For the past two decades, T.A. Sciences® is dedicated exclusively to creating research-based, clinically tested wellness products that help address telomere shortening through the science of Telomerase Activation.
Folks, I am just honored, thrilled, excited to be talking to my dear mentor and friend Dr. Jeff Bland on this episode of New Frontiers in Functional Medicine. Not only is Dr. Bland the father of functional medicine, but he’s also the founder of Big Bold Health, a company whose mission is to enhance immunity at the global level through rediscovery of ancient food crops and superfoods which support immuno-rejuvenation. Join me as I pick his brain on genetics, aging, SNPs, DNA repair, and senolytics, and find out why your genes are not a death certificate but rather a ‘uniqueness certificate’ that requires specific approaches. You won’t want to miss this in-depth conversation! And if you want to find out Dr. Bland’s personal longevity pearls and his approach to increasing healthspans you can download a recording of my exclusive MasterClass when you pre-order the Younger You book. Listen, learn, and if you would be so kind, leave a review on iTunes or wherever you hear my voice. Thank you! ~DrKF
Epigenetics, SNPs, and Aging with Dr. Jeff Bland
Is aging genetically pre-programmed or is it a modifiable process? In this episode of New Frontiers, we are joined by no other than the founder of the Institute for Functional Medicine, Dr. Jeff Bland, to answer this question and explore the world of epigenetics and aging. With over 40 years of experience in healthcare and education, Dr. Bland advocates for the power of immuno-rejuvenation and is on a mission to enhance immunity at the global level through the Big Bold Health company. He discusses the challenges of genome-wide association studies, how epigenetics regulates single nucleotide polymorphisms (SNPs) expression in individuals, and the importance of nutrition and lifestyle as upstream regulators of the aging journey.
In this episode of New Frontiers, learn about:
- Mendelian genetics vs. molecular gerontology
- BRCA1 and BRCA2 mutations
- Modifiable genetic conditions
- Role of the microbiome in phenylketonuria
- Single nucleotide polymorphisms (SNPs)
- Pitfalls of genome-wide association studies
- Junk DNA
- Epigenetic modulation
- Selective pharmacology
- DNA repair and aging
- Quercetin as senolytic
Dr. Kara Fitzgerald: Hi, everybody, welcome to a New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine. And of course, today is no exception, I am just honored, thrilled, excited, to be talking to my dear mentor, and friend Dr. Jeff Bland. You know him, but I do want to read his bio, because it’s his new career, and actually, Jeff, I think you articulate it so lovely, I look forward to reading it.
So, he’s the founder of Big Bold Health, a company that you’re hopefully familiar with now. It’s on a mission to transform the way people think about one of nature’s greatest innovations, the immune system. Through Big Bold Health, Jeff is advocating for the power of immuno-rejuvenation, to enhance immunity at the global level. I’m going to just say it again, to enhance immunity at the global level.
And we’ll talk about what that vision is, often through rediscovery of ancient food crops and super foods, and of course, Big Bold Health will walk you through what he’s thinking there. To get to these ancient food crops and super foods, Jeff is building a network of small farms and suppliers throughout the US, that take a clear stance on regenerative agriculture, environmental stewardship, and planetary health.
It’s just a powerful and essential combination at this point in our world. Jeff’s career in health spans over 40 years, he’s a nutritional biochemist by training, he was in academia as a university professor for many years, and then he spent 30 years in the natural products industry, working alongside other pioneers.
A lifelong educator, Jeff has traveled the world many times over in his role as the father of functional medicine. In 1991, he and his wife, Susan, founded the Institute for Functional Medicine, and in 2012, Jeff founded Personalized Lifestyle Medicine Institute. Which is an annual conference that I don’t miss, among other things.
Jeff is the author of The Disease Delusion: Conquering the Cause of Chronic Illness for a Healthier, Longer, and Happier Life, as well as countless additional books and research papers. Dr. Bland, welcome once again to New Frontiers.
Dr. Jeff Bland: Well, Dr. Fitzgerald, thank you. And any opportunity, excuse, that I have a moment to capture time with you is a special privilege, so thank you.
Dr. Kara Fitzgerald: Thank you. So you and I have been talking a lot about aging, it’s just a really interesting culmination of careers for us, that we’re both putting our attention on this. And of course you have said long, I think you really planted it in the minds of many of us, that genes are not our destiny, but I want to ask you about aging and genetics.
We see Blue Zoners, they live long, and they live well, and healthy and many generations out. We see, I was thinking of the growth hormone deficient folks too, in Ecuador, there’s a clear genetic component there.
Certainly, scientists around the world are looking for that age associated gene that they can perhaps CRISPerize, like Klotho [gene] comes to mind, or the ELOVL2 gene. Anyway, so what’s the deal with aging and genetics, is it something that we need to think about, or can we put it down?
Dr. Jeff Bland: Well, no, I think we all have to think genetics, because of the nature that we recognize, that Mendel wasn’t totally wrong. That these crossover, cross-linked, dominant and recessive [patterns] are real, and these concepts of monogenetic diseases are real. Where you get one gene that is mutated or changed, and it causes a significant change in metabolism, that is tracked with an infant disease, like Tay Sachs, Wilson’s, Gaucher disease, Fabry disease, various kinds of hemolytic anemias. So I think genes are real, so they’re not to be dismissed.
But I think for me, where I made the transition in my thinking about genes, because I was a student, like all of us are in my health science training on Mendelian laws of genetics, this hardwired deterministic model. I had this aha experience, probably in the early 70s, at a meeting I was attending, in which at that point a very well-known investigator woman at Harvard, actually at Mass General Hospital, was giving a presentation on first generation Japanese immigrants.
It was part of the Women’s Health study. And she went through the pedigrees of these women, meaning their family histories, their genealogy, and when I looked at the chart that she was showing, I saw that these family trees, that the women in those families historically had lived out to their 90s. Yet the generation that she was speaking to, which had migrated, or immigrated to the United States, these women were sick and had died in their 70s.
And, you would say, well, hold up, there’s generations of genes here, that all have 90-year-old lifespans, and this particular generation that is in a different environment, moving to the United States, presumably they didn’t change their genes when they got off the airplane or whatever, now they’re living on average to their 70s. What’s going on there? And so that actually started me down the road as a professor in trying to ask the question, what are the variables that might influence this process that converts our genes, which are Mendelian, into the expression, which becomes our phenotype.
And that to me is where the story has evolved, by so many different investigators involved in this field of molecular gerontology over the years, to where we now probably would say, that certainly 25%, maybe 30% of our life expectancy, is tightly controlled by our genes, and some of those genes can be obviously very dramatic in their control of our aging process. If you look at some of the mutations of the adapt gene, that lead to people whose lives are only 20 years or less in duration, but for most of us, the genes probably constitute only something like 25 or 30% of the determination of our life experience, life expectancy. And so that gives 25 to 30% of things that are variable, which is a big playing ground for us to be involved in, and that’s what you and your work, and certainly my focus has been on these years.
Dr. Kara Fitzgerald: Let me just ask you about… That’s great, yeah. And it’s pretty neat that you were thinking about this back in 1970, but it sounds like it was a really powerful example, and a very clear example for you.
Something else that you’ve talked about is the BRCA mutation, and the fact that… I’m assuming they discovered BRCA1 and 2, and then they did a retrospective analysis in the blood of women in, I think the 40s and the 50s, and saw that, in fact, the incidence of cancer in those women was much, much lower. I think now it’s somewhere in the neighborhood of 80%, maybe back then it was what, 30, maybe 20%, significantly lower. And so another clear environmental contributor, but I want to say to you, I’ve thought about that quite a bit, and it’s heartening, because it suggests let’s get in there, and get busy from the get go.
But still 80% of women with the BRCA mutation are going to wind up with cancer, at some point in their lives, so both pieces are true. And so therefore a lot of women end up going through prophylactic surgeries to reduce that risk. So yeah, the environmental influence isn’t just, maybe I’m going to choose a salad today.
Dr. Jeff Bland: No, I think that that’s a really good example, because it speaks to both the sides of the equation, as you’ve described. And when I read that paper in Science magazine, talking about the difference in expression in the phenotype of breast and ovarian cancer in women with BRCA1 and 2 type of mutations, the difference between women born before 1965 versus after 1965, the first thing that caught my attention obviously was, well with that same mutation of that gene, what were the lifestyles of the women post 65, how did their environments differ from those pre 65?
But as you stated, we do live in the real world. So if we’re a woman that has a double allele hit with a BRCA mutation, and we know that we could probably do everything we would like, but we’re not sure because we don’t have a specific marker that we can say, “Oh, my lifestyle is definitely going to protect me, because I’m carrying this gene.” I don’t know if I’m on the right side of the curve or not, because I can’t quantify that. Then it gets into, as I’ve seen in a number of women over the years, even women in our field, who have made a decision based upon statistics, which by the way, I think is a rational decision, that they’re going to have prophylactic breast surgery, and actually breast removal.
And so that is still the real sense of where we lie today, until we get a quantifiable marker saying, if you have that gene mutation and you are willing to undergo lifestyle therapy; that you have a marker that says you’re going to get the reward, and you’re not going to end up with a surprise, with a mammogram somewhere that you’ve got cancer. And I think those technologies are starting to be developed, but we don’t have them with a surety today. So we’re in the netherworld, we’re in between the two worlds right now, with regard to decision making.
Dr. Kara Fitzgerald: It’s an extraordinary time. So it’s uncomfortable for those of us in clinical practice managing patients with the BRCA mutation, and needing to make these decisions, it’s hard, and we’re all guiding our patients to live as cleanly as possible. But it’s also exciting because I absolutely agree with you, that we’re within earshot of those tools. They’re not pie in the sky anymore.
Dr. Jeff Bland: Yeah. And there’s a very contemporary application to this, and I know I’m going to tread here in a little bit of a controversial area, so I’ll touch on it only lightly. But there are a lot of people that are making decisions, obviously whether SARS-CoV-2 virus is of major concern to them, based upon their perception of their immune health.
And some people are saying, “I do everything I can to make my immune health good, and my immune resiliency high, so therefore I’m defended against the SARS-CoV-2 because my immune system has never let me down. I’m exaggerating the story just to make the point.
And so they have elected by that reasoning to say, I don’t need to be vaccinated, because I don’t want to run the risk of whatever it might be the untoward potential, no matter what it is for vaccination. I’m going to bank on my natural immunity as being sufficient. Then there are other individuals that would say, given the same set of decision-making challenges. They would say, “Well, I really don’t know exactly what my immune potential is, I’m doing everything I can, but it’s a little bit uncertain to me, and what I do know is that this virus has a high pathogenicity and infectivity, and I have seen some adverse sequelae in individuals who have not been vaccinated, who thought they were doing a good job in protecting their health. And so I’m going to maximize all of my chips on the table by vaccination, but I’m still going to do all these good things. So I’m going to decide to be vaccinated.”
And until we know exactly, quite honestly, how the immune system is working at a functional level in an individual, so that we can say in that individual, “By the way, you’ve got all the right kind of natural killer cells and the right kind of helper cells, and the right kind of neutralizing antibodies, so don’t worry, just go ahead.” Until we can say that with some precision, then it’s a very much a decision of choice that has some uncertainty associated with it.
Dr. Kara Fitzgerald: Yes, that’s a good and important example. So I’ve got a handful of questions here, I want to say, I want to point out just to give an example of genes not being our destiny, because actually I wrote about it in the book, but it was an extraordinary case to me. And I had the opportunity to encounter genetic conditions and address them in the laboratory because we were looking at thousands and thousands of test reports, and so the most unique cases I would get to consult with a physician and assist them in treatment.
We were looking at, organic acids and fatty acids and amino acids, all their essential and conditionally essential nutrients. So we could design with pinpoint precision what we thought was the best intervention. We were looking at the microbiome as well.
And there was a patient who was in the care of a physician that I consulted with really, for years, and he would get this full panel of tests, and he had a collagen defect, excellent collagen defect, that gave him a life expectancy of about five years old. And so he was on a feed tube, he was wheelchair bound, it was profound genetic defect. And his nutrition would be designed based on these laboratory data, and so we would be able to give him exactly what he needed, in the quantity he needed. He would just take it because it was in his feed tube. And the last I was in touch with him, he was graduating high school.
Dr. Jeff Bland: Wow. Isn’t that exciting? No kidding. Yeah, those are the proof of the pudding stories. I think that there are some papers that have appeared even in very high tier journals, like the New England Journal of Medicine, saying that conditions that we considered to be irreversible genetic defect conditions that affect infants adversely, can be modifiable, because they exist in different genetic variant forms, in terms of their severity.
And, one that’s very well known as phenylketonuria, PKU, which, we now test for in neonates with looking at their urine, to see if it has this amino acid phenylalanine that hasn’t been metabolized. And that particular condition is associated with early-stage neurological deficits, and ultimately a short life expectancy.
But it was found, and this is probably the first example of this description of how nutrition can influence a genetic metabolism disease, that if you put these infants on a phenylalanine-restricted diet, that they could go into adolescence with minimum adverse impact on their developing nervous system. And they would kind of, I don’t want to say grow out of it, but they would be much more tolerant to diet variety, as they got over their infancy in their adolescence. And so these people started living into adulthood now, versus previously where they would never make it to adulthood.
So that concept of a PKU-based medical nutrition program, gave rise to the designation of medical foods, that was the first example of a medical food. Well, it turns out that in further study of that, and I know you know this, so I apologize, it sounds like I’m lecturing you, I’m not, I’m just acknowledging a learning curve here. That, that enzyme that converts in our body, phenylalanine to its downstream metabolite, which is tyrosine – another amino acid, which is called phenylalanine hydroxylase, has a specific nutrient co-factor, like so many enzymes do. In fact, the majority of them do have different nutrient cofactors. It could be magnesium as a mineral, or zinc, or it could be a vitamin derived material. In this case, the cofactor is tetrahydro-
Dr. Kara Fitzgerald: Tetrahydrobiopterin.
Dr. Jeff Bland: Yeah. Tetrahydrobiopterin, which is a folic acid derived or related biochemical. And so someone asked the question, or many people ask the question, could you administer that cofactor then, orally at high doses, tetrahydrobiopterin, to push that enzyme that is genetically sluggish, so that it worked a little bit better, and you could then reduce the risk through the phenylketonuric adverse neurological problems. And the answer was yes, they were able to demonstrate that in a clinical trial, that BH4, tetrahydrobiopterin, when administered as a nutritional pharmacology approach, could in fact ameliorate the symptoms of phenylalanine hydroxylase deficiency in phenylketonuria.
Well then to take the step farther, which I found fascinating, this is more recent. People started saying, “Well, why would a person be tetrahydrobiopterin insufficient, relative to their need, to compensate for this sluggish enzyme, that was genetically misshaped?” And they eventually, for all sorts of reasons that I won’t go into detail, went back to maybe think about the microbiome, and thinking about the gut microbial metabolism, and absorption and metabolism.
And so people started saying, I wonder if we could get the same effect by doing gastrointestinal restoration of their microbiome, could we use pre and probiotics? And low and behold, they started to show clinical benefit, for restoration of the microbiome in phenylketonuric infants, by getting them to more effectively metabolize phenylalanine.
And so the story goes on, the more we look into the variables that influence our genetic expression into function, the more we see, in some cases, what we used to think were exorbitantly high doses of certain things are necessary, like a B12-resistant anemia, sometimes require as much as a thousand times the RDI B12 to unblock that blocked enzyme, to get that person to have proper blood cells. So that’s not a genetic death certificate, it’s a genetic uniqueness certificate, that requires specific approaches.
Dr. Kara Fitzgerald: So I’ve got just a lot of questions coming from that one, but I want to ask you about single nucleotide polymorphisms, and just staying on this, and we’re going to get back to aging folks, I promise, I’ve gone into a little bit of a rabbit hole, but I know you probably want to hear this conversation, if you’re tuning in.
A lot of us, myself included, we were excited about the promise of looking at lots of SNP data, and marrying it to the downstream metabolites, and getting an idea of enzyme function, like Linus Pauling and Bruce Ames and you, we’re just talking about. And it is important, while we’ve given a handful of examples of why it’s so essential.
I spent quite a bit of time, looking again at downstream metabolic activity, and being really pretty disappointed, there’s no shoe in here. If I see somebody with a homozygous COMT mutation, which is involved in metabolizing adrenaline, I don’t see any major difference in adrenaline turnover in that individual, or dopamine production and so forth, I don’t on laboratory. And we could talk about analytical reasons why that might be true, or specimen or whatever, but certainly, we all know people who’ve got more famous genetic mutations, like MTHFR, and I do think there’s, reason for us to be thinking about MTHFR, but we don’t necessarily see what we’re expecting to see.
And likewise with other enzymes in the methylation pathway, and enzymes elsewhere. Some do seem to be, certainly with APOE there’s a bigger impact. But the promise of SNPs was far in our world, we were very excited about it. The delivery, I think, left us wanting a little bit, and I’m curious what you’re thinking is.
Dr. Jeff Bland: Yeah. So I think all this conversation by the way does relate to this big topic of aging, because if we were to ask the question, is aging genetically pre-programmed so that it’s inevitable outcome of, if you just got a bad luck of the draw you’re going to die at 65, that’s all there is to it, you might as well live your life three sheets of the wind, because there’s nothing can do about it anyway.
Or is there a lot of variability associated with the aging process, that is associated with metabolic dysfunction, that is associated with not treating your genes with what they need to be treated with. Everything that relates to the examination of that question, ties into then how executable is an anti-aging strategy.
So that’s how I see all this fitting together in a broad intellectual body of information. Now, specifically related to SNPs, I still believe that when you do these genome-wide association studies, so called GWA Studies, that try to define how certain SNPs tie together with specific phenotypical outcomes, that those are good first level interrogations of how genes may, and I want to emphasize, play a role in forming how we travel in our health patterns as we age.
But the discouragement, and I’m, again, saying things that you know very well, the discouragement is that when you go from the broad statistical analysis of a group of people and look at their GWAS analysis, to an individual and ask how does that interrogation of their SNPs relate to their specific disease? Can you take the group data and make it applicable to an individual? That translation is very poor. It seems like in the groups, yes, when you have lots of statistical data from which noise gets separated, in the individual, no, its specificity is not so good. So then I asked, well, “Why might that be?”
And it might be because the SNPs and the regulation of their function is not just controlled by the SNP alone, the single nucleotide polymorphism, the single letter alphabet change in the genetic code. It may be that the operational executive centers above the SNPs, that regulate how they function as groups, because genes generally don’t participate one at a time. They participate multiples at a time, maybe the upregulating control agents, which are the transcription factors, which are often found, they regulate gene expression, but they’re not in the coding portion of genes, maybe there’s all sorts of information in what we call the genes dark matter, used to be called the-
Dr. Kara Fitzgerald: Junk.
Dr. Jeff Bland: Junk DNA, yeah, is where some of this real information resides, that is executable if we’re measuring the right thing. And it always reminds me of this story about the person that lost their keys, and they’re looking under the streetlamp, and someone says, “Oh, it did it fall here?” And they said, “No, it fell over there, but I can’t see over there.”
So we often look for the things that we can see, but maybe it’s the things outside is where the keys lie. And I think there’s part of that, that we’re learning now about epigenetic modulation, because some of the epigenomic effects are not on the coding regions of genes. They’re on the nucleosome, and they talk about how the DNA is compacted, or made accessible. And so we are starting to see that we need to broaden our slit width to what we look at, to determine how the genes ultimately regulate our function.
Dr. Kara Fitzgerald: Yes. And so, well, I have a handful of thoughts, I can say many times at the lab when we would be swimming in uncertainty, Richard always says to embrace the uncertainty, I’m grateful to be practicing what is largely safe medicine, when we exist in such uncertainty, because of what you’ve just spelled out.
As excited as I am about this -omics revolution, and looking at the methylome, and thousands of different methylation sites, DNA methylation sites, and what we can see, and biological age and all of these things that we’re galloping forward into doing, the reality is you’re right, we’ve been looking under the streetlamp, and there is much, much, so-called dark matter. And we do ultimately have to really marry all of these things together. However, we do have some wiggle room if we’re practicing relatively safe medicine and we can form, safe testable hypotheses, I think.
Dr. Jeff Bland: Well, I think you, there, you said something that I believe should be put in bold and with exclamation point. If you ask, how did the medicine that we’re doing today, the pharmacology we use today, how did it evolve, and why has it stayed with us?
It stayed with us because the model started with antibiotics, in which it was able to exploit a difference between human cells and bacterial cells, because bacterial cells have cell walls, and we have cell membranes. So you could find a specific fungal metabolite from a soil bacterium, or some organism in the soil, that then would block the production of cell walls, but would not affect cell membranes. So that was a development of a selective pharmacology of antibiotics. And it sounded marvelous, because you could have one disease that responded to one antibiotic, and you could have one drug to treat it, that was really cool.
Dr. Kara Fitzgerald: Yeah.
Dr. Jeff Bland: But then over time, what we found out that, well, actually most of the chronic diseases we have are much more complex, they’re not so different, that we can say, we’re going to treat them with something and only kill cell wall organisms, because they are a multiple factorial related causative, or caused conditions.
So now we start to say, okay, then what we will do, is we’ll develop a pharmacology around the endpoints of those conditions, whatever their symptoms are. So if it’s high blood pressure, we’re going to find things that block blood pressure. If it’s high cholesterol, we’ll find things that block cholesterol.
If it’s pain, we’ll find things block the endpoints of the pain mechanisms, like COX-2 inhibitor drugs. And that then did produce symptom success, and then the model was, okay, then the best drugs are going to be the ones that most tightly bind to these receptors that cause these downstream effects, these symptoms. And the better drug will be the one that has the highest activity, so it’ll make the smallest pill, but it also has to be safe enough that it can pass through some kind of regulatory process, so that the people that are injured, are going to be far less than the people that are helped.
And so now we will define our pharmacology based upon potency with a small, less important safety. And when I say less important, it’s not that safety’s unimportant, it’s just that we’ll tolerate some untoward effects for the strength of the activity. Now, when you do that, if that becomes your model, then what happens is you override a lot of the genetic differences among people, the SNPs get washed out. Because the drugs that we develop, these molecules, are so hard hitting, that they’re agnostic to genetic uniquenesses. They just say, “I don’t care what SNP you have, I’m going to block you anyway.” And so it then reduces the genetic variability component significantly, when you’re using this kind of medical model, this kind of pharmacology.
Now let’s shift over to diet and lifestyle, and so what are these factors, the things that are in foods? We don’t eat drugs, they don’t have the same potency, fortunately, because if they did, we would be whipped solid around every time we had a meal, and it would be pretty dangerous to be eating food if they were drug-like.
So they have softer touches on the receptors, and they work by what’s called pleiotropic mechanisms across multiple centers, and they tend to regress to the mean. And so, because they’re softer in their touch, they’re more sensitive to different personalities of genes, SNPs. And so we see a greater diversity of response to diet-related bioactives than we would see to drugs. So people would say, “Well, doesn’t that just complicate the situation, because now you’re going to get a lot more variability in a nutrition study, than you’d get in a drug study, because you’ve selected softer touch molecules to evaluate their outcomes.”
So you’re going to have huge data sets of controlled studies, in order to differentiate different cohorts that are responsive from those that are not. And that is why our nutrition studies, have been so difficult to come by with the same security as our drug studies.
But the good news, as you said, on the other side, is it worse, we do no harm. Because safety becomes a major component then. If safety becomes the primary objective, not the secondary objective, efficacy is below our safety, now we have changed the balance point from the drug model, which is efficacy for safety second.
So I think it’s an interesting, depends on where you want to land on that curve. For chronic illnesses, personally, this is my personal philosophy, I don’t want to use drugs that were designed for intensive care unit crisis medicine, that have no ambiguity and they’re agnostic to any genetics. I want to use molecules that have soft touch, that have adaptogenic possibilities to activate when necessary, or to antagonize when necessary to find balance. Therefore, I will choose molecules of nature, because that’s the largest study that’s ever been done, called natural selection, about the safety of molecules. And I will use those over the course of my lifetime, rather than reserve the hard-hitting drugs for the crisis of an intensive care unit.
Dr. Kara Fitzgerald: Yes. Yeah, Amen to that. Gosh, yes. And I think we have enough information with all the limitations of our nutrition studies, but we can certainly look from, again, from how we’ve evolved to be able to pinpoint certain groups of nutrients as likely beneficial for everybody.
There’s not that many Inuit eating just whale blubber, and so I think, there are many nutrients that are appropriate. All right, so I guess I’m going to just take a left shift here, and I want to talk about DNA methylation. So, we’re talking about genes right now, I’ll throw out one thought, I have a handful of thoughts, so I’ll just throw them out, and then you can grab whatever you want to.
We’re talking about genetics, now we can see that is a gene on or not, and we’re able to look at DNA methylation patterns, and see whether or not the promoter region is hypermethylated, and therefore the gene is not available for transcription, or is it hypomethylated, and therefore it is, it can be.
There’s interesting work on looking at BRCA, so if we circle back… First of all, the vast majority of cancers are not… Breast cancer, specifically talking about BRCA, are not associated with a genetic variant, they’re unknown, and they’re not familial. But we can look at the BRCA gene itself and see that in fact it can become hypermethylated and inhibited. Actually, there’s a whole bunch of different BRCA proteins that have the potential to have methylation patterns that turn them off, and these are associated with cancer. There will come a time, actually, the GRAIL test, the Galleri test is out now, that looks at different methylation patterns in at least 50 cancers. And I would imagine, I haven’t studied the specifics of what they’re looking at, but maybe they are looking at BRCA methylation patterns.
So it looks likely that abnormal methylation patterns are contributing to cancers, we just know that to be true, and I’m sure that it’s much, much more impactful than I’ve certainly realized. One of the causes of breast cancer can be, you’ve got a fully functioning BRCA mutation, but it’s hypermethylated and inhibited. That’s one little piece that I want to put out, and the GRAIL test was just purchased by Illumina, which is one of the main research laboratory companies making the DNA methylation arrays, they’ll be offering it. What else? I also want to talk about-
Dr. Jeff Bland: Can I ask you a question on that?
Dr. Kara Fitzgerald: Yeah.
Dr. Jeff Bland: So that’s a really interesting point. So this is a mea culpa, I’m acknowledging a limitation in my own education until a few years ago, when I had an aha experience. Shame on me, after speaking about BRCA mutations for some years, I never asked the question, “Well, what does the BRCA gene do?”
Dr. Kara Fitzgerald: Yes.
Dr. Jeff Bland: “What is its biological function, as far as we know it?”
Dr. Kara Fitzgerald: Yes. Good question.
Dr. Jeff Bland: And when I finally learned that, and I should have learned it much earlier, but when I finally did learn it, I recognized that it’s a member of the family of DNA repair, damage repair genes. It’s involved in the protection of the integrity of our DNA after it’s undergone injury.
And it turns out that BRCA is only one of a whole family of those genes that are involved with the processes that repair damaged DNA in our chromosomes, and elsewhere, DNA even in our mitochondria. And therefore, what happens is, that if you have diminished DNA repair mechanisms in specific tissues, that are undergoing insult from potential mutagenic events, that then increases the likelihood you’ll have a hit, a double hit, on your chromosomes of those cells that could then trigger some kind of oncogenic transition problem that leads to cell replication and immortalization that we call. Which is interesting those cells don’t age, right?
Dr. Kara Fitzgerald: Yeah, that’s right.
Dr. Jeff Bland: They become immortal, so like HeLa cells. And so when I thought about that, in greater detail about the lifestyle connection then to the transition of BRCA into breast or ovarian cancer, I thought what maybe is happening in those lifestyle changes, or maybe environment and lifestyle changes, is that we have reduced the exposure to substances that cause DNA damage, in those individuals that have been born before 1965.
So we’re not actually changing the gene of the BRCA itself, but we’re changing the environment that bathes the gene, and we put less demand on DNA repair mechanisms, by our lifestyle and environmental changes. Now that’s an interesting conceptual framework, because when you now look at doing a genetic screen as a woman at risk to breast, or a man at risk to prostate cancer, it encompasses a whole family of genes that are associated with DNA repair.
And now we recognize that the defects and DNA repair, or the increasing damage to DNA, are all associated with cancers of all sorts of different types, and it even goes back to the work that we’ve talked about, Michael Fenech’s work on nutrients and their protection against DNA damage. And the beta-field test, multi-nuclei test that he developed a number of years ago, which he’s published many papers, it’s a morphological evaluation of how DNA is being damaged at whole cell level.
So I think that we’ve got a lot to go back and reexplore, as it relates to maybe the environment protects against certain gene types by less pressure on those genes that are required to defend us against a bad environment. I hope I’m making sense here.
Dr. Kara Fitzgerald: So there are many actual tumor suppressor genes, like far and wide, whose primary role is to clean up DNA damage, and so you’re suggesting that they’re not able to do their job sufficiently, or are they not being adequately challenged, I guess I’m not… I need you to-
Dr. Jeff Bland: Yeah, I’m saying that those mutations, those SNPs are such that that reduces the repair capacity.
Dr. Kara Fitzgerald: Absolutely.
Dr. Jeff Bland: Which makes you more susceptible to aging that would damage DNA, to their effects.
Dr. Kara Fitzgerald: Yes, yes, yes, yes. So the mechanism of, if you’ve got a BRCA mutation, or a BRCA hypermethylation, or a tumor suppressor hypermethylation, one of the outcomes is increased opportunity of damage? That makes total sense.
Dr. Jeff Bland: And then if you take the next step, of course, which you help me take the step, so I want to acknowledge that, because in my early days, this would be in the early 2000s, say 2003, four or five, when I started doing what I guess we now call webinars, back then there weren’t webinars, they were whatever educational events. And I would talk about the nature of MTHFR and methylation. And I had a very naive conceptualization about MTHFR and methylation, I would be embarrassed to even say what I was saying at that point, because it was very superficially naive.
Because we recognize that methyl groups placed on genes, is more than just the presence and/or absence of activities of MTHFR, as you’ve so eloquently talked about, multiple ways that that’s regulated. But with that said, what I came to recognize more recently, is that the way that these methylating and demethylating enzymes are influenced is upstream by many different regulatory factors, that then can be modulated through lifestyle and nutrition, so that’s what I’m saying is we need to move up to the-
Dr. Kara Fitzgerald: Way up, that’s right, I’m with you.
Dr. Jeff Bland: And we need to take the light that we’ve been looking at and make it a broader scope of light.
Dr. Kara Fitzgerald: Yeah, I got it. Well, let me tell you really interesting in the book Younger You, that I wrote on our study, and thinking about these all important tumor suppressor genes, whose main, one of their main roles is DNA repair, they’ve got a bunch of different hats that they wear these proteins, but certainly DNA repair is big. And these tumor suppressor genes get hypermethylated, and shut down in cancer, routinely, actually they get hypermethylated and shut down in aging itself, and the chronic disease of aging, we just see these collective, this molecular phenotype if you will in the aging journey.
But when you look at these tumor suppressor genes coming from a functional medicine lens, it’s just like, wow. Like glutathione peroxidase enzymes are tumor suppressor genes, and they’re hypermethylated and inhibited in a number of cancers, but particularly genito-urinary cancers. So genes that we know are active and essential for detoxification, also wear a tumor suppressor gene hat. This whole detoxification action cleans us up and keeps us from cancer. And in the world of oncology research, they’re thought of primarily as tumor suppressor genes and not, this glutathione peroxidase enzyme, they don’t look at it through our lens quite as much. Isn’t that interesting?
Dr. Jeff Bland: I think you said it beautifully, and you know what we’re starting to learn, we’ve been talking about this for some time, but we’re starting to fill in the blanks a little bit of the pattern, is that many of these processes that you’re describing cut across many different ultimate diagnostic disease groups. You could see the same thing in cardiovascular disease, you can see the same thing in autoimmune disease, you can see the same thing in neurodegenerative disease. These processes translate into the phenotype in different ways, in different people, but they share common mechanisms. This was the whole reason for the Institute for Function Medicine being founded.
Because I started recognizing, and reading the literature that the confluence of these, if you travel upstream, they all participated in common pathways of altered function. And the regulatory centers, the executive centers that control these things, are things that are modifiable, in their expression patterns based upon the way we live our lives and the environment in which we’re living.
And even ties into, now we’re starting to learn about social determinants of disease, that what we used to think was soft science, it was like, oh, what’s that got to do with disease? Now we say, no, these are psychosocial messages that are transduced by our nervous system and our immune system, and the hard-wired epigenetic effects, that regulates these functions.
Dr. Kara Fitzgerald: Yes, yes, absolutely. Very powerful, very powerful. It’s almost when we look at it from this perspective, really the only light we have is to go upstream, and to be thinking about diet and lifestyle.
Dr. Jeff Bland: So when you look at your study and your book, the shifting seismic contribution that those two bodies of work that you’ve participated in, result in us understanding that the major pathways, the major networks, the major journeys that our body takes through processes that we call aging that ultimately translate into age-related diseases that are generally put on death certificates, our processes, all of which are taking signals from our daily living, starting conceptually on, maybe even preconceptually, I won’t even go there, but at least conceptually on for sure.
Dr. Kara Fitzgerald: Yes, yeah. It’s extraordinary if you think about it. And turning genes on and off in response, or making genes available to be turned on and off in response, that’s right. It’s a game-changing concept. Let me throw two papers out to you, and just get your thoughts on them.
December 2020 in a Nature publication out of Sinclair’s laboratory looking at age-related optic neuropathy that they created in mice. And then they reversed it using three of the four Yamanaka factors, which addressed methylation and demethylation. So they created an age-related illness, it was an aging neuropathic condition, and then they turned it around specifically by addressing epigenetics, and more specifically DNA methylation and demethylation.
And we know Yamanaka factors to back up for anybody who doesn’t. They are a group of four transcription factors that can take a somatic cell and reverse it, or any cell really, and reverse it right back to a pluripotent state. So an inducible pluripotent stem cell that can then go on and become any other cell. Yamanaka factors are crazy transcription factors, that will just wipe away epigenetic information, and I think they do this primarily via DNA methylation and demethylation, but of course, it’s beyond that, that’s just the lens, that’s the streetlamp we can see under right now, and take it back to the earliest life stage.
However, in Sinclair’s lab, they controlled that, they didn’t go back to pluripotent stem cell status. They actually resolved this eye injury extraordinarily enough, and the whole, the optic neurons were actually younger. So that’s study A in December 2020. And then his lab just recently published another animal study, where they induced aging, again, just gunking up epigenetic expression, and then, in an animal model, so global aging, not just one condition, not just one presentation, and reversed it, again, using Yamanaka factors. Really extraordinary, I’m sure that you’re aware of these two papers, but it certainly is starting to zero in on physiologically, a very upstream driver of the aging journey.
Dr. Jeff Bland: Yes. And I’m glad you cited that work. Dr. Sinclair was a presenter at our 9th annual PLMI conference in November, and he did talk about those, what I consider seminal studies, and how certain regulatory networks within metabolism can be modulated to, as you say, erase some of those marks that relate to those expression of those phenotypes.
That also relates to, this whole emergent field that you just discuss, which is senolytics and senomorphics, and I think that the Kirkland work at Mayo and his whole group, and this most recent paper that was just published in Nature Metabolism, which is just one of the most fascinating papers, I believe that I’ve seen recently. And this is specifically going everything from cell-based studies, all the way up through animals, showing that things like ability of rodents to hang on a wire for a long period of time is enhanced, that their muscle energy, their muscle dynamics, their endurance, their respiratory quotient, all their metabolic parameters can be reversed in aged mice, through appropriate intervention using senolytics.
Dr. Kara Fitzgerald: Wow.
Dr. Jeff Bland: And what the senolytics in this case were, because his group was the first group to talk about the use of dasatinib and quercetin. And when I read that first study, this was now probably five years ago, I thought, well, that’s very interesting, because they’ve chosen these two molecules. One, that comes from natural products origin, quercetin, a polyphenol, and the other from early cancer anti-mitotic activities, and I wonder if you could get the same biological effects without having dasatinib, looking at the mechanism of action of dasatinib, and something that is in the natural realm that would do the same thing, but maybe not as hard-hitting.
Dr. Kara Fitzgerald: Yeah.
Dr. Jeff Bland: Well, lo and behold, that’s what this most recent Nature Metabolism study did. They did not use any chemotherapeutic. This was strictly using a complex mixture of natural phenolic compounds in grape seed extract. So it was a grape seed extract study showing all these parameters of cellular aging were reversed. They started with cells, they moved ultimately to animals. Then they asked the question, is there any molecule within that complex mixture that is doing the heavy lifting? And they eventually identified one molecule, procyanidin C1 they call it, it’s a trimer of quercetin actually. That was what they considered the heavy lifting molecule.
Well, if you look at the data carefully, which I did, I spent hours really going through the study, it has tens of different figures and diagrams, it’s really information rich. I think you can tease out of the study, that the natural mixture was fully intact of probably tens of different molecules in the grape seed extract, actually had higher activity in both the senolytic and senomorphic influence, with lower potential adverse effects, than did the single molecule procyanidin C1.
It begged the question, why did they put procyanidin C1 in the title of the paper, and not put grape seed extract? It’s because it’s much easier to understand, in the traditional pharmacological model of one molecule against one activity, than it is to talk about this complex mixture in network pharmacology.
I think that we’re starting to witness an incredible transition in thinking about senolytics, or aging in cells, using network pharmacology, versus traditional one-agent pharmacology.
Dr. Kara Fitzgerald: I think that’s great. I feel like that paper came in my peripheral vision, but I certainly didn’t until… I didn’t attach to it in the same way you did, I’m so glad that you brought it to my attention, it’s incredibly important.
I guess, one of the things that I observe in the biogerontology world, which I’m paying more attention to, because of our study. And it’s an exciting and very interesting, and extremely important place to be, I think as the chronic disease epidemic gallops forward, but there is a hat worn by a lot of the scientists around this reductionistic pharmacology lens, and I absolutely a hundred percent agree with you.
I think maybe we will find a handful of molecules that take us a pretty cool distance, or some of us, because they’re not going to work for everybody, and they’re certainly going to be untoward side effects. And if you’re playing with the epigenome to lower biological age, with those aggressive molecules, it’s going to be risky, and I’m not going to be first in line for some of those. But maybe there will be, maybe we will find some of those molecules, and people will be billionaires or trillionaires, and that kind of thing.
Dr. Jeff Bland: I just learned that I need to unfortunately call this quits, because I’ve got a very important call I need to take. So with abruptness, I’m going to have to beg off here.
Dr. Kara Fitzgerald: Okay. All right, well, we’ll figure out some edit there. All right, thanks, Jeff.
Dr. Kara Fitzgerald: Well folks, sometimes life just gets in the way of our deepest conversations and, such as the case with my amazing chat with Dr. Bland. We will definitely circle back to this again and, of course, you can find conversations with Dr. Bland on New Frontiers in previous years, and he’s also participating in our Master Class for the book launch, so find him there. In fact, if you’ve pre-ordered the book, I’m going to ask him his own longevity pearls – as well as all of those in the master class: what exactly they do, and their longevity, their approach to health span, and vibrant longevity will be released to those who pre-order the book only.
So, thank you again for hanging with me to the end. Know that I will continue this conversation with Dr. Bland.
And if you’re listening to this after months after the book is out, I would love to hear what you think and just your thoughts overall on this journey of epigenetics.
Dr. Kara Fitzgerald: As always, thank you for listening to New Frontiers in Functional Medicine, where our sponsors help bring the very best minds in functional medicine, and today is no exception. Not everyone can be a sponsor on my platform, and I so appreciate the good work, relentless research, and generous support from my friends at Biotics, TA Sciences, and Integrative Therapeutics. These are brands I know and trust in my own clinic and can confidently recommend to you. Visit them at BioticsResearch.com, TASciences.com, and IntregrativePro.com, and please, tell them you learned about them on New Frontiers.
If it’s not too much to ask, I would appreciate a thumbs up and a kind review wherever you listen to New Frontiers. Thanks.
Jeff Bland, PhD is the founder of Big Bold Health, a company on a mission to transform the way people think about one of nature’s greatest innovations — the immune system. Through Big Bold Health, Jeff is advocating for the power of immuno-rejuvenation to enhance immunity at a global level, often through the rediscovery of ancient food crops and superfoods. To get there, Jeff is building a network of small farms and suppliers throughout the US that take a clear stance on regenerative agriculture, environmental stewardship, and planetary health.
Jeff’s career in health spans more than 40 years. A nutritional biochemist by training, he began in academia as a university professor. Jeff then spent three decades in the natural products industry, working alongside other pioneers.
A lifelong educator, Jeff has traveled the world many times over in his role as the “father of functional medicine.” In 1991, he and his wife, Susan, founded The Institute for Functional Medicine. In 2012, Jeff founded another educational nonprofit called the Personalized Lifestyle Medicine Institute.
Jeff is the author of The Disease Delusion: Conquering the Causes of Chronic Illness for a Healthier, Longer, and Happier Life, as well as countless additional books and research papers.
Dr. Kara Fitzgerald FxMed Resources
Clinician Professional Development: DrKF FxMed Clinic Immersion