Ruth Patterson, PhD, on Time-Restricted Eating in Humans & Breast Cancer Prevention
Posted on July 8th 2016 (over 3 years)
Ruth Patterson, PhD, is a professor at the University of California San Diego (UCSD) in the Department of Family and Preventive Medicine. She also serves as the leader of the Cancer Prevention Program at USCD Health's Moores Cancer Center in La Jolla, California, where she is the Associate Director of Population Sciences. In addition, Dr. Patterson oversees the Transdisciplinary Center on Energetics and Cancer at UCSD, whose objective is to find answers to questions regarding links between insulin resistance, inflammation, and breast cancer carcinogenesis.
Dr. Patterson's research interests are focused on the hypothesis that prolonged nightly fasting can reduce the risk of chronic diseases, including some cancers, by improving overall metabolic health.
The lifestyle link to breast cancer
Breast cancer is the second leading cause of cancer deaths among women living in the U.S., claiming the lives of more than 40,000 women each year. Several factors may be at play in the development of breast cancer, but strong epidemiological and mechanistic data point to the roles of obesity, inflammation, and lifestyle factors in mediating risk.
Estrogen and insulin create fertile soil for cancer growth
Data from the Women's Health Initiative indicate that the risk of developing breast cancer among women who are overweight or obese is nearly 60 percent higher than it is among women who are at a healthy weight. In addition, heavier women tend to have a worse prognosis than healthy weight women, presenting with large, poorly differentiated tumors and lymph node involvement. Furthermore, deaths from breast cancer are more than 2-fold higher among the heaviest women.
Some of this increased risk may be due to the fact that women who are obese typically have higher circulating levels of estrogen and insulin. These hormones act as growth factors to create a kind of "fertile soil" that promotes the proliferative processes associated with cancer, allowing it to grow and spread.
Obesity fans the flames of cancer
Obesity also helps drive the inflammatory process. Inflammation involves the activation and release of immune cells, cell-signaling proteins, and pro-inflammatory factors and has been implicated in the pathophysiology of many diseases, including cancer. Fatty tissue is a metabolically active organ that produces many pro-inflammatory cytokines and mediators that work in a synergistic fashion with other pro-inflammatory molecules to create a pro-tumorigenic microenvironment.
Derangements in circadian rhythms promote metabolic dysregulation
Strong evidence also points to metabolic dysregulation in the pathophysiology of breast cancer. This dysregulation arises from perturbations in the body's circadian rhythms, the body's innate 24-hour cycles of biological, hormonal, and behavioral patterns. Circadian rhythms modulate a wide array of physiological processes, including the body’s production of hormones that regulate sleep, hunger, metabolism, and others, ultimately influencing body weight, performance, and susceptibility to disease.
Our modern lifestyle, with extended hours of light exposure and late-night eating, is counter to these deeply ingrained natural rhythms. For example, the body's sensitivity to the effects of insulin varies throughout the day, peaking in early morning and plummeting at night. Skipping breakfast, "grazing" throughout the day, or eating large quantities of food late at night can interfere with the body's ability to properly metabolize the energy provided and promote metabolic dysregulation.
Lifestyle modifications restore the body's natural rhythm
However, small lifestyle modifications, such as time-restricted eating, can reestablish proper metabolic regulation. Time-restricted eating is a form of fasting that limits the daytime hours during which a person can eat to an 8- to 12-hour window, leaving 12 to 16 hours of fasting. When practiced in the earlier part of the day – eating before 7 or 8 p.m. – time-restricted eating aligns the eating and fasting cycles more closely to the body’s metabolic rhythms.
In this episode, Dr. Ruth Patterson describes how an intervention involving more than 2,500 breast cancer survivors who practiced time-restricted eating – fasting 13 hours overnight – reduced their risk of breast cancer recurrence by nearly 40 percent, regardless of what they ate or drank. The participants' metabolic and inflammatory biomarkers showed dramatic improvements, as well. This acceptable, sustainable eating pattern meshed with familial and cultural foodways and manifested in enhanced feelings of self-efficacy that gave rise to other healthy lifestyle behaviors.
Implications for public health
These findings have tremendous public health implications. Many of the factors that drive cancer also drive other chronic diseases, including diabetes and cardiovascular disease. Implementing similar interventions on a wider scale could shift the entire chronic disease risk curve downward, reducing the amount of money spent on healthcare each year and improving the lives of millions of people.
"We think that less than 5 percent overall of breast cancers are the result of genetic factors. And more like 65 percent to 75 percent are the result of lifestyle factors, including obesity, diet, physical activity, and smoking." - Dr. Ruth Patterson Click To Tweet
Learn more about Dr. Ruth Patterson
Rhonda: Hello, my friends. Today my guest is Dr. Ruth Patterson, who's a professor at the UCSD Department of Family Medicine and Public Health and leader of the Cancer Prevention program at Moores Cancer Center, UCSD. Thank you, Ruth, for being here. I am very interested in some of the research that you are have been doing for the past few years and ongoing, in terms of looking at this interface between metabolism and specifically breast cancer risk and breast cancer...increased breast cancer recurrence. So when I think, you know, of lifestyle factors that are modifiable and that are actually known to increase breast cancer risk, obesity comes to mind.
Ruth: Sure. Obesity is definitely one of the big ones, and also physical activity. More recently we've become aware of the importance of physical activity. What's been harder for us to identify is exact types of foods that could reduce risk. In fact, we've not really had a lot of success in identifying individual foods or individual nutrients that seem to make a difference. Although, I think there's more acceptance now, the idea that an entire dietary pattern, let's say the Mediterranean dietary pattern may, you know, influence risk over decades. So I would say those are the probably top concerns, is diet quality, obesity, physical activity, those are the...and even tobacco can increase...some increases breast cancer risk. So there's many things individual women can do to reduce their risk.
Rhonda: I was reading, I think it may be the American Cancer Association had published some statistics on how obesity can increase the risk of breast cancer by twofold. And also, specifically looking at some of the mechanisms by which obesity can increase breast cancer risk. There were a variety of them including increased inflammation, increased hormones, so estrogen, and also increased fasting insulin levels.
Ruth: Mm-hmm. Yes. I think we've known for a long time about sex hormones in particular, estrogen is a risk factor. Because some of our first really successful drugs were based on blocking the action of estrogen. Estrogen is a growth factor so it appears if we can block that, it can reduce your risk or reduce your risk of recurrence. And we have some pretty effective drugs that have made a big difference. It's more recently that we've realized that other growth factors have the same type of impact, and it makes...it's almost common sense. If estrogen is a growth factor and that increases growth rates of tumors, well, what about insulin? It's also a growth factor, it encourages metabolism. So we do believe that perhaps high levels of circulating insulin may be really central to the whole process of developing breast cancer and promoting its growth. And high levels of insulin are definitely found in women who are overweight, if you're less physically active, and then of course among diabetics often have high circulating levels of insulin. So we do...are becoming more aware that sort of that may be kind of a common road where many different syndromes lead to the risk...increased risk of breast cancer.
Rhonda: And so you mentioned that people that are overweight and people that are obese have higher circulating insulin levels. They also have higher circulating estrogen levels, right? So does fat can secrete? Is it...am I right, fat can secrete estrogen, or is that something that...
Ruth: Fat can...yes. So that's pretty central. And then, what we also know is that people who have high levels of insulin have lower levels of serum-hormone binding globulin, something called SHBG which binds estrogen. So it can prevent it from being active. So they seem to be related, they're not just two independent pathways, they actually play off each other.
Rhonda: Interesting. And you say...you brought up something that was very I think important, and that is you said that these growth factors, they promote the growth of tumor cells, of cancer cells.
Ruth: Right. That's in a very general way.
Rhonda: Yeah, so you're... Something, you know, something's causing the initial damage, the cells become damaged and, you know, we have a lot of mechanisms inherent in our cells that can sense damage and say well, okay, I'm going to die, I'm going to kill myself because if I don't, may potentially lead to, you know, a cancer cell.
Rhonda: But if you have all these growth signaling factors happening in the presence of that damage, it's sort of saying, "Hey, no, no keep going, keep growing, don't die. Grow, grow, grow."
Rhonda: And, you know, so that's sort of like I think the combination between things that are causing the damage which possibly high inflammation, so obesity also is associated with high inflammation and then, you know, the combination of the inflammation and the high insulin, the high insulin-like growth factor, the high estrogen it's sort of like this detrimental combination of damage and growth signals to allow them to survive. You also mentioned that the serum binding hormone that...
Ruth: Serum-hormone binding globulin, SHBG.
Rhonda: Thank you. And you mentioned that binds estrogen and sort of makes it inactive from going to, you know, activate I guess in breast tissue or whatever tissues. What about also the insulin, so I mentioned the insulin-like growth factor pathway which is separate but from insulin they're two separate growth factors but they're also very interconnected.
Ruth: Yeah. I think the data on...insulin-like growth factors a little less consistent and a little harder for us to understand. So there's...we think it's also playing a role but studies have been...some studies have found it to be a risk factors and other study haven't. You're talking about circulating levels, I'm sure. Because it's also very complex because there's receptors for these things on the cells that may also play in.
Ruth: So it's a very complex system which is why we've had such a hard time coming up with cures. It is because all...there's lots of redundancies and one system affects another system, and so just finding like that magic pill that can turn of all these different related pathways is virtually impossible, there's so many workarounds for our body.
Rhonda: Right, yeah.
Ruth: Our body is incredibly resourceful.
Rhonda: Right. So these three factors that are known, the fasting, high-fasting insulin, the high free estrogen...
Rhonda: ...and the high inflammatory markers.
Rhonda: So as measured by certain biomarkers like C-reactive protein.
Rhonda: So these are all associated with, in some, cases even two to threefold increased risk.
Ruth: Yeah, I say definitely twofold and maybe a little bit more. I think that's generally what we...what the metric we use, each one of them increases the risk individually by twofold. Combination wise we don't know, it's probably not quite additive, but they still would have a combined effect too that's, you know, reason to look at all these different pathways. But those are definitely the three major metabolic pathways that we think feed into having kind of fertile soil so that when these DNA changes happen, they're in a place where they're kind of like fertile soil and more likely to go to an invasive tumor type.
Rhonda: Okay. And what's so interesting about this is that, your work, so your work and the work of others is showing that these three different biomarkers, let's say, they can be modified by changing your lifestyle pattern.
Ruth: Right. Much of my research lately has focused on timing of meals, which I think is a little bit of a newer hypothesis. We all, you know, evolved to eat during the day when we're out getting our food and then fast at night when we're in a rest state. But now with, you know, modern lighting and with modern lifestyles and short...longer and longer work weeks, you know, our meal patterns less and less resemble the way we evolved to eat. And we believe that it's very metabolically detrimental to eat a lot of energy and then right away lay down. You know, what are you doing? You're laying down, you don't need to have all the energy on board and all that metabolism going on, when actually you should be in a fasting catabolic state.
Rhonda: And most people probably actually eat one of their largest meals in the evening.
Ruth: Right. Which is just so counter...and just even in a common sense way, why do you need all that energy right before you're about to become completely comatose? It makes no sense, right? You really need the energy during the day, you know, when you're busy up walking.
Rhonda: That's a very good point. And I think you also mentioned another important point and that is eating during the day when we're supposed to eat, and timing it with our circadian rhythm.
Rhonda: Which is the biological clock inside of our...every cell we've got a master regulator and different, you know, tissues which we can talk about in a minute. But that master clock, what's interesting is that it does...it...you know, between 10% to 15% of the human genome is regulated by these clocks. And about 50% of those genes are involved in metabolism.
Rhonda: And humans are the most insulin sensitive upon waking, you know, first thing in the morning. And then as the day goes, insulin sensitivity goes down. And so, you know, eating your biggest meal in the evening when you're the most insulin insensitive would increase one of those biomarkers you're talking about.
Ruth: Absolutely, right. Or just metabolically dysregulate you which is what we're trying to have regulated metabolism, and that definitely dysregulates it. And the whole circadian rhythm concept is the idea that, as you mentioned, the master clock is entrained to light, you know, it responds to light. So the master clock's getting the signal, let's say, in the evening, you're done. But if you're eating, the peripheral clocks like in your liver are going, "No, we're waking up, we're getting energy." And we believe that when those two clocks are out of sync that that itself leads to some type of metabolic dysregulation. And we don't have fully metabolic, you know, or molecular understanding of exactly how this works. But it's a pretty solid theory, at least what we've seen in animal research.
Rhonda: Yeah, and so I mentioned to you earlier that I talked about this meal timing with a collaborator of yours, Dr. Satchin Panda who is at the Salk Institute. And, you know, a lot of his research had focused on elucidating this important regulator of the peripheral clocks, meaning the clocks in the non-brain, so the liver, the heart...
Ruth: Pancreas, right.
Rhonda: Right. And how, when you eat your first meal or even taking your first non-water beverage starts that clock. And so, if you start that clock, let's say you wake up at 7:30 in the morning and you have a sip of coffee, 7:30 in the morning the clock starts. And he's shown that eating all your meals within at least a 12 hour time from that when that clock starts seems to be very important for, you know, having a good metabolic health.
Rhonda: You know, good glucose regulation, good insulin sensitivity, being able to maintain, you know, lean muscle mass and keep fat loss off. But what's really in my mind, I was trying to understand, and like you mentioned, we don't know all the molecular mechanisms between the timing of the two, both the master clock and the peripheral clock, but how they do seem to be working together. So, you know, let's say someone fasts in the morning, they don't eat breakfast, they don't eat lunch. And then, so they're fasting, let's say, they're fasting for 12 hours and then they eat a meal right before bed.
Rhonda: We don't know if that's necessarily going to be as good as fasting during the evening in sync.
Ruth: We totally don't think it's as good. You know, so our research seems to show that two things, one we see great...our biggest reductions in breast cancer, for instance, recurrence, with at least 13 hours of fast. And we really believe that fast needs to start around 7 maybe to 8 p.m. at night. When people talk about breakfast, what I often say is, when you're talking to people who skip breakfast, I think skipping breakfast is actually a marker of eating at night. Because if you stop eating early in the evening and don't eat for 13 hours, when you wake up you're starving. You don't skip breakfast. So a lot of times, I think the research showing that not eating breakfast or skipping breakfast is bad, is actually not studying breakfast, it's the people who skip breakfast were eating late into the night. So we think it's both, it's that we need a long stretch of time and there might be some improvements in gut rest or the microbiome. Like, we don't think that your GI tract also was meant to have food constantly in there, you know? So we think it's important to have a long stretch of gut rest but that that gut rest happens at night, starting fairly early, 7 or 8 p.m. and then 13 hours after that. So it's both of those things, either one is not sufficient.
Rhonda: And the microbes in your gut are also on that circadian rhythm.
Ruth: Absolutely. Oh, yes, the GI tract is very, very tied to circadian controls.
Rhonda: Right. You also mentioned another study that you...one of your research kind of said in passing that 13 hours of...at least 13 hours of fast was associated with a lower breast cancer recurrence?
Rhonda: So, do you mind talking about that study for a little bit?
Ruth: Yeah. I'd be glad to. So this was a study in about 2,500 breast cancer survivors and they completed over about seven and a half years of follow-up, they completed many food records, right? So we collected all this information about what they ate. But then, more recently when this hypothesis came out, we went and dug up all their food records and said, well, how about if we don't care what you ate, but we just care about when you ate it? So, we reentered all the data as far as when they started to eat, you know, when they stopped, how long their fasting interval was, how much they ate at night, and then reanalyzed that data. And that's where we found that it seemed at least in this sample of women that the cutpoint of 13 hours reduced their risk of breast cancer recurrence by about 40%. It also reduced the risk of mortality by about 20% or a little more than that but that was not statistically significant. But it was just trending in the same direction, you know, it's possible. Because we do believe it's...although my area of research is breast cancer, we actually believe this dietary pattern could have really positive effects on other diseases and conditions, including type 2 diabetes, or liver...fatty liver, NAFLD, also with acid reflux. You know, the first thing they tell you is try to sit up when you go to bed, don't eat a big meal so that which often leads to esophageal cancer. So we actually feel it can have a positive impact on many aspects of metabolism, not just cancer, it's just that we're very interested in teasing out its impact on cancer.
Rhonda: That's phenomenal, Ruth, those statistics that you just kind of just threw out there, like 40% reduction in breast cancer recurrence in women that were just simply fasting in the evening for 13 hours.
Rhonda: And that is...
Ruth: Regardless of what you eat.
Rhonda: Regardless of what you eat.
Ruth: It controls for whether you're overweight or not.
Rhonda: Because it's really not that difficult to...I think it's much easier to...for people to make a modifiable change of just stopping what they're...you know, stop eating after 7 p.m., versus eat all your vegetables, stop eating your...
Rhonda: ...cake. I mean, people should do that, but just saying.
Ruth: Yes, I still think diet quality matters, but we've done some pilot studies with women adapting a longer nightly fasting interval. And those studies have been amazing in terms of how simple it was for women to do it. We actually had a little app they used and they would text us, "Starting my fast." And then we'd text back saying, "Great. Don't forget, don't eat again before 8 a.m. or 9 a.m." You know, and so many participants said, you know, "I never understood percent energy from fat. It was always so confusing to me, it made me just feel stupid, I didn't even know how to do it but I just got this. In five minutes I got this, I could do it." And self-report ways, they reported often sleeping better. And we did it with a group of Latino women, Latinas in South Bay. And they were particularly positive about it, they said, you know, "In my family, if I tried to change up our entire way we eat, sometimes my family members weren't that positive about that. Where's our favorite foods?" And she goes, "But this, I could do it right away, it was really simple and it didn't affect the family or food ways. So it's very easy for me to do within our family without disrupting all of our family behaviors." They were very positive and often even reported, "I felt so proud of myself, okay, finally I'm doing something, I feel better, well I'm going to start walking too." You know, that kind of self-efficacy kind of spread to other health behaviors, which is our hope.
Rhonda: Yeah, great. So these women were being more compliant which is...
Ruth: Well, they feel successful...
Ruth: ...instead of feeling like a failure, right?
Ruth: You know, writing down everything you eat, running up the calories, you know, you only can do that for a couple days before you just burn out in the entire exercise. So you feel like, "Oh, I can't do it," you know, where this they're like, "I can do this," you know?
Ruth: So we think it's incredibly...that some of the value is the simple feasibility of it. People can understand it and they can generally implement it. Now, we don't think it necessarily is going to have huge impacts on weight. Like you're not...probably not going to lose 50 pounds by just making this one change. But we believe it could be an incredible public health intervention where if everybody did it, we could move like the whole disease risk curve down a little bit. And that would have huge impacts on disease risk. You know, which is the alternative is of course we spend millions of dollars trying to help a small number of very obese people lose weight which is very unsuccessful. But if we could move the entire population this way, to this more healthful pattern, we think that could actually affect disease rates in the United States.
Rhonda: That's awesome. You also, just to kind of dive a little bit deeper into some of your more recent research, you mentioned the 13 hour fast overnight and how that was very robustly associated with the 40% reduction in breast cancer recurrence and non-statistically significant reduction in breast cancer mortality. But you also have looked at some of the biomarkers that are known to increase breast cancer risk. And also there was an effect on some of those biomarkers like inflammation as well, correct?
Ruth: Mm-hmm. We've actually seen probably our most consistent effect on something called Hemoglobin A1C, which is a marker of your average glucose, over about three months. So interestingly enough, we saw the association both in a general sample of women from what's called the NHANES survey, it's a nationally representative survey of women. We saw that women who fasted longer had lower hemoglobin A1C, and then in our own sample of breast cancer survivors we found the exact same association which means, you know, which to us means this is probably strong. So that's one of the reasons we think it might influence...have a huge effect on reducing the risk of diabetes. As far as inflammation, interestingly enough, we only found that it reduced inflammation among women who didn't eat a lot of food late at night. In other words, you know, if your fasting interval was 9 p.m. to 9 a.m., it didn't seem to matter. But if you're fasting interval was early in the day, like 6 to 6, then it seemed like the fasting interval reduced CRP, C-reactive protein, this measure of generalized inflammation. So that's what made us think. It's not just the 12 hours, it's the 12 hours only if they start fairly early in the evening. That's when the positive effects happen.
Rhonda: Very interesting, very interesting. So you...a couple of points that you mentioned, I just want to circle back to the glycated hemoglobin you mentioned, that basically fasting in the evening had a pretty robust effect in reducing that.
Rhonda: And that's a marker obviously, it's a marker of your long-term, you know, blood glucose levels.
Ruth: Absolutely, they use that to approve diabetes drugs. You know, if a diabetes drug reduces hemoglobin A1C, that's how it gets approved. So it's a pretty powerful marker of risk.
Rhonda: So we're talking about, for example, metformin...
Rhonda: which is a very...
Ruth: Any diabetes drugs has to move hemoglobin A1C down a certain amount before it can be approved. So if we can do this with a non-pharmacologic approach, just changing when you stop eating and the fasting interval, I mean, that's pretty exciting.
Rhonda: It's in the brain.
Ruth: It's really exciting because the truth is all these drugs have side effects, they're not that pleasant to take. A lot of people simply discontinue them on their own. You know, so pills aren't necessarily always the answer, and this offers people a lifestyle choice.
Rhonda: And you mentioned that you're...there were women that were involved that you had basically...they made changes, they started fasting in the evening and they also reduced their H1.
Ruth: In our pilot studies, we were really focused on the feasibility and acceptability of it. So we didn't have any biomarkers, we were testing, could they do it and how hard was it for people to do.
Ruth: So that was really a test of...because there's no point in recommending something if people can't do it.
Ruth: And that...so that's what we really focused on there, in our personal pilot work, is just could they do it. And truthfully, the vast...they almost all did it and they also all said they would recommend it as an eating pattern to their friends, so they would recommend the study, you know, which told us, okay, this is feasible and this is acceptable. And, you know, that's what we're interested in, is not, you know, if it works but it's like impossible to do, then it's not a valuable public health intervention.
Rhonda: Yeah. I was wondering, what I was trying to get at is how quick or how soon do you think it could change...
Ruth: We don't have data on that.
Rhonda: ...levels that would...
Rhonda: ...be very interesting to see...
Rhonda: ...if some of that can be moved pretty quickly or, you know, if it takes longer. I don't know how quick these other...like metformin works.
Ruth: Oh, yeah, most of them...the thing about hemoglobin A1C is since it reflects average blood sugar over the past three months, it takes about three months to move it.
Ruth: Even with a really effective intervention, it just...since it reflects the whole vast three months of cycling through, you have to go whole three months to see it.
Rhonda: Red blood cells to turn over. Yeah.
Rhonda: Right, that makes sense.
Ruth: Other markers may be faster, but the...you know, because we already know that if you want to measure these markers, you want people to be fasting. So we know just even one fast, one night's fast makes a difference, right?
Ruth: If you do one night's fast, a lot of these markers will be flatter in the morning than if somebody eats breakfast, right, before they come in. You know, so you're really...what you're doing is you're extending the period of time where you have very low basal levels of a lot of these markers.
Rhonda: Right. I just kind of wanted... All of a sudden something came to my mind because, you know, we've been talking a lot about inflammation and these fasting blood glucose levels, fasting insulin. And it just hit, I remember having a conversation with Dr. Panda, and he mentioned something to me that I wasn't aware of about repair mechanisms and fasting. I knew that repair mechanisms were regulated by the circadian rhythm, and I always knew that when you sleep is when you're repairing a lot of damage.
Rhonda: But it didn't occur to me that also when you sleep is when you're fasting.
Rhonda: And he had mentioned that there's something inherently important about fasting and repair mechanisms. And so, you know, which of course that kind of made me think, wow, that that's really interesting, I never thought about it like that. But if you think about, you know, that the timing of these repair mechanisms and fasting and how, you're repairing damaged, DNA repair mechanisms and also these autophagy, clearing away damaged cells, damaged cells secrete inflammatory mediators. So if you're clearing away the cells that are damaged and secreting more, you know, inflammatory molecules, then possibly that would, you know, the lower the inflammation. But it's really interesting how your data suggested that it really had to occur earlier in the evening.
Rhonda: Do you have any speculation as to why that is?
Ruth: Oh, I suppose we really do think that your body works best when its aligned with the circadian rhythm. But I think that is a really good observation. Certainly, the parallel I tend to think of is, you know, we work out, we actually hurt our muscles. And the muscles don't repair and get stronger unless we stop. We have to stop, we have to give them a rest period. And the same thing, eating is metabolism, there's a lot of oxidative damage that happens just as we eat. And then the theory is that you need a time off from that damage for the repair mechanisms to come in. So it's an interesting observation in parallel. Personally, I don't...I think that's a little molecular for my research, but, yeah, I think it's a good parallel to compare it with like working out.
Rhonda: Yeah, that is, actually. You know, like you mentioned you need a repair time. Stress can activate stress response pathways that can be beneficial, like in the case of exercise.
Rhonda: But if you keep on stressing yourself...
Ruth: You actually get weaker.
Rhonda: Right. There will... You know, repair. [inaudible 00:27:12] stress.
Ruth: You do need to time off.
Ruth: Right. Exactly.
Rhonda: What about meal frequency? So is that...did that play a role? So if you're...I don't know how long between the fasting and fed state. Let's say, we're within the 12 hours in day we're within that 12 hour...
Rhonda: ...you know, feeding time, allotted time. Does the amount of meals that we eat within that time matter?
Ruth: I think it's a little bit of a separate question. We tried to control for it, in case it did make a difference. Because it makes sense if you're eating, let's say 18 hours a day, you're probably going to have more eating episodes per day than if you're only eating for let's say 10 hours a day. So just reducing the number of hours that you eat may actually have some impact on how many eating occasions, which may also relate to disease risk. But we didn't see that to be a really important determinant of disease risk. So we're not really...that's sort of a little bit of a different question, we're not really quite sure. I think that the evidence is really out on meal frequency and disease risk.
Ruth: And I, you know, if you want my...my gut feeling is that if you keep your eating interval fairly short, it may not matter very much. But when your interval is very long, so you're getting, you know, a meal impact and then a long time with no meal. And then, you know, throughout the day all those spikes might be more detrimental. But the data on that are really unclear at this time.
Rhonda: Yeah. I think you made some really good points and that is, you know, if you reduce the amount of time that you're eating, then naturally you would probably then reduce the frequency...
Ruth: You may reduce the frequency, yeah.
Rhonda: ...that you're eating. I just remember, I don't know if this is like one of those wives' tales where, you know, the smaller number of meals you eat was supposed to lower your blood...you wouldn't have as big of a blood glucose.
Rhonda: You know, but then again, you're constantly doing it. So I don't know, you know?
Ruth: I think, you know, I know of at least one study in the field that's actually testing that. You know, testing five meals a day versus three. So I think they're starting to realize we don't really have a good answer to that and trials are underway to clarify that.
Rhonda: Okay. One other thing that I was kind of thinking about in the parallels between how this meal timing is having a pretty profound effect on, you know, for example your...what's considered your long-term blood glucose levels and also to some degree on inflammation, and these are markers of...these markers are known to be associated with increased breast cancer risk. But you said that weight loss may not necessarily occur, but what's interesting, so you may not...let's say you don't change the types of foods you eat but just you're basically only eating, you know, during a 12-hour window during the day. So that in itself may not cause you to lose weight, or it could.
Ruth: Or a significant amount.
Rhonda: Or a significant amount. But what's interesting is that, on the flip side, weight loss, weight loss itself has also been shown to have a positive effect on these same biomarkers.
Ruth: Yes. Right.
Rhonda: And so...
Ruth: So we actually think that some of the positive effect might be independent of weight loss. You get the positive effect whether or not you lose weight. In our pilot study, women over a month lost about a kilogram, or about a little over two pounds. So we did see a modest weight loss, that's very modest. But even the mice study that...studies that Dr. Panda does also tend to suggest that the impacts may be independent, like, it just helps you regardless of whether you lose weight or not.
Rhonda: Yeah. That's kind of what I was getting at.
Rhonda: It seems as though it may just really be affecting your metabolism and making sure that your timing your food intake with when you are...when your metabolism's at its best, when you can process...
Rhonda: ...these, you know, the sugar and the fats and...
Rhonda: ...just everything that you're throwing at it. And that seems to be in of itself extremely important, so.
Ruth: Right. And, you know, we have seen, in our breast cancer survivor study, we definitely saw an improvement in hours of sleep per night when people had a longer fasting duration. And, you know, sleep...bad sleep can also affect biomarkers, and it’s its own risk. So that might be partially...you know, it's partially working through direct metabolic effect but it might be working through other behaviors too by improving sleep and getting more sleep could also help regulate your metabolism and kind of feed into the positive impacts. Similarly, it's very interesting but in several mouse studies, they've shown big improvements in spontaneous activity when they're put on this...when they're not on this fasting regimen. We don't necessarily think that if women or humans adopt a prolonged nightly fast they're going to start working out at the gym, but there might be some more subtle effects on spontaneous activity which frankly is the majority of the physical activity most people have, is just spontaneous everyday normal activity. So now, the animal studies lead us to believe it can have several behavioral impacts in addition to the direct metabolic impacts.
Rhonda: Yeah, that's very interesting. I wonder if there's just changing the brain, you know, lots of...
Ruth: You know, the data is showing that eating a bunch of food and going to sleep disrupts your sleep, has been around a long time.
Ruth: You know, it's just you don't sleep well on a full stomach, [inaudible 00:33:01]. You know, so it's kind of...that's literature's been out there while.
Rhonda: I've been practicing this time restricted feeding...
Ruth: Mm-hmm. Yeah.
Rhonda: ...now for...once I, you know, Dr. Satchin Panda's work was really eye-opening and I, you know, thought well I'm gonna... I usually try to stop, you know, stop eating earlier, like earlier in the day. And it's a lot easier for me in the winter, fall and winter months when it gets darker earlier and I'm not working so late. The thing for me is when I'm working late, you know, once you start working later, it's light out, I'm like, "Oh, I got to keep working, I got to keep working," then you start to like extend your workday.
Rhonda: And that becomes the issue.
Ruth: Surprise, Western lifestyle is carcinogenic. In case you didn't know that, now you do.
Rhonda: So now we have the bright light exposure in the evening.
Ruth: Many things about our lifestyle are carcinogenic.
Rhonda: Right. But I do. It's really not that difficult to do and I'm...just now I'm...I start the clock once I have my first cup of coffee and it's at, okay, well I got to start cooking dinner, you know, at least two hours before that or something so that way I'm done. And you don't...you're not hungry, you know, you're not like starving when you go to bed.
Rhonda: Some people I think their fear is, well, you mentioned it's hard to sleep when you're super full, but on the flip side a lot of people have this mentality that if they're really hungry, you can't sleep.
Rhonda: You know? But I think there's a nice balance between those two, and that is if you just eat something, you know, in a reasonable time, you know, 7, 8 p.m., stop.
Ruth: I mean, along with that, I have to say I probably think it's probably best for you to go to bed at a reasonable hour.
Ruth: You know, not be staying up till 2 in the morning playing video games or whatever, you know, so you know, it can all be synergistic or in a positive way or in a negative way.
Rhonda: Yeah. I want to kind of shift gears one more time. I think a lot of people have in their minds, at least in the context of breast cancer, many women think about risk factors being genetic, you know, there are certain gene polymorphisms, which are variations in the sequence of DNA that alter the function somewhat that can put a woman at risk. Particularly genes that are involved in repairing DNA damage, specifically in the breast tissue.
Rhonda: BRCA1, BRCA2, I think many people are familiar with these genes. But really what your research and what a lot of research out there has shown is that there are lifestyle factors that play a if not equally important role, and certainly in combination with these genetic risk factors would probably be very, very important in modifying breast cancer risk. And not only risk but recurrence. So there are a few types of lifestyle factors that we talked about today that may, you know, dramatically lower a female's breast cancer risk, and also people out...women out there that have had breast cancer, certain lifestyles they should adopt in order to lower their recurrence.
Rhonda: So what do you...if you want to talk about maybe top one.
Ruth: Yeah, you know, sure. You know, BRCA1 and BRCA2, if you have that gene, you know, polymorphism, that's a pretty special case. And those women are at very high risk of breast cancer and recurrence. And it's hard to know for that small percentage of women, how much lifestyle matters. But again, they're a special case, majority of cancers are just sporadic. We think that less than 5% overall of breast cancers are the result of genetic factors. And more like 65% to 75% are the result of lifestyle factors, including obesity, diet, physical activity, and smoking. And alcohol we think maybe for breast cancer. So those are all things you can modify. So the idea that you're doomed by your genetics couldn't be more wrong. For the majority...the vast majority of women, it is your lifestyle choices that will make the biggest difference in your risk, which is not the same thing as saying you're to blame because a lot of cancers are sporadic, but that there are things you can do to reduce your personal risk, a lot.
Rhonda: Well, that's good news.
Rhonda: So don't smoke, moderate drink, you know, don't drink a lot. Lose weight.
Ruth: Lose weight if...and even a small amount of weight. Recently there was a study that seemed to show like they saw huge improvements in metabolic health in the first 5% of weight loss. And then they said, if you looked at 5% to 10% of weight loss, it's like it flattened out. There wasn't, you know, it isn't like a linear thing. So it looks like even modest weight loss can really improve your metabolic health. So I think there's this perception that, well, if I don't get to model skinny, there's no point in even trying. And I think that's a really wrong way of looking at weight loss. Five percent weight loss could really make a difference.
Rhonda: Five percent of your...
Ruth: Five percent and keep it, you know, keep it off. You know, and maybe in a year or two you might go, "Well, maybe I'll lose another 5%," you know? But, the idea that there's like some very linear thing going on, I'm not sure the data really support that. So even modest weight loss, you know, work on the quality of your diet, work on the timing your diet, get some physical activity, please. You know, avoid long periods of sedentary behavior, all those things combined, good sleep, you know, and good food choices I think are...that's the total combination of things is the best thing you can work toward. And just make it a lifestyle to always be working on improving those things as your whole life.
Rhonda: I think that's fantastic advice. And I just want to mention that number again because it really is, you know, the best obviously...no one wants cancer, you know? That...if you can do whatever you can within your, you know, control to give yourself the best possible chance of not getting cancer...
Rhonda: ...then really, really, really, really, really you should do it. That's, you know...
Ruth: And there's a super benefit here, is that it likely will reduce your risk of cardiovascular disease which after all is still the number one killer of women. So, you know, you're really getting a 360 effect on your risk of all the major killers in America, some unpleasant conditions like diabetes and also, hopefully, just feeling better every day.
Rhonda: Absolutely. And that's...
Ruth: Quality of life. Basic quality of life.
Rhonda: I think there's been studies showing like weight loss...
Rhonda: ...improve your mood. You know, inflammation's associated with depression...
Rhonda: ...you know, and inflammation's associated with obesity. So yeah, you're right.
Rhonda: All these things, quality of life.
Ruth: Physical activity is associated with reduced risk of depression or ameliorating some of the effects. So there's, you know, it's not like there's a separate list of things you should do for one disease versus another, it's like the total benefit package.
Rhonda: Right. Yeah, they're all overlapping.
Ruth: Much more overlapping. We used to not think that as much. We used to think they were completely...here's the disease pathway for cardiovascular disease, it's very metabolic, it's blood pressure, it's cholesterol. And here's cancer, and it's a genetic disease and there are two separate pathways. Now, we see that they're actually way more overlapping than we ever knew and it's really good news because it means you don't have to do separate things for each disease. It means the same suite of healthful behaviors can give you 360 protection.
Rhonda: Well said. And just one last time, that meal timing, women that had breast cancer and had fasted for at least 13 hours overnight had a 40% reduction in breast cancer recurrence.
Rhonda: I think that's a pretty good incentive for women to set that clock when they put the first bite of food in their mouth, or the first non-water beverage, that clock set, and making sure that you don't eat food past 7 p.m.
Ruth: 7, right, or 8.
Rhonda: 7 or 8.
Ruth: Satchin Panda's work was...he did...the most recent article he published which I thought was very good, looked at mice where he just had them do restricted feeding five days a week, and then all around the clock, you know, kind of break it, the fast, on the weekend. And he saw much of the same effects which means, you know, you don't also have to be perfect. As long as you most of the time you do it, you don't need to feel like a failure like, "Oh, I went out, I ate so late," it's fine. You know, just pick up the next day and get started again.
Rhonda: Thank you for bringing that up, because, you know, weekends are when we have that social pressure.
Rhonda: You know, we're having later dinners, we're having drinks, you know, so it's nice to know that at least if the animal studies do translate to the human studies, that we can at least break the rules or cheat a little bit on weekend.
Ruth: I think that's a plus side, is that it's not about being perfect, it's about mostly doing it and you'll get most of the benefit, right?
Rhonda: Agreed, agreed. Well, Dr. Ruth, thank you so much for your time and for the phenomenal research that you're doing and...
Ruth: Thank you.
Rhonda: ...I really look forward to reading more and keeping an open line of discussion with you to learn more about some of what your research is showing in terms of the meal timing and breast cancer incidence.
Ruth: Great. Thank you, Rhonda.
An intracellular degradation system involved in the disassembly and recycling of unnecessary or dysfunctional cellular components. Autophagy participates in cell death, a process known as autophagic dell death. Prolonged fasting is a robust initiator of autophagy and may help protect against cancer and even aging by reducing the burden of abnormal cells.
The relationship between autophagy and cancer is complex, however. Autophagy may prevent the survival of pre-malignant cells, but can also be hijacked as a malignant adaptation by cancer, providing a useful means to scavenge resources needed for further growth.VIEW AUTOPHAGY TOPIC
A measurable substance in an organism that is indicative of some phenomenon such as disease, infection, or environmental exposure.
Five to ten percent of breast cancers in the U.S. are linked to an inherited gene mutation, BRCA1 and BRCA2 (BReast CAncer genes 1 and 2) are the best-known genes linked to breast cancer. People who have a BRCA1/2 mutation have a greatly increased risk of breast cancer and (for women) ovarian cancer.
The set of metabolic pathways that breaks down molecules (such as polysaccharides, lipids, nucleic acids and proteins) into smaller units that are either oxidized to release energy or used in other anabolic reactions.
The body’s 24-hour cycles of biological, hormonal, and behavioral patterns. Circadian rhythms modulate a wide array of physiological processes, including the body’s production of hormones that regulate sleep, hunger, metabolism, and others, ultimately influencing body weight, performance, and susceptibility to disease. As much as 20 percent of gene expression in the human body is under circadian control including genes in the brain, liver, and muscle. As such, circadian rhythmicity may have profound implications for human healthspan.
In a state of deep unconsciousness for a prolonged or indefinite period, especially as a result of severe injury or illness.
C-reactive protein (CRP)
A ring-shaped protein found in blood plasma. CRP levels rise in response to inflammation and infection, or following a heart attack, surgery, or trauma. CRP is one of several proteins often referred to as acute phase reactants. It binds to the phosphocholine expressed on the surface of dead or dying cells and some bacteria, activating the complement system and promoting phagocytosis by macrophages, which clears necrotic and apoptotic cells and bacteria. The high-sensitivity CRP test (hsCRP) measures low levels of CRP in the blood to identify low levels of inflammation that are associated with risk of developing cardiovascular disease.
A naturally occurring substance capable of stimulating cellular growth, proliferation, healing, and differentiation. Growth factors typically act as signaling molecules between cells. Examples include cytokines and hormones that bind to specific receptors on the surface of their target cells.
Hemoglobin A1C (Glycated Hemoglobin)
A blood test that measures the amount of glycated hemoglobin in a person’s red blood cells. The hemoglobin A1c test is often used to assess long-term blood glucose control in people with diabetes. Glycation is a chemical process in which a sugar molecule bonds to a lipid or protein molecule, such as hemoglobin. As the average amount of plasma glucose increases, the fraction of glycated hemoglobin increases in a predictable way. In diabetes mellitus, higher amounts of glycated hemoglobin, indicating poorer control of blood glucose levels, have been associated with cardiovascular disease, nephropathy, neuropathy, and retinopathy. Also known as HbA1c.
A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.
A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.
Insulin-like growth factor 1 (IGF-1)
One of the most potent natural activators of the AKT signaling pathway, stimulator of cell growth and proliferation, potent inhibitor of programmed cell death, primary mediator of the effects of growth hormone, and has been implicated in contributing to aging and enhancing the growth of cancer after it has been initiated. Similar in molecular structure to insulin, IGF-1 plays a role during childhood for growth and continues later in life to have anabolic, as well as neurotrophic effects. Protein intake increases IGF-1 levels in humans, independent of total caloric consumption.
A diet pattern thought to confer health benefits found traditionally in Mediterranean countries, characterized especially by a high consumption of vegetables, olive oil, and a moderate consumption of protein.
The thousands of biochemical processes that run all of the various cellular processes that produce energy. Since energy generation is so fundamental to all other processes, in some cases the word metabolism may refer more broadly to the sum of all chemical reactions in the cell.
A drug commonly used for the treatment of type 2 diabetes. Metformin is in a class of antihyperglycemic drugs called biguanides. It works by decreasing gluconeogenesis in the liver, reducing the amount of sugar absorbed in the gut, and increasing insulin sensitivity. A growing body of evidence suggests that metformin may prevent genomic instability by scavenging reactive oxygen species, increasing the activities of antioxidant enzymes, inhibiting macrophage recruitment and inflammatory responses, and stimulating DNA damage responses and DNA repair. 
 Najafi, Masoud, et al. "Metformin: Prevention of genomic instability and cancer: A review." Mutation Research/Genetic Toxicology and Environmental Mutagenesis 827 (2018): 1-8.
The collection of genomes of the microorganisms in a given niche. The human microbiome plays key roles in development, immunity, and nutrition. Dysfunction of the microbiome is associated with the pathology of several conditions, including obesity, depression, and autoimmune disorders such as type 1 diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis, and fibromyalgia.
Non-alcoholic fatty liver disease (NAFLD)
Fat is deposited in the liver due to causes other than excessive alcohol use such as diet, genetics, and long-term medication use. NAFLD is related to insulin resistance and the metabolic syndrome and may respond to treatments originally developed for other insulin-resistant states.
Reactive Nitrogen Species (RNS)
Nitrogen-containing chemically-reactive molecules generated by the immune system. RNS are produced in animals when nitric oxide reacts with superoxide to form peroxynitrite. They can damage cellular components, including lipids, proteins, mitochondria, and DNA. Examples of RNS include nitric oxide, peroxynitrite, and nitrogen dioxide.
A related byproduct, reactive oxygen species, is generated by oxidative phosphorylation and immune activation. Examples of ROS include: peroxides, superoxide, hydroxyl radical, and singlet oxygen.
The two species are often collectively referred to as ROS/RNS. Preventing and efficiently repairing damage from RNS (nitrosative stress) and ROS (oxidative stress) are among the key challenges our cells face in their fight against diseases of aging, including cancer.
Reactive Oxygen Species (ROS)
Oxygen-containing chemically-reactive molecules generated by oxidative phosphorylation and immune activation. ROS can damage cellular components, including lipids, proteins, mitochondria, and DNA. Examples of ROS include: peroxides, superoxide, hydroxyl radical, and singlet oxygen.
A related byproduct, reactive nitrogen species, is also produced naturally by the immune system. Examples of RNS include nitric oxide, peroxynitrite, and nitrogen dioxide.
The two species are often collectively referred to as ROS/RNS. Preventing and efficiently repairing damage from ROS (oxidative stress) and RNS (nitrosative stress) are among the key challenges our cells face in their fight against diseases of aging, including cancer.
Sex-Hormone Binding Globulin (SHBG)
A glycoprotein that binds to sex hormones, and is produced mostly by the liver. Testosterone and estradiol circulate in the bloodstream bound mostly to SHBG. Only around 1-2% is unbound or "free", and thus biological active. The relative binding affinity of various sex steroids for SHBG is dihydrotestosterone (DHT) > testosterone: androstenediol> estradiol> estrone.
Single nucleotide polymorphism (SNP)
A change in one nucleotide DNA sequence in a gene that may or may not alter the function of the gene. SNPs, commonly called "snips," can affect phenotype such as hair and eye color, but they can also affect a person's disease risk, absorption and metabolism of nutrients, and much more. SNPs differ from mutations in terms of their frequency within a population: SNPs are detectable in >1 percent of the population, while mutations are detectable in <1 percent.
A tiny region located in the hypothalamus responsible for controlling circadian rhythms. The SCN maintains control across the body by synchronizing "slave oscillators," which exhibit their own near-24-hour rhythms and control circadian phenomena in local tissue.
Type 2 diabetes
A metabolic disorder characterized by high blood sugar and insulin resistance. Type 2 diabetes is a progressive condition and is typically associated with overweight and low physical activity. Common symptoms include increased thirst, frequent urination, unexplained weight loss, increased hunger, fatigue, and impaired healing. Long-term complications from poorly controlled type 2 diabetes include heart disease, stroke, diabetic retinopathy (and subsequent blindness), kidney failure, and diminished peripheral blood flow which may lead to amputations.
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