anti-inflammatory effects of lithium on cells containing the SOD2 genetic variant rs4880.  The study found that those with rs4880 alanine allele (GG for 23andMe) had more of an anti-inflammatory response than those with the valine allele (AA for 23andMe).  This was a cell study though, so it is hard to know how well this translates to the whole body.

Obesity and Type 2 Diabetes:
What surprised me about the Nov. 2017 study that I referenced above was that Texas counties with higher levels of lithium in their water also had lower levels of obesity and diabetes.  I was surprised by this because one of the side effects of long-term, high dose lithium carbonate usage is an increased risk of hypothyroidism and possible weight gain.

Part of the explanation for the high levels of lithium in water correlating to lower levels of obesity and diabetes may be due to the effects on circadian rhythm. Another possible connection between lithium, obesity, and T2D may be the effect on blood glucose levels. In mice, certain levels of lithium reduced non-fasting blood glucose levels.[ref]

How is lithium affecting our body and brain?
For a long time, it wasn’t really understood how lithium worked for bipolar patients. (Quite a few psychiatric medications have been used for decades without fully understanding the mechanisms by which they work – or don’t work – for people.) Studies over the past decade or two have shed light on the neurobiological mechanisms of lithium and genetic studies have increased that knowledge.

One effect of chronic, low-dose lithium is an increase in BDNF, which is a protein that promotes the growth of nerve cells.[ref]

The American Chemical Society published a great overview the topic in 2014, “Neuroprotective Effects of Lithium: Implications for the Treatment of Alzheimer’s Disease and Related Neurodegenerative Disorders“. One of the effects of lithium is its inhibition of GSK-3β (glycogen synthase kinase-3 beta), which is involved in neuronal cell development and energy metabolism. Genetic mutations of GSK-3β increase the risk of bipolar disease.

Lithium ions compete with sodium and magnesium ions in the body for binding sites in certain circumstances. Lithium’s inhibitory effect on GSK-3β is thought to be due, in part, to binding to a site that is normally occupied by magnesium. For a very thorough overview of the biochemical properties of lithium, including its effect on the activation energy of water within a cell and its effect on mitochondrial function, please read through “Towards a Unified Understanding of Lithium Action in Basic Biology and its Significance for Applied Biology“.

One action of GSK-3β is its inhibition of glycogen synthase, which is an enzyme involved in the reaction that takes excess glucose and turns it into glycogen for storage. Thus inhibiting GSK-3β increases glycogen synthesis and increases insulin sensitivity.[ref][ref]

GSK-3β and Circadian Rhythm:
Our body’s core circadian clock is run by a couple of core genes that are expressed during the day and a couple of core circadian genes that rise at night. It is this daily rise and fall of gene expression that then drives our internal daily cycles of waking and sleeping, temperature, and energy metabolism. GSK-3β is involved in phosphorylation of both the day and night core circadian genes.

Genetic variants that change our circadian rhythm are linked to increased risk for bipolar disorder. People with bipolar disorder who respond well to lithium therapy have changes in their circadian gene expression when they take lithium.[ref][ref][ref][ref]

Alzheimer’s disease is also strongly linked to circadian disruption. [ref]

Prevention of lead toxicity:
A recent article hypothesized that some of the benefits reported for higher lithium levels in the drinking water (lower suicide rate, lower homicide and crime rates) could be due to lithium mitigating the effects of lead toxicity. “Animal studies demonstrated that lithium pre-treatment mitigates lead toxicity.”

Toxicity of lithium:
Lithium is considered by some to be an essential trace element, and a complete elimination of lithium causes a decline in fertility, higher mortality rates, and behavioral abnormalities.[ref] But, like all substances, there is always a toxic upper limit.

Patients taking lithium carbonate or lithium chloride for mood stabilization show a variety of side effects, depending on dosing. Most patients taking prescription lithium carbonate get blood tests done at regular intervals to determine their serum lithium levels. Plasma lithium levels above 1.2 mM cause nausea, diarrhea, and tremor. [ref]  Other side effects noted by patients taking lithium chloride include increased thirst and urination, weight gain, and mental dullness. It was theorized that bipolar patients taking lithium may drink more calories due to increased thirst, thus causing weight gain.[ref] Other side-effects of higher doses of lithium include increased risk of kidney problems and interaction with hypothyroidism.

Lithium orotate, as a supplement, comes in much, much lower doses than the lithium in prescription lithium carbonate. There is one case report, though, of nausea and mild tremor from a teenager taking 18 tablets of a supplement that contained 100mg of lithium orotate.

Side effects of Lithium Orotate:
There aren’t any recent research studies or case reports (other than the one above) on lithium orotate side effects, so this section is n=1 personal experiences and internet hearsay. A couple of people that I’ve talked with have reported that lithium may make them tired or a little sleepy during the day, but this was pretty subjective and could have been due to other reasons. An article from a holistic doctor who suggests lithium orotate to most of his patients notes that very few have any side effects. He does suggest taking lithium orotate before bed instead of during the day. This makes sense in light of the circadian rhythm effects via GSK-3B inhibition. A study from 1986 on using lithium orotate for alcoholism listed minor side effects to the treatment (included more than just lithium orotate -e.g. low carb diet and other supplements) as loss of appetite, mild apathy, and muscle weakness. [ref]


Lifehacks:

If after reading through all the information about lithium orotate you want to add it to your supplement list, here are a couple of brands that are well regarded by my family: Weyland’s Lithium Orotate and Seeking Health Lithium Orotate.

As with any supplement, I suggest talking with your doctor if you are on medication or if pregnant or nursing.

The study on stacking lithium with caffeine, theobromine, and catechin for an increased anti-inflammatory effect was interesting. If you are considering this combo, a good source of theobromine is cacao nibs.  Catechins and caffeine are found in green tea.

 

 

 

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?

 

Weight Loss: Optimizing your diet based on your genes

Diet gurus, talking heads on TV, government food pyramids, and your friend who lost 20 pounds…

What do they all have in common?  They all know the perfect diet that will whip you into shape and make you feel good.

If that diet doesn’t work for you?  Well, you must have been cheating. You didn’t eat clean enough.  You didn’t stick it out through the ‘keto flu’ long enough….

It must be all your fault that you are failing on their perfect diet.
Or is it?  We all accept and embrace our differences when it comes to skin color, hair color, etc — different phenotypes based on our gene expression.  It is time for everyone to realize that we are all different when it comes to diet and weight loss as well.

Table of Contents:
The Very Basics
Circadian Foundation
Matching your genes to current diet trends
Genes Related to Weight Gain
The Gut Microbiome Influences Weight
Final Thoughts


The Very Basics

I’m assuming that most people reading this already have the basics in place:  eating healthy food, organic when possible, and not smoking or drinking alcohol in excess.  If you are eating a PopTart for breakfast and washing it down with Mountain Dew, well…    back up and start off by getting rid of the processed junk food.

Why get rid of junk food?  I think most of us have a sense that the preservatives, additives, colorings, and unrecognizable words on the ingredients list are probably not all that healthy. One thing that you may not have considered, though, is the impact of emulsifiers and surfactants in foods. Recent studies have looked at the effects of some substances, such as cellulose and polysorbate 80, which are used as emulsifiers to change the texture of foods. They found that these food additives, which are considered safe by the FDA, change the mucosal barrier in the intestines, allowing bacteria closer contact with the surface of our intestinal cells, leading to irritation/ inflammation. This leads to weight gain without increased food intake, and for some, an increased risk of IBD.  Read through the following article to check to see if your genes put you at a higher risk for having problems with emulsifiers in foods:  Microbiome Microbiome + Genetics + Emulsifiers = Obesity

Building the platform for good health
Most people want to lose weight to ‘get healthy’. We are inundated with stories on the horrible health consequences of being overweight, accompanied by photos of protruding bellies and people eating giant burgers. Being overweight causes cancer, diabetes, heart attacks… and well, it is just generally loathed because fat people are smelly slobs with no common sense or self-control. Right? Well, maybe not. For example, read up on the ‘obesity paradox’, where large studies (~250,000 people) have shown that mortality rates are lower for those who are overweight. It is a U shaped curve for mortality after heart attacks, where those who are overweight are least likely to die and those who are underweight or morbidly obese being at the highest risk for death.[study]

Perhaps we are all looking at weight loss backward. Instead of losing weight to get healthy, we should get healthy and then naturally lose weight. We can look at being overweight or obese as a symptom of the wrong diet and lifestyle for our genes, with finding our own genetically correct diet and lifestyle as the way to get to get healthy first.


Circadian Foundation

Fundamental to health for everyone is good sleep and a healthy circadian rhythm.

Don’t stop reading here! Even if you are thinking, “I sleep ok”, please read on.

Circadian rhythms — biological activities tied to the 24-hour cycle of light and dark — are something that we all recognize in animals and plants. We all know that there are nocturnal animals and insects, and we’ve all seen the cool time-lapse videos of flowers opening in the day and closing at night. But somehow it seems to escape us that circadian rhythms, fundamental to all life forms, apply to humans. They are foundational to our biology and our health.

Thomas Edison invented the lightbulb in the late 1800’s, and cities began lighting up at night just over 100 years ago. Prior to that, humans only had light from fire (candle, oil lamps) in the evenings, which emit a yellow/red shifted light. More recently, color TV’s came into everyone’s living room by the ’80s, computers in the ’90s, and then we all got laptops, smartphones, and tablets in the 2000’s. Edison’s incandescent bulb, with its warm yellow light, went by the wayside with the introduction of the CFL bulb and subsequent leap to LED bulbs.

Light at night disrupts our circadian rhythm, which makes sense when you think about it. But the bigger problem came with the TV, computer, cell phones, and CFL/LED bulbs. They all produce a lot of light in the shorter, blue wavelengths (~480 nm), which is the wavelength that signals through receptors in our retina to set our circadian clocks. For the thousands of years before electricity, our bodies’ exposure to blue wavelengths came each day when the sun came up in the morning. Now blue wavelengths are inundating us late into the night, making our body think that it is still mornings.

Before anything else for our health, we need strong circadian rhythms with melatonin onset in the evening when the sun goes down and sunlight hitting our eye in the morning as the sun comes back up.

There is a ton of research coming out about the health effects of messing with our circadian rhythm, and the Nobel Prize was just given for the discovery of the circadian clock genes.

Why am I going on and on about this for a weight loss article? Studies show that low levels of light at night (like from a night light or street lights shining through the window) cause mice to gain fat compared to mice eating the exact same amount of calories but with dark at night. Weight gain due to light at night is backed up by many studies of people working late shifts. Other circadian rhythm disruption consequences include increased risks of cancers, heart disease, and diabetes (yep, same health risk list as above for obesity).

Genetically, some of us are more sensitive to disruptions of circadian rhythms and melatonin production than others. Some people are a double the risk of diabetes from a melatonin receptor variant, and that risk can be mitigated through the timing of meals and, perhaps, blocking blue light at night. Read through my Melatonin and Circadian Rhythms articles to check your genes for higher susceptibility to circadian disruption: Color TV has made us fat: Melatonin, Genetics, and Light at Night and Circadian Rhythms: Genes at the Core of Our Internal Clocks

Even if you aren’t at a higher risk genetically, blocking blue light in the evening with blue-blocking glasses will benefit everyone from a health standpoint. From all the research studies that I’ve read, the biggest thing that we can do for our health (other than not smoking or excess alcohol) is to get our circadian rhythms on track by blocking blue light for two or three hours before bed, sleeping in the dark, and getting outside in the morning to see the sun.


Matching Your Genes to Current Diet Trends:

If you are looking at current diet trends to give you some ‘rules’ to follow, you may be reading up on Paleo, ketogenic, intermittent fasting, Mediterranean, vegan, juice fasts, and detox cleanses.

How do your genes play a role in which diet to choose? Well, they actually may play more of a role in which diet to eliminate…

Saturated fat consumption is tied to increased risk of heart disease for people with certain genetic variants. So a diet high in saturated fat, such as Paleo or keto, might not be a great long-term solution for some people depending on their genes. Read Saturated Fat and Your Genes and check your genetic data to see if you are at risk.

Fasting or a ketogenic diet is counter-indicated for people carrying genetic mutations that decrease their ability to burn fatty acids for energy. Check out Short Chain Acyl-CoA Dehydrogenase Deficiency and Medium Chain Acyl-CoA Dehydrogenase Deficiency to see if you carry one of those mutations.

Some people are genetically better at breaking down carbs than others. Amylase is the enzyme your body produces to break down starches, and we vary genetically in the amount of amylase that we produce. Read through Digesting Carbohydrates: Amylase Variants to determine if you are a high or low amylase producer. This plays more of a role in whether you are likely to regain weight rather than in initial weight loss.

Carbohydrates play a role in blood glucose levels as well, and this is modified by your genetic variants. A Paleo diet which is low in carbohydrates may work well for someone who has a higher insulin reaction to carbs. Check out your likely reaction to carbs in Carbohydrate metabolism: Your genes play a role in insulin and blood glucose levels

When you eat may be more important than what you eat. If you are considering Intermittent Fasting (or really, any diet), you should check on your melatonin receptor genetic variants. Melatonin interacts with insulin release and overnight blood glucose levels, and some people are at a higher risk of diabetes if they eat later in the evening. Read Color TV has made us fat: melatonin, genetics, and light at night.

Clean eating may be a key for those who have problems with detoxifying endocrine disruptors, which can lead to weight gain. Check out BPA: Genetics and Detoxification and Detoxifying Phthalates: Genes and Diet.


Genes related to weight gain

There isn’t one smoking gun ‘fat gene’ that makes people gain weight, with a few rare exceptions. But there are a lot of minor players in the field of genetics and obesity. Quite a few different genes have been found to correlate to an increase in BMI of say a half to one or two points. Knowing how you are genetically predisposed to weighing a little more may help you find a diet that works for you.

FTO genetic variants have been linked in many studies to an increased risk of obesity. Check your FTO variants and read about the possible lifestyle and diet solutions.

MC4R is a gene involved in regulation of appetite and metabolism. Variants in the gene have been linked to a higher risk of obesity and metabolic dysfunction.  Read more and check your genetic variants in the article Obesity Genes: MC4R.

Our cannabinoid receptors are involved in more than just getting high on cannabis.  Some people have more active cannabis receptors which have been linked to increased appetite and weight gain.  I think of it as a minor case of the munchies.  Check your cannabinoid receptors: Cannabinoid receptors, metabolism, inflammation, and obesity.


The Gut Microbiome Influence Weight

There have been several studies showing the influence of the gut microbiome on weight. The most intriguing studies have shown that transplanting the fecal microbiome from an obese mouse to a normal weight mouse will make the normal mouse become obese.

How can you know if your gut microbiome is to blame? You could do a test through a service like uBiome. They can tell you how your microbiome compares to other people’s samples, but they can’t give you a miracle probiotic pill to change anything.

Your genes also play a role in your gut microbiome, influencing which bacteria are likely to thrive there. Bifidobacteria strains have been associated with a reduced risk for obesity.
Read more: How our genes shape our gut microbiome and our weight


Final Thoughts

For almost all of us, gaining too much weight isn’t something that has just one cause. Thus, losing weight may need multiple solutions applied together.  Focusing first on health may bring about the weight changes naturally.

Getting the foundation down through blocking blue light in the evening, thus increasing melatonin synthesis and regulating circadian rhythm, will help with many aspects of health including weight loss.

Prioritize the rest — whether to remove toxins, go on a ketogenic diet, or try intermittent fasting — based on your genetics.

Finally, ensure that your gut microbiome is healthy and not adding to your weight problems.

Circadian Rhythms: Genes at the Core of Our Internal Clocks

Circadian rhythms are the natural biological rhythms that shape our biology.  Most people know about the master clock in our brain that keeps us on a wake-sleep cycle over 24 hours.  This is driven by our master “clock’ genes.

It turns out that we also have circadian cycles (peripheral clocks) in most organs such as the liver, pancreas, and fat cells. These peripheral rhythms drive cyclical production of proteins in our organs. One example of why this is important is the research being done on the timing of chemotherapy drugs based on the circadian rhythm of enzymes produced in the liver. [study]

Not to be left out, our gut microbiome also has a circadian rhythm, and disruption of our circadian rhythm can disrupt the microbial rhythm. [study]

Getting a little Geeky…
There is some pretty cool terminology involved in chronobiology (a nifty term for the study of biological rhythms) that you will want to be familiar with before digging into the research papers on the topic.  The part of the hypothalamus that controls the central clock is called the “suprachiasmatic nucleus” (SCN), which sounds a little sci-fi to me.  And the external environmental inputs, like the time the sun rises or lights at night, are known as zeitgebers.  Some things are named more predictably, like one gene controlling circadian rhythms which is called the CLOCK gene ( an acronym for Circadian Locomotor Output Cycles Kaput).

It is probably not a big surprise that our core circadian rhythm is set by sunlight since night/day rhythms can be seen in all animals.  In a nutshell, light from the sun in the short, blue wavelengths hits receptors in the eye (intrinsic photosensitive retinal ganglion cells) which signals to the suprachiasmatic nucleus synchronizing the circadian 24-hour cycle.

There are two factors that can mess up our circadian rhythms:  light at night (specifically, blue wavelengths ~450-480nm) and lack of sunlight in the morning.  Add to that the individual genetic variants that affect our clock gene functions and you can begin see the importance of this topic.

So what happens when our circadian rhythms go askew?  The effects can be far ranging and include increased risk for the following: diabetes, cardiovascular disease, certain cancers, mood disorders, and obesity.  The amount of scientific research coming out on the topic in the past few years is astounding.  While not talked about much in the mainstream press, the evidence is strong enough that in 2007 the IARC (cancer research arm of the World Health Organization) listed chronic exposure to light at night as a possible carcinogen.

Quick Recap:
Circadian rhythm is at the base of good health.
Blue wavelengths set circadian rhythm.
Sunlight in the morning is good; blue light in evening alters the circadian system.

Genetic Variants in Clock Genes:

The CLOCK and BMAL1 (ARNTL) genes are the core clock genes that target and turn on other genes. They are regulated and turned off by rising levels of the cryptochromes, CRY1 and CRY2,  and the period genes, PER1, PER2, and PER3.[ref]  This forms the daily feedback loop of rising CLOCK and BMAL1 that are then inhibited by rising levels of CRY and PER giving a 24-hour rhythm.

CLOCK gene variants:

One well-studied variant of CLOCK is rs1801260 (G is the minor allele for 23andMe orientation, also known as 3111T/C ) with quite a variety of effects:

  • Carriers of the G allele have higher activity in the evening, delayed sleep onset, and less overall sleep time on average.  [ref][ref]
  • A 2016 study looked at body temperature changes, activity and position in a group of women based on carriers of the G allele. They found that those with the minor allele had higher evening activity, and different body temperature variations over a day leading to a conclusion of ‘less robust circadian rhythm’.  [ref]
  • Carriers of the G allele had higher BMI and less weight loss on a calorie restricted diet in a study of obese patients[ref]. They also lose less weight after bariatric surgery.[ref]
  • Those with the G allele had slower gastric motility.[ref]
  • G allele carriers had higher resistance to weight loss, lower intake of total carbohydrates and monounsaturated fat, and high intake of saturated fat.  Ghrelin (hunger hormone) concentrations were also higher. [ref] [ref] [ref]
  • Blood pressure circadian rhythms are lower in those carrying the G allele [ref]
  • In those with bipolar disorder, the G allele is associated with increase manic episodes [ref]

Check your 23andMe results for rs1801260 (v.4 and v.5):

  • GG: higher activity in the evening, possible delayed sleep onset, risk for obesity
  • AG: somewhere in between
  • AA: normal

Another CLOCK gene variant, rs11932595 (G is the minor allele), has also been found to affect circadian function:

Check your 23andMe results for rs11932595 (v.4 and v.5):

  • GG: somewhat increased risk of miscarriage, risk of male infertility, shorter sleep
  • AG: somewhat increased risk of miscarriage, risk of male infertility, shorter sleep
  • AA: normal, longer sleep duration

Studies show:

  • Sleep duration for those with the AA genotype is likely to be longer [ref]
  • Those with the minor allele were less likely to have non-alcoholic fatty liver disease. [ref] and sleep disturbance in depression [study]
  • An increased risk of miscarriage was found for those with AG, GG[ref]
  • An increased risk (1.9x) for male infertility for those with the G allele.[ref]

 

Check your 23andMe results forrs4864548(v.4 and v.5):

  • GG:  increased risk of obesity[ref][ref]
  • AG:  increased risk of obesity
  • AA: normal

 

BMAL1 (ARNTL gene):
BMAL1 binds with CLOCK to increase the production of the PER and CRY circadian genes.  One of the BMAL1 variants, rs3816358 (A is the minor allele), has been studied in reference to breast cancer risk, cardiovascular disease risk, and diabetes risk.

Check your 23andMe results for rs3816358 (v.4 only):

  • AA: less of a risk of breast cancer than other shift workers [ref]
  • AC: less of a risk of breast cancer than other shift workes
  • CC: regular risk of breast cancer compared with other shift workers


rs7950226
(A is the minor allele)

  • increased risk of diabetes and gestational diabetes [ref] [ref]

PER1 gene:
PER1 codes for the ‘period circadian protein homolog 1’ protein which, along with CRY (below), is the other half of the core genes involved in our circadian rhythm.

A study in 2012 found that a variant, rs7221412, altered the natural timing of activity. Those with the AA genotype may naturally wake up about an hour earlier than those with GG, while AG falls in the middle.

Check your 23andMe results for rs7221412 (v.4 only):

  • AA: one hour earlier peak in circadian rhythm, more like to wake earlier [ref] [Article]
  • AG: peak was midway between AA and GG
  • GG: one hour later peak in circadian rhythm, more likely to wake later

PER2 gene:
A recent study looked at the expression of clock genes after weight loss and found that PER2 expression was increased after weight loss. [ref]

Check your 23andMe results for rs2304672 (v.4 only):

  • CC: associated with abdominal obesity, snacking, stress with dieting [ref] higher lipids [ref]
  • CG: associated with abdominal obesity, snacking, stress with dieting, higher lipid levels
  • GG: normal type (23andme orientation)

CRY2 gene:
A study of obese and lean women tracked their clock gene expressions in fat tissue over a 24-hour period.  The study found that CRY2 and REV-ERB  ALPHA are up-regulated in obesity over a 24-hour period.  [ref]

For rs7123390, postmenopausal women with AA had half the risk of estrogen and progesterone receptor-negative breast cancer.  [ref]

NR1D1 (REV-ERB Alpha)

rs2314339 (T is the minor allele)

  • REV-ERB alpha is associated both with a circadian mechanism and the biological action of lithium carbonate.  For bipolar disorder, those with at least one copy of the T allele were 3.5x less likely to improve on lithium carbonate therapy.  [ref]
  • Minor allele (T) carriers are less likely to be abdominally obese. [ref]

rs2071427 (T is the minor allele)

  • The minor allele, T, is associated with higher risk of obesity and higher BMI. [ref]

Other genes:

FTO is a gene with variants that are associated with increased risk of obesity (nicknamed the fatso gene).  A 2015 study found that FTO deficient mice had robust circadian locomotor activity rhythms, while “Overexpression of FTO represses the transcriptional activation by CLOCK and BMAL1.”[ref]  Other studies have shown that over-expression of FTO leads to increased body fat.[ref]


Lifehacks:

Blocking Blue Light:
Blue light at night has a big effect on your circadian rhythms. (Read my melatonin article).  Blocking blue light in the evening for a few hours before bed with blue-blocking glasses is one solution that will have multiple positive benefits on sleep and circadian rhythm. Get some inexpensive orange safety goggles and wear them every evening. Or upgrade to some nicer looking blue-blocking glasses. This seriously makes a difference in sleep quality and circadian function.

Sleep in the dark:
Even dim light at night can affect the body.  A study found that after two weeks with dim light during their dark cycle, “mice gained significantly more mass, reduced whole-body energy expenditure, increased carbohydrate over fat oxidation, and altered temperature circadian rhythms.” [ref]  So get some light blocking curtains, put electrical tape on any LED charger lights, and sleep in true darkness.

Time your meals right:
When you eat may matter more than what you eat:  “we recently showed that the timing of the main meal was predictive of weight loss during a 20-week dietary intervention and that this effect was independent from total 24-h caloric intake. The importance of caloric distribution across the day on weight loss therapy was supported by a recent 12-week experimental study showing that subjects assigned to high caloric intake during breakfast lost significantly more weight than those assigned to high caloric intake during the dinner.”[ref]  Another study showed that for bariatric surgery patients, those who ate their main meal later in the day were much more likely to be poor responders and lose less weight. [ref]

For those with melatonin receptor variants, eating dinner earlier can significantly decrease the risk of type 2 diabetes!

Intermittent fasting or restricted feeding time would also be something to explore.  Mouse studies on restricting feeding time to a four-hour window resulted in less weight gain, even though equal calories were eaten.  Possibly more importantly, it reset some of the circadian rhythm markers in those mice.  [ref]

Ketogenic Diet alters circadian system:
A mouse study looked at the effects of a ketogenic diet on clock genes.  It found that: “Clock genes showed delayed rhythms under KD. In the brain of KD-fed mice, amplitudes of clock genes were down-regulated, whereas 6-fold up-regulation was found in the liver. The metabolic state under KD indicates reduced satiety in the brain and reduced anabolism alongside increased gluconeogenesis in the liver.”  The study also found that the ketogenic diet “led to 1.5-fold increased levels of blood glucose and insulin.”  [ref]  There are other studies as well on the circadian rhythm changes induced by a ketogenic diet [ref]

NAC:
N-acetyl-cysteine (NAC) reversed the effects of BMAL1 deficiency in mice in regards to aging and oxidative stress.  Additionally, “Bmal1-deficient mice that received NAC weigh less than the corresponding control animals drinking regular water”, but they also drank less water.[ref]  This may be something to look into more as far as the timing of when it is best to take NAC.

Colors shift on iOS:
You can turn on an accessibility feature on iPhones to set up the phone to do a complete shift to red light. This is a handy feature if you need to look at your phone for some reason during the night.  Turning on a color shift to red on iOS phones. 

Final thoughts:
There is an incredible amount of research coming out about the impacts of disruptions to our circadian rhythms, which has convinced me that this is one of the most important bases for good health.  Significant increases in the risk for breast and prostate cancer have been tied to being exposed to light at night, as well as increased risk of metabolic syndrome and diabetes.

Personal update: While I’m not ready to go back to using candles for illumination in the evening, I am rocking the orange glasses every evening and sleeping like a rock each night.  Plus I’ve moved my evening meal earlier (5:30  or 6 pm) and cut out snacking at night to give my body the signal that the day is done.  All of this has resulted in weight loss without cutting out calories or changing my regular way of eating.

More to read:

Circadian Rhythm and Mood Disorders

Circadian Rhythm and Weight Loss

 

 Updated and revised Dec 2017, Aug. 2018

PPARG: A genetic variant that can protect against obesity and type-2 diabetes, but only if you eat the right diet.

The PPARG (peroxisome proliferator-activated receptor gamma) gene has been associated with obesity, metabolic syndrome, and risk for type-2 diabetes. This gene is involved in the regulation of fatty acid storage and in glucose metabolism.

PPAR-gamma is activated by omega-6 polyunsaturated fatty acids and regulates adipocyte differentiation. More specifically, PPARG is a nuclear transcription factor that involved in our natural circadian rhythm, regulating genes involved in storing fat and insulin sensitivity over a 24-hour cycle.[ref] Continue reading “PPARG: A genetic variant that can protect against obesity and type-2 diabetes, but only if you eat the right diet.”