0:30 Julie – Welcome to Dr Dayan Goodenowe, founder and CEO of Prodrome Sciences. In 1999 he invented a technology platform that’s been used to analyze thousands of human samples around the world. Through collaboration with international researchers and doctors, Dr Goodenowe is an expert on the biochemical basis of neurological diseases, including Alzheimer’s, Parkinson’s, Multiple Sclerosis, autism, bipolar disorder, and schizophrenia. He is an inventor of numerous patents, an author of numerous scientific publications, and an international speaker. He is passionate about demystifying science for accessibility to everyone. Dr Goodenowe has developed blood tests and dietary supplements designed for individualized health optimization which he believes is the key to disease prevention and longevity. Dr Goodenowe has been working with ApoE4 community for about 2 years now.
3:12 Dr G – The ApoE4 community is unique with some members who are very well informed, similar to other communities with genetic or special needs. The scientific community is conservative, but individuals of a specific community can become experts at their own disorder/issue, more so than the scientists because they can follow different rules.
7:08 Julie – It is also a good thing when researchers recognize the importance of partnering with patients to find our own cure. We have skin in the game. We’re trying to save our own lives. N=1 rules.
7:51 Dr G on his background – Chemistry and biochemistry, then further into neurochemistry and psychiatric disease in terms of the neurobiology and the neurochemistry of the brain. Also agriculture as a farm boy from Canada. A synthetic and organic chemist.
8:27 Dr G – There are three main levels of organization: biology, chemistry, and physics.
9:59 Dr G – From a human perspective everything comes down to chemistry. Chemistry is what we have most control and power over.
10:58 Dr G – We are fundamentally biochemical reactors. We convert carbohydrates, proteins, and fats into small molecules, and those small molecules get circulated through the body and they keep us alive. For a great period of our life, this works very well. We have a good prototype for what good health is.
12:23 Dr G – All organisms have a genotype, that genotype drives structure and all the proteins in the body come from the genome. Our organizational structure can be broken into three categories:
- the genome (the genetic material of an organism),
- the proteome (the entire set of proteins),
- the metabolomics (the small molecules)
13:36 Dr G – The genome is like the city planning map, it gives limits of what the city can achieve. One can look at a map and see traffic problem areas, where the constraints are, based on the structure, not even looking at the cars on the roads.
14:30 Dr G – The proteins (proteome) are like the actual roads. For example, other genomes have 6 lane freeways for carrying cholesterol, but ApoE4s have 3 lane freeways for carrying cholesterol, which at 3 o’clock in the morning is fine, but at rush hour is inadequate.
15:36 Dr G – Small molecule chemistry, i.e. metabolomics, is measuring the cars on the road, which is unrelated to the genome or proteome. By measuring the actual activity we see what is really happening. At 3 o’clock in the morning, we have complete functionality, the predisposition of a constrained freeway isn’t a problem at that hour. However, at rush hour this changes, metabolomics measures that. During rush hour, ApoE4s have cars on side streets where they shouldn’t be. Upon such an observation, one can work back as to why something happens, that’s what metabolomics does, and we can work to optimize our biochemistry.
18:30 Julie – So you think the reduced cholesterol transport is our biggest issue?
18:38 Dr G – It is the biochemical mechanism of the ApoE4 protein. It can cascade into other systems, but that is fundamentally the core biochemical difference. That may translate into different things.
19:20 Dr G – As with all genetic predispositions, it’s a matter of identifying what your predispositions are or what your optimal space is, and upon finding your optimal space, keeping it there.
19:30 Julie – Metabolomic testing gives us a snapshot of our current state of functioning to manage our health. Talk about plasmalogens and ApoE4.
20:08 Dr G – With genetics we can sequence the genome and the basis of the genome translates into proteins. So when the proteomics of the ApoE4 genotype is measured it can be mapped it back to the genome. Metabolites are not genome dependent. In order to make headway with the biochemistry, I had to find a way to measure thousands and thousands of small molecules simultaneously. That was the core technology that I invented, called non targeted metabolomics. This allows taking a blood sample or any biological sample and measure thousands of small molecules under different conditions. When implemented in clinical trials around the world what kept coming up in the cognitive studies and Alzheimer’s studies was that plasmalogens were lower in those with cognitive impairment. The lower the plasmalogen level, the more severe the cognitive impairment. The association was powerful. The original association with plasmalogen was with cognition, but then it became clear it was also associated with other neurological disorders: stroke, Parkinson’s, ALS, schizophrenia, bipolar disease.
23:02 Julie – Plasmalogens are also correlated with lower overall mortality
23:09 Dr G –Yes, but we need to be careful, the tendency is when we find one association we get obsessed.
24:23 Dr G – Plasmalogen is a critical component of neuromembranes. It has three critical functions that work together or in isolation depending on the individual. One is membranes of the whole body. The human body is made up of trillions of cells. These cells are 3 dimensional, like a building with walls, without the cellular structure we’d just be soup. What defines the cells of the body is the phospholipid bilayer, the lipids that make up the structure of the cell walls. There are the organelles inside the cells, like mitochondria and peroxisomes, and they have membranes around them too. As membranes become stiff or more restrictive, the proteins that work in those membranes have to change their biological activity. When they change their biological activity, they compensate. That’s what’s happening in ApoE4s in terms of amyloid. The impaired ability for ApoE4 to export cholesterol out of membranes ends up with an excess cholesterol composition within the membranes and that increased cholesterol causes the membranes to be stiffer. When they’re stiffer, the enzymes that process amyloid, the amyloid precursor protein, shifts the equilibrium to the bad protein which is the beta-secretase from the good protein which is the alpha-secretase. So when you shift to more beta, you get amyloid formation. Since ApoE4s have a predisposition to reduced cholesterol clearance, then there’s a predisposition for increased amyloid. The amyloid is a biomarker of impaired membrane structure which leads to impaired neurological function.
28:10 Dr G – So of the three things, one is that the plasmalogens are critical for membranes: membrane fluidity and membrane structure and function.
28:19 Dr G – The second one, which is why the association with cognition, is that plasmalogens are also involved in a specific membrane function, the vesicular release of neurotransmitters. Our neurons are a biochemical circuit board, in order for signals to pass from one neuron to another neuron, the communication is biochemical, they have to be released into the synaptic cleft and the release of neurotransmitters is dependent on plasmalogen composition.
29:19 Dr G – The third is that plasmalogens are very powerful antioxidants and free radical scavengers. By orders of magnitude they scavenge more free radicals and oxidative stress than all other antioxidants in the body combined. We make a lot of plasmalogens, it’s about 20% of the brain, we have high concentrations in the heart, lungs, kidneys, retina. In addition to making a lot, we use a lot. It is designed to protect other molecules. Ordinarily, we have the ability to make a lot of them, but over time, and with other diseases, at some point our ability to make plasmalogens can become less than what we need. Once that is out of balance, the plasmalogens deplete.
31:25 Julie – Tell us about plasmalogens in the ApoE genotype, ApoE2s have high plasmalogens versus ApoE4s have lowest levels of plasmalogens?
31:57 Dr G – There is no association between ApoE genotype and plasmalogen levels. The association is that the risk of dementia is dependent on the plasmalogen level. An ApoE4 carrier with high plasmalogens does not have increased risk of dementia, the high plasmalogens are protective. It’s the level of plasmalogens that’s required for that protection which is dependent on the genotype. So if a person is an ApoE3 carrier, the level needed for protection is, strictly for illustration, say 50. If the individual is an ApoE4 carrier that level might be 80 and if an ApoE2 carrier it might be 30. The key point is how many plasmalogens you need is dependent on your genotype. An ApoE4 carrier needs higher levels of plasmalogens than an ApoE2 carrier.
34:14 Julie – An ApoE4 homozygote (ApoE4/4) might need even more plasmalogen?
34:19 Dr G – Exactly
34:20 Julie – Your metabolomic testing can show us what our plasmalogen levels are, what about surrogate biomarkers?
34:38 Dr G – Plasmalogens are made in the peroxisomes of our body. If you have high HDL and low triglyceride levels, that’s usually an indicator of good plasmalogen levels. The plasmalogens are transported on HDL particles in the body. There’s a correlation, those with high plasmalogens have high HDL. I typically ignore LDL. Folks with good peroxisomal function have higher levels of both HDL and LDL. Cholesterol is made from molecules in the peroxisome. People who have good functioning peroxisomes will have naturally higher levels of cholesterol, usually the good cholesterol, HDL. Peroxisomes also consume triglycerides. The essential fatty acids, DHA and EPA, act as peroxisome stimulators and one of the outcomes is reduced triglyceride levels. When someone has high triglyceride levels it usually means someone has reduced peroxisomal function. You can infer that if you can get fasting triglyceride levels low naturally, not through drug use, you will aid peroxisomal function. Artificial changes in certain biomarkers don’t actually change the underlying function, the drugs just change the results of the biomarker test. If diet and lifestyle results in naturally low triglycerides and naturally high HDL, you can infer that you are optimizing plasmalogen levels. Also resistance training can build plasmalogen levels.
38:04 Julie – Resistance not aerobic?
38:09 Dr G – Absolutely, especially in the elderly. There’s a balancing act. We’ve seen anecdotal evidence of low plasmalogen levels in super athletes. You can overdo it, positive effects of the exercise are offset by the negative effects. Exercise does create oxidative stress. You want a balanced exercise routine, especially in the elderly, where you’re stimulating the growth and biochemistry of the muscles, but not overdoing it. The other part is a low inflammatory diet to reduce the body’s consumption of plasmalogens. So you want to increase plasmalogen production by increasing peroxisomal function and you want to decrease the consumption of plasmalogens by making sure your body has other anti-inflammatory antioxidant capacity to help carry the weight of the plasmalogens.
39:33 Julie – Can you describe a diet that would promote healthy plasmalogen levels?
39:43 Dr G – Before designing and manufacturing a supplement, I had my dad on such a diet. He has plasmalogens in the 85th to 90th percentile and he’s in his 80s. He has higher functionality now than 20 years ago. His routine: moderate resistance training 3 – 4 times a week, and stimulating peroxisomal function with Omega-3, mostly DHA, supplementation, and then reducing oxidative stress through natural supplements like Coenzyme Q10, acetylcysteine, and acetylcarnitine. No overdosing of those, just enough. We know you can’t overdose plasmalogens.
42:00 Julie – Was there a specific diet that you had your dad on?
42:11 Dr G – Just the basic ingredients, we’re farm boys, basic meat and potatoes diet, eggs and vegetables too, trying to keep the processed carbohydrates down. Basically a mini-paleo, balanced diet.
42:45 Julie – The meat and eggs are good sources of choline which is very important.
42:48 Dr G – That’s one of the main deficiencies we find in people. Even people that have a diet that looks like it has enough choline can still be choline deficient. Choline supplementation or ethanolamine supplementation, we need both of these in our diet. You can’t make ethanolamine, you have to get it in your diet, choline we can make, but the energy needed to make choline is quite high. We’re learning more about supplementation in the longevity space. My thinking has moved from disease focus to optimized function focus. We’re preprogrammed to look at the bad and to try to fix the bad, we think of everything as a disease. We’re moving away from this disease focus.
44:53 Julie – That’s what your testing allows us to do. It allows us to intervene in that prodromal period. Tell us about the supplement you created.
45:26 Dr G – So with plasmalogens, we saw this powerful correlation with neurological disease, especially Alzheimer’s and cognition. So the next step was to ask how do we get more of them? In theory we should be able to eat them.
46:18 Julie – There are clinicians who recommend that, they recommend ApoE4s eat lots of shellfish because they’re high in plasmalogens. Does that work?
46:30 Dr G – It does to a certain degree. The reality is this vinyl-ether bond of plasmalogen has a special quality that gives it its very potent antioxidant and free radical scavenging capabilities but the downside is when exposed to acid it gets broken down to an aldehyde. If you consume high levels of plasmalogen in your diet, you’re generating toxic aldehydes, because the stomach acids will convert the vinyl-ether bond, which is why we can’t absorb much through diet. Some plasmalogens have the ether bond, not the vinyl-ether bond, and those plasmalogens make it through the food supply, but that’s not the majority. So from a chemistry perspective, we had to design a molecule that would survive the gut. It’s bioidentical, but instead of the vinyl-ether bond it has the ether bond so that it’s stable in the gut. Also, not all plasmalogens are the same, we want the Omega-3 plasmalogens, we want the DHA plasmalogen. It’s the phospholipid DHA that’s important, but you can’t get phospholipid DHA from the diet.
48:32 Julie – Dr Rhonda Patrick a theory that DHA in phospholipid form is preferential for ApoE4 carriers to get DHA to the brain, she recommends salmon roe caviar.
48:54 Dr G – Nothing in the body is completely absolute, but we’re designed to eat animals and plants and convert that in to what the body can use. Our digestive tract has a number of enzymes and processes to ensure just the critical components enter our system. On triglycerides, fats are triglycerides meaning they have a glycerol backbone with three fatty acids. Triglycerides don’t get absorbed into the body, they need to get processed first. First one fatty acid at the sn-1 position is taken off, then the second fatty acid at the sn-3 position is taken off, leaving a monoacylglyceride which is what is absorbed into the bloodstream to circulate in the body. The liver puts the fatty acids back on to send to the adipose tissue. The triglycerides in an Omega-3 fish oil supplement is going to have DHA on a triglyceride backbone, but the triglyceride doesn’t go in the body, the monoacylglyceride does.
51:05 Dr G – Phospholipids are metabolized differently. When you eat phospholipids from the food supply the phospholipase cleaves off the sn-2 position which is where the DHA is, the fatty acid that you want. You absorb what is called a lysophospholipid, it doesn’t contain DHA. Generally, we’re not getting DHA phospholipid from the food supply.
51:55 Dr G – We want to get the DHA Omega-3 on the plasmalogen phospholipid in the blood stream. So we designed a molecule to do that. It is metabolically engineered based on human biochemistry. The molecule we designed for a supplement is an alkylglycerol, it’s like a triglyceride only it has the plasmalogen bond at the sn-1 position which is stable in the gut.
52:35 Dr G – The second big difference is we put the DHA molecule at the sn-2 position. Unlike a triglyceride where a monoacylglycerol is being absorbed, in a triglyceride the sn-1 and sn-3 positions are the same. But in a plasmalogen glyceride, as in my plasmalogen supplement, the sn-1 position has the ether bond. This means instead of a monoacylglycerol being absorbed in the blood, the DHA at the sn-2 position is absorbed. That gets directly converted into a phospholipid and that DHA is conserved through the biochemistry of the body.
53:25 Julie – Have you tested humans with your supplement to see if their plasmalogen levels are increasing?
53:35 Dr G – Yes. We can double plasmalogen levels in 24 hours. We have measured several people. Six of us did a formal trial and we doubled our plasmalogen levels of the target, DHA. The plasmalogen supplement is a high concentration of Omega-3s, DHA, and a little EPA and that converts directly into DHA plasmalogen.
54:26 Julie – How much did you have to take?
54:28 Dr G – We took a higher dose, we took 100 mg per kilogram which was about 10 mils. We sell the bottle as a 30 mil bottle, a month’s supply, so our dose worked out to be about a third of a bottle.
54:45 Julie – You’re a brave man.
54:47 Dr G – It’s just oil, not a big deal.
54:50 Julie – I say that because I’ve tasted it.
54:55 Dr G – It does taste horrible.
55:03 Julie – I think the taste is improving, is that my imagination?
55:07 Dr G – It’s not your imagination. The next batch you’ll love. We just went to a 100% vegan supply. The problem is there’s no efficient way of chemically making DHA, so we rely on food sources. The classic source is from fish products. We’ve been able to source a high purity algae source. The next round of product should have zero fish taste or smell and have a little bit higher DHA concentration.
56:50 Julie – We mentioned before we’ve been working together allowing our members to use your metabolomic testing. We hope to make an announcement in the near future as well as incentivized pricing and packaging. We’re also using a software platform to capture data points. We want to help members of our community do self-directed research. Members could get a baseline, use the plasmalogen supplement for a couple months and then retest for results.
57:45 Dr G – We’re a huge supporter of N of 1 work. We believe ultimately human health will benefit from average users sharing their experiences, systematically improving their biochemistry. You can’t fix what you don’t know. You need to know what to fix before you get sick. Let’s not wait for disease to occur.
58:42 Julie – For listeners who want to get the metabolomic testing and supplement right away, go to this Dr Goodenowe’s website, prodromesciences.com. If an ApoE4 carrier, when you place your order, please note that you want to join our group project once it’s launched, we think we’re close to launching.
59:40 Dr G – I want to demystify biochemistry, people should feel they have the power to do this. If you get the biofeedback as well as a visceral feeling of feeling better, this gives a sense of empowerment. Changing diet and behavior is hard work. People need positive feedback, it’s hard to maintain positive behavior. People have the power to control a lot of variables. If you get the biochemical feedback early on, it helps a person to maintain a program. Sometimes the physical symptomatic observation lag behind the biochemical changes.
1:02:06 Julie – I am part of a small group who got to try your supplement, I was surprised at the number of people who felt almost an immediate difference.
1:02:25 Dr G – We’ve got trials going on around the world right now. In people with cognitive impairment, 100% of their caregivers are saying they’re seeing improvement in engagement, awareness, interaction, and cognition.
1:03:22 Dr G – With Alzheimer’s the idea of improvement is “out there”. Currently the approach is to reduce the rate of decline, no one talks about improving function. What we’re seeing is improved function, and what we want is to improve and sustain.
1:04:38 That’s what our community is trying to do. We see anecdotal, N of 1 evidence all the time. People change their lifestyle, diet, and take targeted supplements, they feel better, they feel cognitively sharper. It’s not a clinical trial, but we see it in hundreds and hundreds of our members. We’re with you, we believe cognition is much more fluid than researchers lead us to believe and it’s based directly on lifestyle factors which we have control over and metabolomics testing will allow us to measure.