Huberman Lab Podcast “Intermittent Fasting to Improve Health, Cognition & Longevity” Annotated Summary

Dr Huberman's show notes:

In this episode, my guest is Satchin Panda, PhD, professor and the director of the Regulatory Biology Laboratories at the Salk Institute for Biological Studies. We discuss his lab’s discovery that “time-restricted eating” (TRE) aka intermittent fasting, is beneficial effects for metabolic health and longevity. Dr. Panda explains how TRE, and also longer fasts, can positively impact obesity, diabetes, cardiovascular health, age-related chronic diseases, and improve mood and cognitive performance. He also describes how the timing of eating, light exposure and exercise that ~50% of all people engage in, negatively impacts their health and explains how specific simple adjustments to these can positively shift their subjective feelings of health and biomarkers of cardiovascular function, glucose regulation and metabolism. We discuss how our circadian behaviors, which include our patterns of eating, sleeping and socializing, have an enormous impact on our biology, mood and health and how by simply confining our calorie consumption to a semi-regular daily window, can positively impact our physical health, mental health and longevity.

Dr. Satchin Panda

Other Resources

Articles

Revival of light signalling in the postmortem mouse and human retina (Nature)
Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice (Science)
Time-restricted eating with or without low-carbohydrate diet reduces visceral fat and improves metabolic syndrome: A randomized trial (Cell Reports Medicine)
Embers of society: Firelight talk among the Ju/’hoansi Bushmen (Proceedings of the National Academy of Sciences)
Circadian Entrainment to the Natural Light-Dark Cycle across Seasons and the Weekend (Current Biology)
Feasibility of time-restricted eating and impacts on cardiometabolic health in 24-h shift workers: The Healthy Heroes randomized control trial (Cell Metabolism)
Access to Electric Light Is Associated with Shorter Sleep Duration in a Traditionally Hunter-Gatherer Community (Journal of Biological Rhythms)
Daily Eating Patterns and Their Impact on Health and Disease (Trends in Endocrinology and Metabolism)

Books

The Circadian Code
The Circadian Diabetes Code

Annotated Summary

1k RSC bounty opportunity: I was unable to find a bunch of the papers referenced in this episode. If you want to help, leave a comment with a paper I added a citation for, but was unable to find myself I will reward you with a 1k RSC!

Segment 1: Dr. Satchin Panda (00:00:00)

Dr. Panda is a professor and director at the Salk. His lab studies mental + physical health, specifically the extent to which circadian rhythm is ingrained within human biology. He is interested learning more about how feeding patterns impact human biology and has dedicated much of his attention to studying the practice of intermittent fasting.

This podcast will explore how restricted feedings can impact your physical and mental health. During the podcast Dr. Panda and Dr. Huberman will review a number of studies that explore intermittent fasting in a varied study populations.

Segment 2: Time-Restricted Eating (TRE), Calorie Restriction (CR) & Health (00:07:24)

The first topic of conversation is Dr. Panda's latest Nature paper in which his research group was able to measure neural activity up to 5 hours post-mortem in macular photoreceptors - "Revival of light signalling in the postmortem mouse and human retina" [2-1].

Dr. Huberman starts the conversation by asking Dr. P to clarify the definitions of time-restricted eating vs intermittent fasting - is one term more correct than the other? Dr. Panda responds by describing how intermittent fasting is an umbrella term that describes a number of specific frequency-based diets. The phrase “intermittent fasting” was created over 100 years ago and due to its age is embedded into the field of caloric restriction.

The initial hypothesis that created this field was - if humans can reduce their caloric intake by 20%, then they would both reduce their likelihood of falling ill and increase their capacity to heal themselves.

It turns out that everyone is always subconsciously monitoring their caloric intakes, so most people have trouble going without food for extended periods of time. Dr. Panda wanted to explore this phenomenon, specifically he was curious about devising a feeding regime that:

Conferred the health benefits of intermittent fasting
Is convenient enough that the average person could take advantage of the strategy.

To get started he began to study caloric restriction in rodents. By feeding the mice on an every other day basis, he saw the same beneficial health results as continuous caloric restriction [2-2]. Unfortunately, real world humans love calories and are not as as compliant as the mice in Dr. P's first study. Dr. P saw more value in occasional, acute caloric restriction rather than chronic, intermittent fasting and/or caloric restriction - because he thought it would be more effective as a clinical intervention. He found that reducing calories for one or two days per week was also pretty effective at inducing the positive effects of full caloric restriction.

Dr. Panda returns to the initial question by responding that the modern concept of “intermittent fasting” is more accurately labeled as “time-restricted eating”.

The way his lab defines "time-restricted eating" is eating all of your physical + liquid food within a period of 6-8 hours. While it is better to have longer time-periods for fasting, Dr. Panda suggests that to gain the practical benefits of time-restricted eating one should consume all calories within 10-12 hours. He chose this timeframe from a public health perspective because it is manageable for most people.

References

[2-1] Abbas et al. 2022. “Revival of light signalling in the postmortem mouse and human retina”. Nature. https://www.researchhub.com/paper/1275265/revival-of-light-signalling-in-the-postmortem-mouse-and-human-retina

[2-2] Hatori et al. 2012. “Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet”. Cell Metabolism. https://www.researchhub.com/paper/1275364/time-restricted-feeding-without-reducing-caloric-intake-prevents-metabolic-diseases-in-mice-fed-a-high-fat-diet

Segment 3: Mealtimes & Circadian Clock (00:14:38)

Is getting used to a cadence of regular feeding windows good for one's health? Dr. Panda begins to answer this question by communicating that the circadian clock that is present within every cell in the human body. He describes a predetermined time table within all cells that predicts their gene expression, and therefore function within the body.

Around 2002 Ueli Schibler observed how circadian clock genes reacted when mice were fed at unusual times. He found that the liver circadian clock began to readjust to the new feeding intervals [3-1]. Outside of the Suprachiasmatic nucleus ("the master circadian clock") almost all of brain cells will adjust their circadian clocks to feeding times instead of light exposure. For example, when daylight savings time happens it causes people to feel groggy and not at their best for about a day. It takes people about a day for your brain/body to catch up for every hour of change.

Figure 3-1: Phase entrainment of peripheral oscillators. The pathways by which the SCN master clock may synchronize circadian oscillators in peripheral tissues through direct and indirect zeitgebers are schematically depicted [3-1].

Segment 4: Circadian Rhythm, Meal Anticipation, Digestion (00:21:34)

Your body's circadian rhythm is responsible for preparing you to wake up. It will also prompt your GI system to activate at certain times of the day. Everything from saliva production in the mouth to secretion of digestive enzymes in the gut is regulated by circardian clock genes. Your body will prepare for meals based on a regular physiological pattern.

Supplementary Media 4-1: What is a biological clock?

Dr. P shares an anecdote from his own habits; he starts to eat at 8am and stops at 6pm. If he changes time zones by one hour, his stomach will not be optimally prepared for digestion at the same hour. Dr. H asks if Dr. P can expand on anticipatory signals for autonomic functions like waking up and preparing for digestion.

He mentions how waking up abruptly to the ring of an alarm clock will leave you feeling groggy. This is because your body did not anticipate waking up. It did not prepare the body/mind to wake up via it's regular physiological process of secreting cortisol an increasing cardiovascular activity among many other things. The Drs. eventually conclude that there is a positive benefit to eating at a regular cadence because it allows your body to adjust and prepare for digestion.

If you are interested in learning more about circadian clocks in the digestive system, check out Segers and Deportere, 2021 [4-1].

References

[4-1] Segers & Deportere. 2001. Circadian clocks in the digestive system. Nature Reviews Gastroenterology & Hepatology. https://www.researchhub.com/paper/1275366/circadian-clocks-in-the-digestive-system

Segment 5: Breaking a Fast, Burning Fat (00:25:28)

What does breaking a fast entail? Does a coffee with a teaspoon of sugar break a fast? What is a “fasted state” exactly?

Dr. P responds with a tough answer - it's really hard to tell in humans. Indirect telemetry is the best option. It's a measure of the ratio between the CO2 you exhale and the 02 you inhale. The difference in these two gasses will give you insight into a person's metabolic state, specifically what fuel (fat or carbohydrate) their body is currently using for fuel.

Mice have a different metabolism than humans. Generally, they store less glycogen than the average human. Within 12-14 hours, their respiratory exchange ratio (RER) will start at about 1 and slowly go to .7 - this shift indicates they are now mostly running on fat. As soon as these fasting mice are given a few hundred milligrams of their food, their RERs will begin to rise within 15 minutes. In theory, that small amount of food was capable of breaking a mouse's fast - at least temporarily [5-1].

Fun fact! In this fasting state, the mice fuel their metabolism with fat from body fat stores, not dietary fats. When you are in a fasted state your metabolism will be fueled by ketone bodies instead of glucose. These ketones are derived from the body's natural fat stores - not recently digested dietary fats.

References

[5-1] Joo et al. 2016. The acute effects of time-of-day-dependent high fat feeding on whole body metabolic flexibility in mice. International Journal of Obesity. https://www.researchhub.com/paper/1275494/the-acute-effects-of-time-of-day-dependent-high-fat-feeding-on-whole-body-metabolic-flexibility-in-mice

Segment 6: CR, Time Restricted Eating, Circadian Rhythm & Longevity (00:34:04)

There is an awesome paper that showed that mice who had their calories reduced by 20% or 30% all displayed extended lifespan [6-1]. Dr. P highlights that during this experiment the researchers gave the caloric restriction test-group mice were fed in a single daily bolus, when typically rodents will eat at a slow pace throughout the night.

Supplementary Media 6-1: @conqueragingordietrying1797's YouTube summary of "Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice”, the paper mentioned by Dr. P above

The experimental design in Dr. Takashi's study begs the question - was the observed longevity due to caloric restriction, or the timing of the reduced calorie feeding? Unfortunately, in order to study it - the mice would need to be fed in 8-10 extremely small portions throughout the course of the day. Sadly, grad students were not interested in volunteering for this project so Dr. Takahashi invented a tool that can be programmed to feed rodents varying amount of food at varying times.

This allowed for an experiment that tested how a continual fed state (never fasting) would affect a rodent's health and lifespan. Mice were fed every 2 hours for their entire lives so they never had the chance to enter a fasted state. Surprisingly, these mice also lived 10% longer than the control group [6-2].

This experiment was repeated, but the mice were only fed during the daytime and the mice live 20% longer than controls. It turns out that mice normally feed at night, so this was the equivalent of asking humans to eat all their food at night time. The experiment was repeated a third time, but the mice were only fed at nighttime and they lived 35% longer than controls [6-3,].

Dr. H then asks about the best metrics one can use to assess the efficacy of time-restricted feeding + caloric-restriction. Lifespan is often used in studies with rodents, but obviously this metric is not practical for human studies or personal analytics for individuals who want to assess the health impacts of their dietary lifestyle choices.

Dr. P mentions that another lab group repeated the above experiments while specifically monitoring every known biomarker for longevity - but they did not observe any that had significant associations with lifespan. That's not to say there are not any biomarkers for the health effects of caloric restriction, just that we have not discovered them yet [6-4].

Dr. Takashi allowed mice to eat a caloric restricted diet that was also time-restricted (either 2 hour window, or 12 hour window) and found that neither feeding cadence impacted longevity. This insinuates that the feeding window of time-restricted eating is that not super important as long as it is less than 12 hours [6-5].

References

[6-1] Acosta-Rodríguez et al. 2022. “Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice”. https://www.researchhub.com/paper/1270673/circadian-alignment-of-early-onset-caloric-restriction-promotes-longevity-in-male-c57bl6j-mice

[6-2] Bass et al. 2010. Circadian Integration of Metabolism and Energetics. Science. https://www.researchhub.com/paper/1275367/circadian-integration-of-metabolism-and-energetics

[6-3]

[6-4]

[6-5]

Segment 7: Gender, Hormones & CR; Relative Energy Deficient in Sports (00:47:20)

Interestingly, many of the studies exploring CR and TRE only study male mice. This is a huge problem because, on average, men & women have different metabolisms and therefore have the potential to respond in a nonuniform fashion to dietary alterations. Luckily, this has been identified and the NIH/NSF now requires that biological sex is included as a variable in these types of studies. This way researchers can observe if any effects of dietary alterations that are seen are sex-dependent.

🚨🚨 new acronym alert: RED-S 🚨🚨

Relative Energy Deficit in Sports (RED-S) occurs when super active people who are participating in a time-restricted diet unintentionally do not consume enough food to cover their caloric costs from an active lifestyle.

Supplementary Media 7-1: An overview of RED-S

In females, RED-S can lead to amenorrhea (loss of the menstrual cycle) which is considered to be detrimental for one's overall health. Over long periods of time, RED-S in women can result in poor bone health and disruption of the hypothalamic-pituitary-gonad axis (HPG axis) and hypothalamic-pituitary-adrenal axis (HPA axis). Because of this Dr. P does not recommend the OMAD diet (one meal per day) because it is easy to become calorie deficien when you only eat once per day. Instead, he suggests a feeding window of around 8-10 hours. Dr. H asks if a 10-12 hour feeding window could help athletes reduce the incidence of RED-S and Dr. P is unwilling to commit to that conclusion.

Segment 8: Physical Activity, Nutrition & Feeding Window (00:52:40)

One of Dr. P's collaborators located in Europe tried to study time-restricted eating in humans. He divided them into two groups - one received the traditional Swiss advice given to diabetics in a clinical setting, and the second group was told to simply time-restrict their eating to a daily twelve hour window. Importantly, the participants were allowed to eat whatever they preferred. This study found that both groups lost the same amount of body weight and improved their health [8-1]. In addition, the authors analyzed each participants specific diets and found that the group receiving traditional advice ended up improving the quality of their diets while subjects that were asked to try time-restricted eating did not consumer higher-quality food. This scores an insignificant point in favor of time-restricted diets!

References

[8-1]

Segment 9: Nutrition Timing, Quality & Quantity; Low- Carbohydrate Diet (00:59:04)

Dr. P mentions another study that examines the impact of time-restricted feeding (12-hour window) on mice with healthy diets. Dr. Rafael de Cabo from the NIH found that even if mice only eat healthy food, eating within a 12-hour window can help to increase lifespan [9-1] . He's reproduced this study with two separate types of healthy diets and found the same results. Dr. H mentions another study that found time restricted diets increase lifespan even when the underlying diet is low-carbohydrate.

Dr. P states that the quality, quantity, and timing of meals are all important factors.

References

[9-1]

Segment 10: Caffeine, Nighttime Socialization, Fire, Breakfast (01:03:00)

To switch gears, Dr. H prompted Dr. P to discuss the health benefits associated with using a regular, repeated feeding cadence from day-to-day (regardless of if that cadence employes time-restriction or calorie restriction). He states the main time-keepers for the mammalian circadian clock are: 1. light 2. feeding 3. activity 4. social connection 5. temperature and asks Dr. P to discuss how these factors are intertwined.

Dr. P starts to answer by asking everyone to pay attention to when they break a fast. He mentions how an individual's personal situation can impact the timing of this. If someone has anxiety that is exacerbated by caffeine, they might be less likely to drink a coffee early in the morning on an empty stomach - so they will likely break their fast earlier.

At this point Dr. H asks Dr. P about his opinion on caffeine. Dr. P asks the audience to take a detour and discuss “night-time activity”.

Humans have been on the earth for around 200,000 years, but only in the last 5,000 years did we have complete control of starting and extinguishing a fire. Dr. P believes that controlling a fire is a human-specific behavior, no other animal is capable of this. It turns out that fire created the potential for “night-time activity” in human society where people could gather and accomplish tasks using communal fire light. Dr. P believes that fire unlocked many complex human interactions that would typically occur via a “fireside chat”.

Supplementary Media 14-1: FIREPLACE 4K 🔥 Cozy Fire Sounds (12 HOURS).

In Turkey during the 1600s, people would gather at night to drink coffee, dance, and discuss politics. At the time, the Turkish population was largely muslim and therefore would pray five times per day. The first of these was early in the morning, and the people found that drinking coffee all night would allow them to socialize all night and still feel good for the morning prayer.

In summary, coffee's initial purpose (in Turkey) was to extend night time activity instead of the current typical purpose of enhancing a person's morning cognition. In fact, the Turkish people began to eat breakfast early in the morning to help them cope with the negative side effects associated with the incredibly strong and thick traditional style of Turkish coffee.

Segment 11: Circadian Rhythm, “Night Owls” & Genetics (01:16:20)

Dr. P continues to opine on the concept of the “fireside chat”. He mentions a sociological researcher who traveled to Africa to observe how a traditional tribe interacts - specifically she was curious about how the content of conversation changed from daytime to nighttime. At night, people discussed politics, matchmaking, hunting strategy [11-1]. Dr. P finishes this thought by saying that what a person chooses to do between sunset and when they go to sleep has a tremendous impact on their health.

Horacio de la Iglesias, an incredible researcher from Argentina, does the grueling research that others are interested in, but don't necessarily want to conduct themselves due to it's challenging nature. He will travel to remote corners of the earth to observe how a traditional societies with no access to electricity behave. Typically, they will fall asleep about 3 to 3.5 hours after sunset and there was almost no standard deviation around this timing [11-2]. In general, everyone would wake up as the sun rose as well. So in theory, there were no morning people or night owls - everyone operated on the same sleep/wake schedule.

Dr. P mentions how he currently wakes up around 5 or 6, but during college and graduate school he was a night owl. He believes the change happened after he had his first child, because his sleeping schedule had to adjust to his infant's. After that, he found it easy to fall asleep around 10 or 11pm.

Dr. P mentions Ken, a friend from University of Colorado, who conducted two studies that observed how peoples' physiology changes after camping for a weekend. They found that, just after two days of camping, one's inherent hormonal rhythms became adjusted to begin the day at sunrise and this change persisted for multiple weeks upon returning to a normal living environment [11-3].

Dr. H's takeaway from this portion of the conversation is that he feels the notion of a genetic-component to being a morning person or night owl needs to be re-considered. Dr. P is not so sure. He mentions a heritable disease called, familial advanced sleep phase syndrome, that causes people to fall asleep regularly at a 8pm. People with this condition are unable to stay up until 9-10pm regardless of activity or consumption of stimulants. It was established this condition is the result of a specific mutation in a circadian clock gene.

References

[11-1]

[11-2] Casiraghi et al. 2021. Humans synchronize their sleep with moon cycles. https://www.researchhub.com/paper/866471/moonstruck-sleep-synchronization-of-human-sleep-with-the-moon-cycle-under-field-conditions
[11-3] Stothard et al. 2017. Circadian Entrainment to the Natural Light-Dark Cycle across Seasons and the Weekend. Cell Current Biology. https://www.researchhub.com/paper/866471/moonstruck-sleep-synchronization-of-human-sleep-with-the-moon-cycle-under-field-conditions

Segment 12: Morning vs. Night time Discussions, “Me Time” (01:26:37)

Dr. H then returns to Dr. P's point around the content of conversations change between day-time and night-time discussions. From both an ancestral and modern perspective, most morning discussions are about the practical aspects of one's work, while nighttime conversations are about self-expression. At night people would discuss politics, culture, music, and other personal interests.

Dr. P believes that the time between sunset and when one falls asleep can be reclassified as “me time” - the time when one can control their actions and, as a result, activities tend to be around self-expression.

Segment 13: Light Sensitivity & “Night Owls”; Puberty, Melatonin (01:30:08)

Dr. P then returns to the concept of a “night owl” and admits he doesn't feel the story has be fully told yet. He mentioned that there are currently genome-wide association studies (GWAS) exploring a potential genetic association with the behavior of being a night owl. While these efforts are worthwhile, Dr. P is curious if we may be missing an important variable in the equation - variation within an individual's sensitivity to light.

Some people have circadian rhythms that are quite light sensitive, while others are less so. It's possible that the night owl behavior is a consequence of a person's sensitivity to artificial lighting. There's a 10x variation among individuals when it comes to blue light sensitivity of retinal ganglion cells [13-1]. Apparently this light sensitivity starts to kick in around puberty - which is why teenagers always complain about bright lights in the morning. Dr. H adds a personal anecdote - he brings a red light bulb with him when he travels because he only uses red light fixtures before falling asleep!

He then transitions and asks Dr. P to comment on the validity of a common phrase he knew growing up: “every hour of sleep before midnight is worth two hours of sleep after midnight”. Is going to sleep at about 3 hours after sunset healthier than trying to stay up late and sleep in late?

Dr. P responds that this is probably true! There are physiological adaptations humans have that allow them to sense light while they sleep, and use it as a cue to begin the process of waking up. If someone stays up late, but also sleeps in late - they are still exposed to light while they sleep during the morning, which will likely reduce their overall sleep quality.

References

[13-1]

Segment 14: Shift Workers, Health & Disease (01:36:05)

Dr. H then mentions a study from Dr. P's lab that explored time-restricted eating within firefighters [14-1]. Dr. P starts to explain by going over the concept of a “shiftworker”. Technically, a shiftworker is defined in Europe as someone that “stays awake for two or more hours of your habitual sleep time doing a professional activity”. Deviating from one's normal sleep schedule by two hours once per month can result in cognitive decline.

In the United States, we do not do a good job of tracking the number of people who are considered shift-workers - but it's generally accepted that 20% of Americans are shift workers. If you include everyone who has a shift worker-esque sleeping schedule (students, new mothers, gig workers) the final total is about 50% of all adults.

This shift working lifestyle makes time-restricted eating more difficult, and shift workers are more likely to develop metabolism-based health concerns [14-2]. Interestingly, shift-workers are often excluded from research studies because they have a more difficult time being compliant with health interventions and their lifestyle makes pharmaceutical treatments less effective. In fact, if a normal healthy person lives the lifestyle of a shift-worker for only five days their blood glucose levels will begin to appear as if the individual is pre-diabetic. These facts made Dr. P interested in specifically studying this population of people.

Supplementary Media 14-1: The health risks associated with being a shift worker

References:

[14-1] Manoogian et al. 2021. “Protocol for a randomised controlled trial on the feasibility and effects of 10-hour time-restricted eating on cardiometabolic disease risk among career firefighters doing 24-hour shift work: the Healthy Heroes Study” BMJ Open. https://www.researchhub.com/paper/1275370/protocol-for-a-randomised-controlled-trial-on-the-feasibility-and-effects-of-10-hour-time-restricted-eating-on-cardiometabolic-disease-risk-among-career-firefighters-doing-24-hour-shift-work-the-healthy-heroes-study

Segment 15: Artificial Lights, Young Adults & Sleep, Metabolic Dysfunction (01:45:43)

Dr. H mentions a PNAS study that found that dim lights while people are sleeping for one night can lead to disruptions of morning blood glucose levels [15-1]. He also cites a Horacio de la Iglesias paper that suggests young people stay up later in the winter when compared to the summer [15-2]. Dr. H begins to shift the conversation towards metabolic disorders and the obesity epidemic. He postulates that artificial light and the lack of a regular eating could be contributing to the rising rates of obesity.

References

[15-1]

[15-2]

Segment 16: Firefighters, Sleep & TRE; Cardiovascular Health, Blood Glucose (01:50:59)

Dr. H then refocuses the conversation on Dr. P's firefighter study [14-1]. Dr. P chose this population because shift workers are often excluded from clinical studies. Less than 50 of the 400,000 currently active clinical trials are focused on improving the health of shift workers. Dr. P gives props to The Salk Institute for their collaborations with UCSD which allowed them to conduct this study.

It turns out that firefighters are extremely susceptible to heart disease and cancer. Also, 70% of full time firefighters will occasionally work a 24-hour shift in an irregular schedule. After studying this population for a while, Dr. P compared firefights to new mothers due to the amount of times they are forced to wake up throughout a given night.

Supplementary Media 16-1: The science behind fire fighter cardiac incidents

For this study, Dr. P and his group asked a population of firefighters to keep their normal working schedules, but also attempt to limit eating to a 10-hour window throughout the course of a day. 50 firefighters were asked to follow the mediterranean diet as a control, while 75 were asked to eat normal meals within any consistent 10-hour timeframe. The primary outcome of interest was “can the firefighters maintain a time-restricted diet?” and the second outcome of interest was “what health benefits are associated with a time-restricted diet?”.

Figure 16-1: Study design and timeline. CGM, continuous glucose monitor; CV, clinic visit; FSV, fire station visit; mCC, myCircadianClock [14-1]

It turns out the firefighters were able to stick to the time-restricted diet for about 5 out of 7 days. In addition, the concentration of low-density lipoproteins (LDL) reduced across all participants. Among firefighters with high blood pressure, the effects of time-restricted eating almost mirrored the efficacy of an antihypertensive medication. In addition, prediabetic firefighters also saw reductions in blood glucose after time-restricted eating.

Segment 17: Shift Workers & Sleep; Alcohol & Caffeine (02:05:18)

When firefighters return from a night-time call, the first thing they will do upon returning to the firehouse is attempt to sleep. Because firefighters have the ability to sleep during their 24-hour shifts, they are a little different than most other shit-workers like healthcare workers or long haul truckers. Therefore Dr. P's findings cannot be extend to other shift workers.

Interestingly, when the firefighters were forced to eat within a 10-hour window (typically starting at 8am) they also tended to drink less alcohol because they were eating earlier. Less alcohol consumption resulted in better sleep along with related downstream health benefits. Dr. H goes onto emphasize how bad alcohol consumption can be for a person, even if they are consuming just two alcoholic drinks per week.

Segment 18: 12- Hour Feeding Window for Adults & Children, Sleep (02:09:15)

Dr. H repeats that Dr. P's recommended feeding window is 12-hours because this window is seemingly manageable for the grand majority of people. In fact, this behavior can result in significant gut microbiome changes. He mentions that mice will eliminate larger proportions of fat and sugar (meaning less fat/sugar is being absorbed) when fed in a time-restricted manner [18-1]. In addition, brown fat metabolism will also increase.

Dr. P then gives a shout out to The Salk Institute. He mentions that a great aspect of working there is that the administration will find ways to help you if your science is going well. The conversation turns to an aside on grant funding. Dr. P mentions The Salk was lucky to have funding from Irwin Jacobs, a founder of Qualcomm, because he was a former academic and understands the pain of seeking grant funding. Dr. H confirms this and says the NIH will only fund extremely conservative study ideas that are very likely to work. This practice limits the likelihood of producing really groundbreaking work in Dr. H's opinion.

Dr. P then describes how his lab created an app called “MyCircadianClock” that attempts to allow for the minimal interaction required to track what and when a person eats. Dr. P's lab uses this app to help their study participants document their food consumption and timing with more ease and accuracy. After starting to use this app, they observed participants eating habits with no specific instructions over a 3-week time period. They found that the average participant eats 7 times per day over a 15+ hour feeding window. In fact, the top 10% of participants eat 12 times per day. Only the bottom 10% of participants were eating within Dr. P's recommended 12 hour feeding window [18-2].

Supplementary Media 16-1: Instructions on using MyCircadianClock

Dr. P then shifts gears to sleep schedules. He reports that children + teenagers should be getting between 9-11 hours of sleep per night. This means that 90% of high school students are chronically sleep deprived.

References

[18-1]

[18-2]

Segment 19: Meal Timing (02:22:10)

Dr. H then mentions one of his neurosurgeon friends has the habit of skipping either lunch or dinner every day. This results in a pretty varied feeding window depending on if he skips breakfast or lunch in a given day. Dr. H is curious if this is an effective strategy, or if it is better to try and keep a consistent feeding window every day.

Dr. P responds that circadian rhythm plays a role here - he responds that Dr. H's friend is likely dealing with some “metabolic jet lag”. He might not feel any negative effects now, but it's impossible to tell if there are negative long term consequences. Circadian studies of meal timing is a fairly new field, but people are currently exploring this question so there's probably not enough research available to provide a conclusive answer at the moment.

Segment 20: “Complete Fast”, Longer Fasts, Physical Health & Mental Health (02:25:20)

Next the conversations turns to more extensive fasting behaviors. Dr. H mentions that he has some friends who will occasionally go on 24 hour fasts. Dr. H is curious if there are any known positive or negative effects of this sort of behavior.

Dr. P begins his answer with the anecdote that many religions incorporate the behavior of complete fasting into their culture and there are definitely benefits to this behavior. Both mouse and human studies have shown positive health benefits associated with “every other day eating” [20-1]. Also, there are currently health clinics in Germany that help people conduct complete fasts in a supervised setting. At the end of these supervised fasts, people seem to be pretty healthy! People even thing complete fasting can have a huge impact on the brain. Dr. P mentions that there are anecdotes of complete fasting helping people come out of treatment-resistant depression.

In the future, more studies will explore how fasting can impact mental health. There is a growing understanding of how “the gut-brain axis” influences mental health. In theory, microbiome changes in the gut play an important role

References

[20-1]

Segment 21: “Fat Fasting”, Blood Glucose & Insulin (02:28:12)

Dr. H then asks Dr. P about his opinion on “fat fasting”, a habit where people will try to limit their blood glucose by only eating healthy fats. This behavior combines two major themes of modern healthy eating: 1.) time-restricted eating is good + 2.) low blood sugar is good.

Supplementary Media 21-1: Background information on “fat fasting”

Dr. P believes that the average person puts too much negative focus on blood sugar spikes at the moment. If someone is too effective at blunting blood sugar spikes, they are essentially telling their pancreatic islet cells to take time off! Dr. P worries that a lack of use over long periods of time will cause atrophy in a similar fashion to skeletal muscle. It will be interesting to see if there are any health consequences to following a strict ketogenic diet over very long periods of time.

In theory, the occasional blood sugar spike is a good thing! Along with insulin secretion, there is a release of insulin like growth factor (IGF-1) that results in a variety of metabolic alterations throughout the body.

Segment 22: Fasting, Metformin, Rapamycin & Longevity; Human Applicability (02:31:57)

Two very popular compounds for life extension and longevity are metformin and rapamycin.

Supplementary Media 22-1: Peter Attia compares metformin and rapamycin on his podcast

Metformin can activate AMP-kinase, the protein responsible for sensing if a cell is in a fasted state. In theory, this drug can “mimic" fasting to a certain degree. Dr. H then gives a shout out to berberine, a compound isolated from tree-bark extract that can result in similar effects to metformin. Rapamycin reduces mTOR activation. Many studies have shown that both of these compounds are able to increase mammalian longevity [22-1], [22-2].

During the day mice are in a fasted state. Therefore their AMP-kinase levels should be high and their mTOR levels should be low. Interestingly, as mice get older they start to eat a little bit during the day - when they normally eat nothing during the day. He believes that it is possible this increased daytime eating as mice age might be confounding results around the efficacy of metformin + rapamycin to regulate AMP-kinase and mTOR activity. He cites a study that found that the time of day during which you take metformin can impact its ability to reduce blood glucose levels [22-3]. Dr. P thinks that, over the long-term, the time at which metformin is consumed will drastically impact its capacity to extend mammalian heathspans. The same questions around timing and efficacy exist for rapamycin too in Dr. P's mind.

Dr. P reports that he does not personally take metformin or berberine, although some of his colleagues who study AMP-kinase do. Dr. H admits that he's tried berberine, and saw that it flattened out his blood glucose spikes when taken alongside a meal rich in simple carbohydrates. On the other hand, when Dr. H took berberine and did not eat a meal rich in carbohydrates along with it he personally experienced extreme hypoglycemia.

References

[22-1]

[22-2]

Segment 23: Circadian Rhythm & Metabolism (02:39:14)

An interesting study done by one of Dr. P's colleges at the Salk found that almost all nuclear receptors (receptors found within a cell's nucleus) have a circadian pattern in some tissues [23-1]. He believed that almost all metabolic processes followed a circadian rhythm in order to take advantage of time-based feeding patterns.

References

[23-1]

Segment 24: Ontime Health App, Circadian Clock App (02:41:36)

Dr. H concludes the podcast by thanking Dr. P and restating how applicable the advice discussed during this episode is. These strategies do not cost anything and can be implemented by anyone in the audience who is willing to change their eating patterns. Dr. P is one of very few scientists who conducts both animal and human studies. He structures his animal studies to provide the maximum possible insight for human health.

Dr. P compliments Dr. H for the effort he has put into scientific communication and mentions his application OnTimeHealth - which helps people make good circadian health choices and is available in all app stores.

Preprint

Preprint

Huberman Lab Podcast “Intermittent Fasting to Improve Health, Cognition & Longevity” Annotated Summary