Gordon: You know, I look at your body of work, and I just think about how influential it currently is. Barely a day goes by without someone talking to me and talking about time-restricted feeding or circadian rhythms. And it really is an incredible influence that you’re having on people’s health right now. And so it’s-it’s very exciting to talk to you about that. Satchin, this is something you’ve articulated extremely well is how much of our health is potentially under our control if we put our mind to it. And, you know, your book, “The Circadian Code,” really lays out a plan for us to be much more mindful about  our health and what we can do about it. At the same time, you know, that there [is] genetic influences, and I want to get to genetics in a bit. But for human life expectancy, it seems like genetics isn’t a big deal, right?

Satchin: Yeah, I would say that genetics is not a big deal. I mean,  there’s always interaction between genes and the environment. But when it comes to extending lifespan, we are still in infancy in the sense, for example, if we can study supercentenarians and see, uh, whether they have a genetic makeup. The question is it becomes very difficult to figure out what is the contribution of lifelong exposure to different factors – nutrition, physical activity, sleep, uh, and pollution and other factors. So since it’s very difficult to measure that part, then it becomes difficult to figure out whether somebody who lived up to the age of 90, 95 and for example  [laughs] — it’s not good for them to do that, but who was a lifelong smoker, for example.

Gordon:  Yeah.

Satchin:  Was there a — was there a zeal that actually dented the bad impact of smoking? So similarly, we do find there are a lot of people who are overweight and maybe medically obese, but they do live to the age of 80, 85 with perfectly normal cognitive ability and intellectual ability performance and those are the areas where there’s huge potential for discovery.          

Gordon: So we’ve had many guests on the podcast that are interested in aging interventions or more drug-like, you know, finding-finding chemical compounds and natural products or metabolites that potentially could extend health span. And it seems like you’re not waiting for these! Your strategies are for now, and there’s no wait for  these interventions. Do you think that circadian rhythms and even these sort of feeding cycles are druggable things within themselves?

Satchin: Yeah, so this is where two things come. One is the drugs that we know the geroscience community wants to promote in humans. The question is part of their effect on longevity mediated through a circadian clock. Second, whether those drugs can be optimized for a specific time of the day so that we can even increase their efficacy. So for example, if you’re giving metformin at the wrong time of the day, maybe you’re not seeing much benefit. Is there a right time of the day where you can give metformin for better results? Same thing goes for rapamycin and many of the other drugs that are in — under trial right now. So the timing of drug is another important aspect of circadian rhythm because we know that nearly 85 percent of FDA approved drug targets themselves are circadian, or their metabolism is circadian. In fact, metformin does have a very different effect even on glucose regulation in healthy or diseased mice, whether it’s given in the morning or evening. The second question is, are there drugs that can be active as circadian clock components and, if they do, then what are the benefits? And this is the case where there are at least two different compounds. Um, one is, drugs that target, uh, one of the components of the clock rebirth, alpha and beta, these are nuclear hormone receptors. These are developed by Scripps Research, so that’s why the name is S909, S9011. And now we know that these components are very effective against treating age-related disease, whether it’s metabolic disease, liver disease, cancer — we published a paper on that, dementia, et cetera. So there is hope that even drugging the clock can be beneficial. And then there is also another one, uh, nobiletin, which is a citrus extract which also improves the robustness of the clock. And there are animal studies showing that it increases — it improves health and makes them resilient to age-related disease. So yes [laughs]!

Gordon: Yeah.

Satchin:  From a drug perspective, the current drugs for extended lifespan should be tested for efficacy at different times of the day. And clocks are druggable, and those drugs, sometimes even food supplements or food, may hold promise to improve lifespan.

Gordon:   Super. You know, it makes me think about the fact that we’re all wondering whether things like metformin are gonna work for everyone, or if genetic background is going to be a major influence. You know, and actually, in worms, genetic background is a huge influence in whether you’re going to respond to metformin or not. It reminds me of the studies with caloric restriction where different genetic background mice, you know, different isogenic lines, respond in sometimes opposite ways to the same level of caloric restriction. And I’m wondering if this is something you think about in terms of even time-restricted feeding, whether this is something that has to be catered to the individual based on the genetics.

Satchin: Yes, of course, uh, those who are more prone to hypoglycemia, uh, whether they should be restricted to eight hours or twelve hours or ten hours, is an important issue. Um, the same thing goes for, um, people who actually want to build up their muscle mass and want to eat more to prevent sarcopenia. Uh, the question is, can they absorb enough nutrients within that six or eight hours because there’s a [unintelligible] six or eight hours [laughs] to maintain that. So, um, hopefully in the next few years, we’ll have more and more to tell]because, uh, we do have [a] app called My Circadian Clock that is being used in at least now a dozen different clinical trials. The nice thing is we can have meta-analysis of all these results, uh, that are collected on the same platform.

So we can analyze them for this obvious reason, [uh] specific type of time restriction that are better for some people than the other. And since we’re also collecting sleep activity [data], then the question is is there any traction between sleep and time initiating because if you’re doing time restricting but not sleeping enough, does that reduce the benefit of time restricting .Or you could not — if you’re eating very health diet but you’re eating within twelve hours, not eight, and sleeping enough, is that as good as time restricting.

Gordon: Mm-hmm. Yes.

Satchin:   So all these interactions will come up in future years. But we just woke up to its importance because we humans built our anthropocentric world without paying attention to circadian rhythm. And now we have a crisis of circadian disruption, which is very pervasive. Almost every single person will go through at least a few years of chronic circadian rhythm disruption. And we’ll come to that — wha-what I mean by circadian rhythm disruption. And that circadian rhythm disruption for a few weeks, months, or years can compromise resilience in many cases, flare ups of certain disease, can increase risk for disease. And then if somebody already has disease, then the prognosis of cure becomes difficult. Like if somebody’s cured, then back to full play. Or coming back to full performance months also becomes difficult. And we all can relate to all this because we humans will go through — in our lifetime will go through various bouts of sickness, whether it’s an infectious disease, whether it’s, for example, common cold to serious, uh, disease, accidents, injuries, depression, et cetera. And then the question is, we need intervention, or we need something simple that can prevent, manage, reverse, and accelerate cure from these diseases. And only then can we think of how to increase lifespan because on a day-to-day basis, we’re not thinking about whether I make it to 150 years. What we are all what — concerned about is, can I maintain my performance today, and can I come back to full performance tomorrow? So in this context, circadian rhythm or the timing of food, exercise and sleep becomes important, and it’s within our control.

Gordon:  So paint a picture for me of the-the perfect situation with circadian rhythms  what’s the-the perfect picture of a healthy person?

Satchin:  Yeah, so this is always debatable because people always say, oh, well, I’m not in that particular situation. An-another thing is, um, as people live in different latitudes and in different seasons then what is considered perfect or optimal may be different for different seasons. But let’s –  start with some rule of thumb that everybody can relate to and, uh, there is enough science to back this up. Uh, so one thing is — first thing is, uh, your day — our day actually begins on the night before. So that means the previous night, what time we decided to go to bed has a huge influence on how we perform today. So in that sense, rule number one is, uh — the formula number one is try to go to bed at a consistent time and be in bed for at least eight hours so that you can get seven to seven and a half hours of sleep, restorative sleep. Why that is important is there are a lot of epidemiological studies that have shown that people who sleep somewhere between six and a half hours and seven and a half hours appear to have less disease, and they seem to have a slightly longer lifespan. So having this, six and a half to seven and a half hours of sleep for adults is very important. And when it comes to younger adults, for example, children up to teenagers, they actually needed more sleep, so eight to nine hours. And during sleep, uh, there are a lot of things going on. One is, for example, a growth hormone spike that happens in the last couple of hours of sleep. And growth hormone is extremely important, uh, for the repair and rejuvenation of many parts of our body, including our gut-gut lining, skin, all the epithelial cells or cells that are exposed to the outside environment 

Gordon:  And I just turned 30 a few months ago. Oh, no, wait a minute. 60.  

 And, uh, so what-what should I expect now? That picture’s potentially gonna change for me, right?                  

Satchin:  Yeah, so still, at six and a half to seven and a half hours of restorative sleep is very important. What happens is, as we get older, our arousal threshold reduces. So that means small disturbances in our sleep environment can wake us up. It’s possible that there was some noise. It was possible that your core body temperature increased, or your bed was warmer. Or, uh, for example, if, you woke up to go to the bathroom, then your arousal threshold is very low, and sleep pressure is pretty low. So it becomes difficult to go back. So the way I look at it is, uh, you know, when you are younger, it’s almost like your body almost, uh, runs on its self-driving mode, and then [laughs] as you’re in middle age, it switches to like the automatic mode, but you still have to take care of it. And then as we get older, it’s almost like a manual driving truck [laughs].

Gordon:       [Laughs]

Satchin:       We have to pay attention —

Gordon:       Yeah, yeah.

Satchin:        — we really have to pay attention to all these, uh-uh, levers. So during sleep, uh, we also — uh, there is synaptic plasticity of the brain cells connect with each other, and then there is, um, cleaning up, um, uh, toxins from our brain and body. So that’s why all of these are important, uh –. The number one is try to go to bed at the consistent time and be in bed for eight hours so that you can get six and a half hours of restorative sleep.   Gordon:  Okay. And y-y-you touched on it there, but, I mean, do we have a-a reasonable understanding of the-the biology behind why aging is driving these changes?

Satchin:  We really don’t have any, uh, good understanding of how aging reduces sleep pressure or reduces sleep pressure or reduces how to — recovery from loss of sleep.  So for example, when you are younger, if we lose one night of sleep, then the next day there’s enough sleep pressure that we will stay in bed until noon. And that’s what happens with teenagers, uh, the high school and college students. They would stay in bed up to one, two in the afternoon on the weekends. But as we get older, our brain cannot process how much sleep debt we have and how much our body requires that sleep to be made up. And this is one fundamental question, for aging biology or gero-science, how our brain forgets or loses track of how many hours of sleep we need and how many hours of sleep we’re getting.

Music Break

​​Gordon:   Just thinking about circadian rhythms it’s impossible for me not to think about Seymour Benzer and those studies that determined genes and proteins that really were the circadian clocks. So Seymour Benzer discovers these these proteins that are that are actually measuring time in some way. And first of all, I guess the question is, is it the same kind of thing that’s happening in mammals and humans? 

Satchin:  Yeah, so,  this is where it becomes very, I would say, philosophical or [laughs] — because there is some correlation going on here. So the reason we — why we have the, uh, need for tracking time is, I know, life forms appeared on this planet maybe two to four billion years ago. And, um, there’s been only one constant for the last three to four billion years that is the pl-planet is rotating around its axis. And then there’s 24 hours of light and darkness. So that means every organism on this planet is experiencing this very profound change in light and darkness, and this predictable change in light and darkness. And with these changes, there is change in humidity level. There’s change in temperature. There is change in availability of food, and for plants, availability of sunlight. That’s the primary source of photosynthesis, so carbon fixation. And as we all know, to anticipate time and get things ready gives us a very fundamental survival advantage. For example, you know, we scheduled this podcast at 11 o’clock. And at 10:45 [laughs] there was an alarm that went off. And then I thought, okay, so I’ve got to get ready for this podcast so that I don’t want to be late for this. And, uh, the same thing happens. Um, the plants have to prepare their apparatus so that they can catch the first ray of light and convert and use it to-to make carbohydrates — fixed carbon. Similarly, animals, or we humans have to prepare our body even before we wake up by increasing our heart rate, increasing our blood flow, increasing respiration so that when we wake up, we feel rested. We feel full of energy. So that’s anticipating time to prepare ourselves. And secondly is, uh, separating incompatible processes and conversely combining compatible processes. So for example, our physiology is designed in such a way that we actually consolidate our sleep through the nighttime. At the same time, our hunger and satiety signals are also arrested so that we can go through the entire night — eight, ten, twelve, or fourteen hours — without feeling excessively hungry. And this hunger/satiety, sleep/work, and also activity/rest. So for example, our muscle tone is much better in the late afternoon because that’s when our ancestor hunter-gatherers and farmers were running back to a safe place to spend the overnight in darkness. And just imagine, if your muscle tone was at its peak in the middle of the night, then [laughs] we’d be acting out our dreams [laughs] and essentially telling predators, “I’m here; come and eat me.”

Gordon:  [Laughs]

Satchin:  So-so this is the fundamental, uh, [at the] whole organism level these are the function of circadian clocks. So that’s why we all have clocks. And in fact if you look at all the animals and microbes, et cetera, those who have a circadian clock, they do live longer than those who do not have a circadian clock, those species. So you’ll not find a species that lives more than a month and doesn’t have a circadian clock.

 Gordon:  So where-where is the clock in our body?

Satchin:  So initially, people thought that the clocks must be only in the nervous system because the nervous system controls sleep-wake cycle and everything. And again, it goes back to Ron Konopka and Seymour Benzer because they challenged this idea, uh, because Ron and Seymour had found that if you decapitate a fly, [laughs], that is if you remove the head, the body actually stays alive and there’s still circadian rhythm activated. That body, the fly body will actually walk around —

Gordon:   Wow.

Satchin: — for almost — more than 12 hours in their circadian rhythm. So that indicated that there must be [clocks] everywhere else. 

Gordon:    Mm-hmm. 

Satchin:    And then what is the role of the brain clocks or the — when they had all these poor mutant flies, they actually took the head from [laughs] — they did a head transplant, literally. They put the head on the abdomen of other flies and found that you can change the circadian rhythm of activity/rest by changing the head. [Laughs]

Gordon: Astonishing

Satchin: But  later on, we found that clocks are present in almost every cell in the human body, animal body. For example, if you take skin hypoblasts from humans, then there are clocks in those skin hypoblasts. So clocks are everywhere. 

Gordon: And-and the clocks are talking to each other? Is there one governing organ or principal that’s setting those clocks in each of the other tissues?

Satchin:  Yeah, so the, um, idea is there’s a master clock, um, in 20,000 neurons in the brain of animals and humans. So these are called — these — this particular brain center is called suprachiasmatic nucleus. So that means it’s right above the optic chiasma where the right and left optic nerves crisscross. There are roughly 20,000 neurons. They, uh, cluster together to the size of a pinhead. And those neurons somehow have assumed the role of master regulators because, if we remove those 20,000 neurons, then the animal has no sense of time. They eat, then go back to sleep for two to three hours, and then wake up and move around again. So in terms of aging, the idea is, maybe as we get older, some of the SCN, suprachiasmatic nucleus neurons; either they become defective — they cannot generate rhythms, or the communication between then becomes weaker so that they cannot consolidate rhythms. And in fact, in many cases of Alzheimer’s disease and neurodegenerative disease, people have found postmortem that the SCN neurons have signs of degeneration. And that might explain why the sleep-wake cycle becomes fragmented in many dementia patients. 

Gordon:  Mmm. It makes me wonder, are there any gender differences in circadian rhythm degradation during aging or even in young people?               

Satchin: There are gender differences and also age differences, how our intrinsic rhythms are, uh, organized. For example, we know that, uh, many kids, babies for example, wake up early and those babies — they know that babies wake up — very early. As we hit puberty, then somehow there is some interaction between sex hormones and the  circadian clock so that teenagers have an intrinsic drive to sleep, go to bed later, and also wake up later. And that’s very well established in human literature. And as we — as women hit menopause or we males also reach the age of 50-55, again we go back to the state of the little kids [laughs]. So then we tend to go to bed a little earlier and also get up a little earlier. 

Gordon:  So it sounds like actually this is in line with our evolutionary history and what we were doing. Before we begin to wrap up here, Satchin, I need to ask you- what’s so bad about blue light?           

Satchin:  Yeah, so, the blue light story goes back that, um, our circadian rhythm, particularly the SCN, the suprachiasmatic nucleus clock, has to be in alignment with the night cycle. Although our ancestors did not fly across time zones or did not do shift work, uh, there was a constant change in day length. We know that the day length — that the sunrise time is slightly different from one week to another week. And the clock, our activity/sleep cycle should also align with that. And that alignment happens through light- straight through the eyes and acting on the suprachiasmatic nucleus. And for a long time, scientists knew that people who are blind, because they have lost rod and cone cells, can still trend their clock. And similarly, mice that have lost rod and cone cells that give us vision, they can also reset their clock. But if you remove the eyes from animals, then they cannot trend their clock. So we, in three different labs in around 2001, discovered that there is a blue light-sensing protein called melanopsin that’s present in the retina, the surviving neurons of the blind mice and blind humans can sense blue light and reset the clock. And subsequently, the function of these blue light-sensing proteins have expanded. We now know that the same cells connect to the part of the brain that controls depression or feeling happier. So that means during daytime, we should be exposed to a little bit more of daylight, uh, not looking at the sun but even on a chair or sitting next to a large window. That increases alertness, uh, reduces depression. And at nighttime, we should reduce our exposure to bright light, bright activity light, and so dim down the light for better sleep. 

Gordon:  Right. Um, you know, in some ways  you’ve set a-a blueprint for a healthier life for all of us. And, um, it’s spec — a spectacular body of work. And I guess what I’m interested in right now is, what-what-what are you interested in right now? What are the big questions that you want to know, go  and solve?

Satchin:  The holy grail of circadian rhythm is why some animals are day active, why some animals are night active. What makes us diurnal or nocturnal?            

Gordon:  Mm-hmm.

Satchin:  And similarly, can we understand this very fundamental rule and then change it in a way to address the emerging   problems for our next generation because if we know what controls our master circadian clock, for example, in humans those working in shift work or those kids who are staying up all night to cram for exam, can we reduce the long-term, uh, health disruption to the circadian rhythm. That’s on the health side. And in agriculture, for example, we know that there are many crops that flower during daytime, they fertilize and then they produce grains, for example, rice flowers in the early morning. As global warming — as the planet warms up, then [laughs] these flowers actually, as soon as they open, they wilt and they die. So the yield goes down.  So there is another case if we know the fundamental principle of circadian principle, maybe we can find new rice varieties, new crop varieties that actually flower in the middle of the night, for example, when it’s cooler so that they can — they have a much better chance of survival and producing and sustaining crop growth. So —

Gordon:  Oh, that-that’s fascinating. That’s — [laughs]

Satchin:   Yes [laughs], so multiple —

Gordon:  Yeah.

Satchin:  — there are multiple uses of, uh, understanding fundamental principles of circadian rhythms

Gordon:   So obviously smartphones and wearables are, uh, a major tool in-in your research going forward. And, uh, it just begs the question, what-what should we all be doing today, uh, if we’re not babies, we’re not teenagers [laughs]?

Satchin:  [Laughs] Yeah, so, um, we kind of started- So be in bed for eight hours so that you can get —

Gordon: Yeah.

Satchin:  — six and a half to seven hours of sleep. After waking up, wait for at least one, ideally two hours before your first meal because that’s when the stress hormones and the sleep hormones, they’re kind of criss-crossing each other. We won’t go into the biology of it, but the bottom line is our body’s not ready to eat and absorb nutrients. After waiting for two hours, then have your first meal, breakfast, at a consistent time. Eat within eight, nine, ten, or maximum twelve hours. That’s number three. And the fourth is to try to get at least 30 minutes of daylight. Fifth one is to try to get at least 30 minutes of physical activity every day, ideally in the afternoon because that’s good for reducing blood pressure and reducing blood sugar, particularly for older adults, and reducing risk for injury. And number six is,  two to three hours before your habitual bedtime, avoid food and avoid bright light. Those are the six .

Gordon: Wonderful. What a great summary. Uh, Professor Satchin Panda, thank you so much, uh, for this, um, eh-eh, time we’ve had together today.

Satchin:  Good to see you!

SHOW OUTRO

Thank you so much for listening. Please subscribe, share and give us a five star review on Apple, Spotify or wherever you get your podcasts. We’re Not Getting Any Younger, Yet! is produced by Vital Mind Media: the Buck Institute’s very own Robin Snyder as the executive producer, Wellington Bowler is right next to me here directing the recordings, Stella B is behind the scenes ready to debrief when we wrap, and the esteemed Sharif Ezzat weaves the show together for you. 

If you’re listening to this podcast, you know that there’s never been a more exciting time in the research on aging. Discoveries from our labs or moving into the clinic to help us all live better, longer. The Buck Institute depends on the support of people like you to carry on our breakthrough research. Please visit us at Buck Institute dot org to learn more and to donate.