Saunas and longevity: Another example of putting the preclinical cart before the horse [Respectful Insolence]

Among quacks, epigenetics is the new quantum theory.

I know I’ve said that before, but it’s worth saying again in response to a new quack I’ve just discovered, courtesy of an article in The Daily Mail Fail by one Dr. Sara Gottfried pimping her books and health empire, From taking a sauna to drinking pinot noir, a fascinating book by a hormone doctor reveals how to… switch off your bad genes and live longer.

Epigenetics. She’s talking about epigenetics. Of course, she keeps using that word. I do not think it means what she thinks it means. Indeed, if what’s in this article is a taste of what’s in her book Younger: The Breakthrough Programme To Reset Our Genes And Reverse Ageing, it looks as though we have another misguided doc who thinks that epigenetics means that wishing makes it so and that we can easily “reprogram our genes” with whatever woo they are selling. In fact, it turns out that this article is an excerpt from that very book, which means that, yes, presumably this is a taste of what’s in the book, designed (of course) to sell it and published by The Fail because, well, it’s the sort of sciencey-sounding tripe they love, a bunch of extrapolation and misinterpretation of preclinical and very early clinical evidence, all gussied up with “epigenetics” and how saunas (and other things) can “reset your genes” to make you live longer. I’ll get to the saunas in a moment. First, let’s take a look at Dr. Gottfried.

Oddly enough, I had never heard of Sara Gottfried before, but it didn’t take long to find her website, where she bills herself as “Dr. Sara Gottfried, MD.” Now, whenever I see a doctor using both “Dr.” before and “MD” after her name, I can’t help but think that she’s really trying too hard to impress, because, really, you only need to use one or the other, not both, to communicate to people that you’re a physician. (I also can’t help but think of the title of this movie.) Then I read her bio on her website, and—hoo, boy—is this woman full of herself. She describes herself as having been the 4 “F’s” – frazzled, frumpy, fat, and “you can imagine the fourth ‘F.’” But don’t worry about it. She fixed herself and turned her fix into The Gottfried Protocol. I don’t know about you, but whenever I see a doctor naming a treatment protocol after herself, I’m just dying to deflate the ego, particularly when she says without clinical trial evidence that it’s “worked gloriously well on the 10,000+ people I’ve seen in the past 10 years.”

What she describes in her protocol sounds very much like the epitome of “complementary and alternative medicine” (CAM) or “integrative medicine” in that it rebrands simple, uncontroversial interventions as somehow being “alternative” or, in Gottfried’s case, revolutionary. Interventions such as eating healthy food, spending quality time with her husband and making time for her best friend, and hanging out with her daughters become the “Gottfried protocol.” Of course, there’s more to it than that. (Isn’t there always?) Gottfried slathers on a bit of the quack’s favorite gambit of telling each patient she’s unique and individual:

I’m a gynecologist, but I don’t treat problems. I don’t even treat symptoms: I specialize in root cause analysis because I know – and evidence shows – that the greatest health transformations are triggered when you address the root cause, not the signs.

Rather than treating problems or symptoms, I treat people. I treat women. I see women – and what I see every day is that each woman is a special snowflake. Sometimes I prescribe supplements that fill nutritional gaps that you might have. Sometimes I prescribe an iPhone app that helps you connect to your heart. Sometimes I prescribe botanical therapies with a very low risk profile. Sometimes I prescribe bio-identical hormones. Many times I prescribe all of the above. With every patient I see, I consider her unique context, physiology and preferences…and then invent a treatment plan to promote maximum health and happiness. It’s not one method fits all. It’s not fix-’em-up-and-send-’em-home. It’s a mission.

My mission at The Gottfried Institute – and in life – is to help women feel sexy, vital and balanced from their cells to their souls.

You know, the term “special snowflake” is usually used to make fun of people who think they are so special and unique that the universe should cater to them. This is the first time I’ve actually seen an alternative medicine doc actually use the term unironically to describe her patients. But it fits! Maybe she’s inadvertently saying something about what she does and who her patients are without realizing it. In any case, this is the same sort of patter that alternative medicine docs of all stripes, be they homeopaths, naturopaths, “functional medicine” followers and their touting of the “biochemical individuality” of each patient, or practitioners of traditional Chinese medicine (TCM)use to lure the marks in. You’re special! You’re an individual! I cater to you and develop a treatment plan based on your special snowflakeness!

It turns out that Younger isn’t the first book by Gottfried. (Of course it isn’t.) She’s also written The Hormone Cure: Reclaim Balance, Sleep and Sex Drive; Lose Weight; Feel Focused, Vital, and Energized Naturally with the Gottfried Protocol and (of course!) The Hormone Reset Diet: Heal Your Metabolism to Lose Up to 15 Pounds in 21 Days. I’ve noticed that “hormone balancing” is a favorite dubious treatment plan. Indeed, whenever you hear a doc like Gottfried say “hormone balancing,” substitute the word “humor” for “hormone,” and you’ll be closer to the truth. What’s really going on here is the appeal to “balance” in pseudoscientific medicine, in which the reason you don’t feel good or are sick is that something in your body is “out of balance.” TCM, based as it is on ancient Eastern religious beliefs more than any sort of science, is based on the same idea, that something “out of balance” in your body causes disease, be it dampness/dryness, heat/cold, etc. Add a little functional medicine, in which many hormone levels are checked, thus virtually guaranteeing that one or more “abnormalities” will be found to “treat,” and that’s what we’re looking at here. If you don’t believe me, consider that Gottfried likes to use terms like “biohacking my hormones” to describe her “journey” to wellness.

If you have any doubt how dubious what Gottlieb is selling is, simply consider this. She uncritically advocates “detoxification”:

Detox is nutrient rehab. Detoxing means cleaning out the body, removing toxins, clearing out your jammed hormone receptors, and resetting key hormones. Most simply, detox is a tool of functional medicine: remove the obstacles to radical health, and add in the factors that support you. We accumulate junk mentally, emotionally, physically, and spiritually on a daily basis.

And later:

Heavy metals such as mercury and lead and toxic chemicals can build up in our bodies and cause a number of issues, including increasing our risk to certain diseases and making us resistant to weight loss. We are constantly exposed to these heavy metals and toxic chemicals in our environment: Mercury can get into our bodies by way of fish, particularly large fish and shellfish; medications, such as thiazide diuretics, prescribed for high blood pressure; vaccines, which may contain thimerosal, a mercury compound used as a preservative; and dental fillings.

Furthermore, we can be exposed to lead and other toxic chemicals in our drinking water, as seen by the recent lead poisoning case in Flint, Michigan, and reports by the Natural Resource Defense Council about rocket fuel (perchlorate) and atrazine contamination of our drinking water.2 (Perchlorate is a toxic chemical used in making rocket fuel and explosives, and atrazine is a pesticide and a known endocrine disruptor, meaning it interferes with our hormones, even at extremely low levels.)

Detoxing can help our bodies get rid of the inevitable buildup of heavy metals and toxic chemicals that happens in modern life. It can flip the switch toward healing and repair.

Great. She’s parroting antivaccine pseudoscience, too, namely that bit about vaccines and thimerosal, which has been absent from childhood vaccines for 15 years and isn’t even in most flu vaccines any more. In any case, as I’ve pointed out time and time again, whenever you hear a doctor promoting “detox,” that doctor is promoting quackery, because “detox” is unnecessary. Basically, it’s nothing more than a form of ritual purification gussied up with scientific and pseudoscientific language. Oh, and fear of modernity and, above all, chemicals.

But back to The Fail article, which I’ve neglected too long as I’ve wandered off through Dr. Gottlieb’s website:

The female body is magnificent, but it doesn’t come with a lifetime warranty or an owner’s manual.

However, as a doctor — a gynaecologist and hormone specialist — I am fascinated by the role that our genes play and the power that we have to change them.

I believe it’s all about finding the genetic switches that control metabolism, weight, disease and ageing and am convinced that by turning your good genes on and your bad genes off, you can prevent ageing no matter how old you are.

This last statement is so ridiculous that I laughed out loud when I read it. (I hope no one around me was disturbed. I am at a medical meeting, and it was between sessions that I was catching up on blog reading.) Nothing prevents aging. Now, eating a healthy diet and exercising, not being overweight, not smoking, and not abusing alcohol, among other things, will help mitigate or slow down the deterioration of the body and prevent the adverse consequences that derive from smoking, drinking, being overweight, and leading a sedentary lifestyle, such as type 2 diabetes, cancer, arthritis, and cardiovascular disease, but your body is still aging and deteriorating in ways that time mandates and can’t be prevented. OK, OK, maybe I’m being a bit pedantic, but this is the problem. Gottfried is overselling what can be done and, strictly speaking, nothing prevents aging per se.

This overpromising on aging is all a relatively minor issue compared to what Gottfried starts blathering about later in the article. For example:

Regular sessions in a sauna give the body a shock of heat, which appears to help reset its fine-tuning mechanisms, including DNA.

A sauna activates the longevity gene FOXO3, which turns on genes for stress resilience, production of disease-fighting antioxidants, maintenance of proteins (to keep muscles strong), DNA repair (prevents mutations) and tumour killing.
So using a sauna is handy as we get older because it seems to boost exactly the genes that become less effective with age.

In addition to turning on other important genes, FOXO3 helps you make something called ‘heat-shock proteins’.

These work to ensure proteins in your body are folded like a fitted sheet, not bunched up and wrinkled. Poorly folded proteins clump together and cause damage in the form of furred-up arteries, heart failure and diseases such as Alzheimer’s.

Heat-shock proteins also work to counteract ‘oxidative stress’ — the natural rusting process that happens to the body over time. Studies show when you make more FOXO3 (because you are genetically predisposed to do so or because you enjoy a regular session in the sauna), you triple your chance of living to 100. Even if you have a sauna only once every couple of months your heart will benefit.

This is what we in the biz refer to as taking findings in basic science and epidemiology and running with them to the point that you run off of a cliff.

FOXO3 is actually an interesting gene. It encodes the transcription factor forkhead box O-3 (FoxO3). Transcription factors are proteins that bind to specific DNA sequences associated with specific genes in order to turn those genes on or off, so that they make more or less of the proteins that they encode. Indeed, transcription factors are a very common epigenetic mechanism by which gene activity is regulated. If you really want to get into the weeds, you can consider that there are transcription factors and other epigenetic mechanisms that regulate how much FOXO3 is made, which then in turn regulates its target genes. The network goes on and on, both “upstream” and “downstream” of FOXO3, and I’m not even considering other layers of regulation, such as how the FOXO3 protein is modified after it is made.

While looking at Gottfried’s claims, I found a rather interesting recent review article about FOXO3 and its affect on longevity, and it’s true. FOXO3 regulates processes associated with energy homeostasis, DNA repair, oxidative stress, and other processes. Actually, though, there are more than one FOXO genes, and they are all involved in similar pathways. The article notes that overexpressing (forcing the cells to make a lot more than normal of) FOXO3 in model organisms such as Drosophila (fruit flies), Caenorhabditis elegans (a species of tiny roundworms that are often used in genetic experiments), and mice.

The authors caution, though, that the effect sizes are inconsistent and can be very strain-dependent. For instance, interventions that increase FOXO3, such as calorie deprivation, do not extend the lives of wild mice, and findings in calorie-restricted rhesus monkeys have been inconsistent. The authors further caution that the GenAge database lists over 1,000 genes that have been associated with longevity or ageing in model organisms, including >1,000 in C. elegans and >100 in mice, 51 of the latter being able to extend lifespan but that there is little evidence to date for any of these being involved in human longevity. What is the evidence? The authors describe it:

Because of its actions and strategic position in relation to intracellular pathways, FoxO3 has long been considered to play a pivotal role in the molecular basis of longevity [6]. This led researchers at Kuakini Medical Center in Honolulu to perform a genetic association study of single-nucleotide polymorphisms (SNPs) spanning the human FoxO3 gene (FOXO3) and flanking DNA in a cohort of American men of Japanese ancestry well characterized for ageing phenotypes. Longevity ‘cases’ were men aged over 95 years, and ‘controls’ were birth-cohort-matched men of normal lifespan for this population (mean age 78.5 years). This revealed an association of three FOXO3 SNPs with living to extreme old age [20]. Eleven independent studies of populations of diverse ancestry in multiple different countries have now confirmed and extended this finding. A meta-analysis in 2014 of the various studies found that 5 of the FOXO3 SNPs tested retained statistically significant associations with longevity [21]. The strongest association was for the minor allele of the SNP reported originally to exhibit the most robust association, namely, the G allele of rs2802292 in men (odds ratio, 1.54; 95% confidence interval, 1.33-1.67).

SNP stands for “single nucleotide polymorphism” and represents a difference in a single nucleotide. For example, a SNP may replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of DNA. There are estimated to be 10 million SNPs in the human genome and are used as markers of genetic variability. When they are found within a gene, they can indicate a variant of the gene that changes the function of the protein made. Or, when found near a gene or in a regulatory region of a gene, they can affect how much of the gene is made or how the initial RNA transcript made from the gene is spliced to form the final messenger RNA that is translated into protein. In the case of FOXO3:

The various longevity-associated SNPs are located in or near intron 2 of the 125-kb FOXO3 gene [23,24,25]. After performing extensive sequence analyses of coding DNA, the Kuakini team ruled out involvement of coding variants (amino acid differences) as an explanation for the genetic association [25]. To date, the causal SNP(s) and the reason underlying the protective effect of the longevity-associated allele(s) in human longevity remains to be delineated. The Leiden 85-plus study has, nevertheless, found an association of FOXO3 haplotypes with all-cause mortality, stroke and cardiovascular mortality [26]. The rs2802292 TT genotype is, moreover, associated with the rare hamartomatous polyposis syndromes [27]. Research is needed to compare FoxO3 levels in various tissues of long-lived and normal lifespan individuals with TT and GG genotypes. The findings might help inform experiments aimed at identifying factors that could be relevant to the genetic association findings in humans.

Introns are the stretches of DNA between the exons and are what get spliced out when the initial RNA transcript is spliced into its final messenger RNA form. In other words, this is a case where the favorable FOXO3 variants have SNPs that do not affect the sequence of the gene that is actually coded into protein. However, there can be sequences within introns that are binding sites for proteins that regulate gene expression. So it’s possible that these SNPs alter the function of the intron in a way that increases FOXO3 expression. The bottom line is, contrary to what Gottfried claims, we don’t know, or, as another review puts it, the role of FOXO genes in human longevity is “complex and remains to be fully elucidated.” This other review also notes:

To further comprehend how FOXOs affect longevity, it is of high importance to understand how human FOXO sequence variants (namely FOXO3A) affect protein expression, its structure, or transcriptional activity. In order to see how these variants translate into physiological profiles, future investigations should address how these variants affect the level of FOXO proteins and their downstream effectors in serum.

Basically, Gottfried is massively oversimplifying and putting the cart before the horse, as doctors of her ilk, who promote their own protocols without doing the rigorous scientific and clinical research needed to validate them, are wont to do. We don’t know that increasing the level of normal FOXO3 will prolong life, and we certainly don’t know that saunas will boost its level in any meaningful, longlasting way; that is, if my multiple searches of PubMed and their failure to find any decent studies are any evidence.

I think I know where this linkage could have come from. There was a study in 2015 that looked at sauna use in Finland and found that increased frequency of sauna use was correlated with decreased risk of sudden cardiac death, fatal coronary heart disease, fatal cardiovascular disease, and all-cause mortality. Speculation turned to heat shock proteins and the role of FOXO3, and this was quickly repeated as though it were scientific fact; e.g., here.

If there’s one thing that docs like Dr. Gottfried do, it’s to take preclinical findings from in vitro and animal experiments and to extrapolate them beyond breaking. Then they write self-help books. It’s a far easier way to become famous and make money than actually doing the boring experiments required to confirm a hypothesis. If they can somehow invoke epigenetics, so much the better. “Quantum” medicine is so…1990s.