#67 - AMA #8： DNA tests, longevity genes, metformin, fasting markers, salt, inflammation, and more
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Summary
In this episode, my analyst, Bob Kaplan, joins me to talk about my thoughts on DNA sequencing and aging. We talk about the benefits of DNA sequencing, inflammation, and inflammatory markers, and how they impact our ability to live longer.
Transcript
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Hey everyone, welcome to the Peter Atiyah Drive. I'm your host, Peter Atiyah.
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Welcome to AMA number eight, featuring once again, my head analyst, Bob Kaplan. In this episode,
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we talk about my thoughts on DNA and genetic kits, genes that can drive longevity, top guests that I'm
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hoping to have on future episodes of The Drive, inflammation and inflammatory markers, NMR lipoprofile
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versus other tests for advanced cardiac measurements. In addition to a conversation around
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the recently emerging use of electrophoresis, we talk about taking metformin for longevity,
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as well as a little side conversation around berberine. We talk about what drugs I think are
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the most exciting drugs on the planet today. We have a little conversation around salt,
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and we talk about markers and metrics that surprised me during my most recent nothing burger.
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So without further delay, please enjoy AMA number eight.
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Hi and hello, podcasters. Bob Kaplan here. Peter Atiyah over there. Let's light this candle.
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He's a little hot. Here we go. Are DNA kits useful in providing actionable info and any thoughts and
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information on using genetic testing to guide nutrition and exercise? I assume they're talking
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about like 23andMe, that type of SNP testing. I mean, I think we need to put this in a broader
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context, which is exactly 20 years ago, we were on the cusp of, and by we, I don't mean me. I
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specifically exclude myself from being a part of that.
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Yeah, exactly. We were on the cusp of what was hailed as perhaps the biggest revolution in all
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of medicine. It's one thing to certainly understand the structure of what DNA meant and how to
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understand the coding language and how DNA becomes a template to make RNA as the template to make
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protein. But 20 years ago, sitting there on the cusp of actually decoding the human genome, and we now
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know that there are, it depends. I mean, I used to typically nominally say 20,000 genes in the human
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genome. I think some would actually revise that upward and say maybe even closer to 30 now,
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but relatively finite number of genes. And it turns out that hasn't panned out. This notion that
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knowing the genome was going to change everything, it hasn't panned out. It hasn't panned out for several
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reasons. So first of all, most things that we concern ourselves with are either wildly polygenic
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or the only way you get the thing, either good or bad, is when the environment, for lack of a better
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word, turns on the gene. And so if we talk for a moment about the pathology side of things and use
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cancer as an example, this seemed to be the most interesting place where we would think that the
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genetic revolution would help and that by knowing your genes, you might know your susceptibility to
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a type of cancer. So I think the first thing we want to talk about here is the difference between
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somatic mutations and germline mutations. So the germline is the gene that you inherit. So when you
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do a test like a 23andMe, I think for the purpose of not getting too far in the weeds on this, this is
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actually worth a dedicated podcast. So maybe we can make note of that and just do a dedicated podcast
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on genetic testing because it is such an important topic. I'm not going to get into the difference
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between what a 23andMe is doing versus what a whole genome sequence is doing as far as the
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accuracy of it. So notwithstanding the huge inaccuracies that show up when you do these short
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kit SNP tests, what you're doing is looking at the template you inherited, hence germline. Now,
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there are some cancers that are driven by germline mutations. In other words, there are a subset of
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cancers where just knowing you inherited a certain gene dramatically increases your risk of that
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cancer. So the BRCA mutation would be an example of that. Lynch syndrome, which is an acquired
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genetic syndrome, would be an example of that, where all of a sudden you have one of these mutations and
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the probability that you're going to get cancer is very high. In the case of Lynch syndrome, it's
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virtually guaranteed you're going to get cancer. In the case of BRCA, it's not quite as high,
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but depending on which variant of it, it can be still quite high, probably approaches 80%
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with at least one variant. Would knowing that information be helpful? Oh my God, of course it
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would be helpful. As a general rule, unless you are adopted, you generally know that without a genetic
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test. That's how penetrant these things tend to be. So in other words, it's very unlikely that you show
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up and you're in your thirties or your twenties and you know your ancestry. So you know who your parents
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are and you know who your grandparents are and aunts and uncles, you're going to get a surprise
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on a genetic test by showing up with one of those syndromes. So the first thing I put on the back of
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my mind is patients who are adopted probably benefit from this. And I have a friend who was adopted
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and who got Lynch syndrome. And that was a real surprise to all of us because why was a guy in his
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early forties getting colon cancer? And especially the way he got colon cancer was very atypical
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in terms of the actual clinical presentation of the disease. And of course, because he was adopted,
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we don't know that clearly one of his parents also would have gone through this. But the probability
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that say you are listening to this and that you have this, it's very low. This is kind of a long
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winded way of saying that probably north of 95% of cancers are not germline mutations. They are
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somatic mutations. They are mutations that are acquired after you've received all of your genetic
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material. And I think we've known that for quite some time. We didn't need sort of the coding of
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the human genome to figure that out. But the problem is the current type of genetic tests that
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I think this question is asking about don't measure those mutations. You can't find those mutations
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in the DNA of the base cell. You have to look for those cells like a needle in a haystack. You're
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looking for those cells usually in the blood. And the good news is there are companies and technologies
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that are looking at these things. This belongs into a subheading of things called liquid biopsies
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where you could do a blood test. And in theory, you could find that needle in a haystack. You
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could find that cancer cell. You could say, well, wow, this is a colon cell and it has an acquired
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mutation. And that mutation is giving it the capability to escape the colon and take up residence
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somewhere else. So I think from the standpoint of cancer, I don't think there's a lot of value.
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From the standpoint of cardiovascular disease, I would also say very little value. The most
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important genetic test that you would look at from a heart disease standpoint would be
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LP little a, which we've spoken about at length. So if you have the LPA gene, which honestly
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somewhere between about eight and 12% of the population does, maybe even higher, that's
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important to know. But guess what? You don't need genetic tests to do that. You can just measure
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the phenotype, meaning you don't need to know if you have the LPA gene, you can actually
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measure LP little a. It's even easier to measure. So again, that sort of alleviates somewhat the
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need of knowing that. Now, whenever someone gets one of these tests, it tends to spit out
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a lot of information. Like you're at increased risk of heart disease. You're at increased
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risk of diabetes. I think this is an area where I probably differ from a lot of the current crop
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of people who love precision medicine. And I don't find that information very helpful.
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I think that if you go deep enough on the phenotypic side, you will get that information
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and you will get it in an even better way. And you will have a metric with which to track
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as you try to reverse the process. So taking diabetes for an example, does it help me to
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know that someone has a genetic predisposition to type two diabetes? Not nearly as much as it
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helps me to know while they are still non-diabetic, that they have hyperinsulinemia. And even if they
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don't have it while fasting, to know that they have postprandial hyperinsulinemia, it's very
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important. To look at other subtle markers of insulin resistance, the elevation of ferritin,
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some of the other things that we see, other patterns of glucose disposal, these things
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matter a lot more. Frankly, just wearing a CGM and knowing over the course of months how
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your glycemic response is, that is orders of magnitude more insightful and perhaps more
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importantly, more actionable. So I think the one place where I do think that the genetic information
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can be somewhat helpful is with Alzheimer's disease. I do think that knowing your ApoE status
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is quite an empowering thing. I think truthfully, I don't think it should change that much of what
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we do. In other words, even if you have an ApoE3 or an ApoE2, it should be a much lower risk gene.
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I wouldn't let that information in any way, shape, or form detract me from taking an all-hands-on-deck
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approach to avoiding dementia. As Richard Isaacson said when we had him on the podcast,
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if you have a brain, you're at risk of Alzheimer's disease. And so even though 25% of the population
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has ApoE4 positive gene, meaning they're either one or two copies of ApoE, and most of those 25%
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are single copy, they make up about two-thirds of the case of Alzheimer's diseases. But of course,
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that means 75% of people who don't have any E4 still make up a third of the cases. So in that sense,
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E4 is helpful if you need a little extra motivation to work harder. Again, it might be a little helpful
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if you're thinking about it through the lens of your kids. Should your kids play contact sports?
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We talked about this before where the susceptibility to head trauma could go up with an ApoE4. So maybe
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that causes you to think, we'll play tennis instead of soccer. One of the questions was about nutrition,
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I think, and exercise. And I got to tell you, I am still not convinced that we can extract much
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value vis-a-vis what we should be eating or how we should be tailoring our exercise from the current
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genetics. Now, there are probably some tests that are emerging that could be kind of interesting.
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There are probably certain genes in the PPAR family, for example, that might speak to our ability
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to metabolize fat, that might speak to whether or not we will do better or do worse on a certain type
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of diet. But I would counter that by saying, you can empirically determine that so easily that I'm
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not sure it's adding value. And even if you saw that you had a genetic predisposition to one diet
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or another, it still doesn't mean that that's going to work. You still have to go through the
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empirical step. So I think this is a long-winded way of saying, I'm just not over the moon excited
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about using sort of the current crop of genetic tests. Although we do it and virtually every one
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of our patients comes in the door with a genetic test, usually it's sort of one of these cheap kind
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of easy snip tests. Probably 10% of them still show up with the whole sequence. And we do the full
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analysis and we look at it, but it'll take me a while to remember the last time a piece of information
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emerged from that that made me change the way we were doing something, which doesn't mean it won't
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happen. It just means overall the yield is not that high and one should sort of calibrate their
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expectations for that. Well, along those lines, so another snip question, do you think those snips
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panels like 23andMe are useful for practice of longevity tactics? And what are the 8 to 12 genes
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that increase longevity that you always talk about? You can find all of this information and more
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at peteratiamd.com forward slash podcast. There you'll find the show notes, readings and links
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