Video Blog: Discussing Recent Criticisms of Biological Age Clocks
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By the end of 2020, the majority of health practitioners in North America will know what a plasmalogen is. Decades of data show that low plasmalogen levels have severe health effects and that plasmalogen supplementation has positive health effects. November 2019 marks the first time a synthetic plasmalogen has been used in humans: six adults took a dose of our Prodrome-Neuro Plasmalogen Oil supplement and blood plasmalogen levels successfully increased by over 50% after 12 hours and were maintained for 24 hours in every person1.
What are Plasmalogens?
Plasmalogens are a special type of phospholipid. They are found in high concentrations in the brain and heart. Plasmalogens are not some trace nutrients, they actually build a big part of the brain, as much as 20% of the dry weight.
Plasmalogens act as a reservoir for important fatty acids including oleic acid, arachidonic acid, and docosahexaenoic acid (DHA)2. Plasmalogens are anti-inflammatory, are powerful antioxidants, are a critical part of cell membranes, maintain optimal brain function, and are a major structural part of lipoproteins, myelin, and synaptic membranes3.
Plasmalogen levels in the brain increase up to 30 to 40 years of age and then significantly decrease by around 70 years of age4. There are no adequate food sources. The body makes plasmalogens in the peroxisomes of cells; the majority are made in the liver. The body’s ability to make plasmalogens becomes impaired as peroxisome function is compromised with age and plasmalogens are degraded from inflammation and oxidative stress.
Why are low levels of plasmalogens bad?
There is no question that plasmalogens are important for health. But what about having low levels of plasmalogens – just how bad can it be? I have made a lot of graphs in my career and only one graph has actually scared me: the relationship between blood plasmalogen levels and death (Figure 1).
Plasmalogens and Death.
Figure 1. Probability of dying in 5.3 years
Data from the Rush University Memory and Aging Project. Final dataset: 1262 participants, participants still living since last clinical visit = 896, participants deceased since last visit = 862. Average age at enrollment = 81. Low plasmalogens = 5th percentile +/- 95% CI. High plasmalogens = 95th percentile +/- 95% CI.
Data from the Rush University Memory and Aging Project showed that a 95 year old with high plasmalogen levels had the same chance of dying in five years as a 65 year old with low plasmalogen levels. A 95 year old with high levels had an almost 70 percent chance of living to their 100th birthday whereas a person the same age with low plasmalogen levels had a less than 20 percent chance of living to their 100th birthday5. These results were shocking.
Plasmalogens and neurodegeneration.
Plasmalogens are involved in several diseases. I have studied plasmalogens since 2006 when I first discovered and hypothesized about the role of plasmalogens in the cause of dementia6. Since then, research evidence has expanded to show that plasmalogens are part of the root cause of neurodegeneration that leads to Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.
Most published data available is for plasmalogens and dementia. Plasmalogen deficiency is associated with cognitive impairment and Alzheimer’s disease3, 6, 7. The severity of dementia correlates with the severity of plasmalogen deficiency, irrespective of APOE allele status which is the second biggest risk factor for Alzheimer’s disease after age3,7.
Why do we get low levels of plasmalogens?
The body makes a lot of plasmalogens and consumes a lot. Plasmalogen deficiency occurs when the body can no longer make as much as it consumes. This can happen due to increased oxidative stress which degrades plasmalogens8 or decreased biosynthesis caused by aging and chronic exposure to xenobiotics9.
Plasmalogens and the cause of diseases.
What happens when there are not enough plasmalogens in the body? Plasmalogens have both structural and functional roles in the brain. Plasmalogen deficiency leads to cell membrane changes in structure, geometry, and function as the body is forced to substitute other molecules such as phosphatidylethanolamines3 in place of plasmalogens. This leads to cellular signaling abnormalities and neurotransmission deficits as well as lowered antioxidant defenses10.
Inflammation can lead to a vicious cycle where oxidative stress degrades plasmalogens which further reduces the anti-inflammatory and antioxidative capacity of the tissues ultimately leading to clinical symptoms of disease11.
Alzheimer’s disease.
Alzheimer’s disease results from neurodegeneration of neurons responsible for cognition: cholinergic neurons. Cholinergic neurons are especially sensitive to decreased membrane fusion activity caused by plasmalogen deficiency because, unlike other neurons, membrane fusion is necessary for both neurotransmitter release and re-uptake. Reduced membrane fusion reduces neurotransmission which reduces cognition.
Parkinson’s disease.
Parkinson’s disease results from neurodegeneration of neurons responsible for fine motor control: dopaminergic neurons. The direct cause of Parkinson’s is unknown, but some environmental neurotoxins selectively target dopaminergic neurons and cause Parkinson’s in animals. Plasmalogen deficiency increases susceptibility to neurotoxins.
Multiple sclerosis.
Multiple sclerosis results from neurodegeneration of cells that insulate neurons: myelin or oligodendrocytes. Myelin has the highest concentration of plasmalogens in the whole body. When immune cells are activated to clean up a mess (inflammation), part of the myelin can be damaged and extra plasmalogens are needed to repair the cells before they die. If cells cannot be repaired before they die, the debris creates even more inflammation and degeneration. High levels of plasmalogens prevents demyelination by improving remyelination.
Plasmalogens to prevent disease.
Plasmalogens prevent neurodegeneration in animal models; the majority of the publications are for Parkinson’s disease. In a mouse model of Parkinson’s disease, an oral dose of plasmalogen at 50mg/kg was fully neuroprotective. Several publications demonstrate the neuroprotective12 and anti-inflammatory properties in mouse and monkey models of Parkinson’s disease13,14,15,16
Our natural, scientifically designed plasmalogen supplement.
Our Prodrome-Neuro Plasmalogen Oil supplement is a synthetic, natural plasmalogen precursor that survives the gut and is then converted to the target plasmalogen molecule independent of peroxisomal function.
I first designed and invented a series of plasmalogen drugs because at the time there was a patent protecting the use of natural plasmalogens for dementia which just expired last year. I have since designed and developed our natural plasmalogen supplement, Prodrome-Neuro, that has the same activity as my previously invented PPI-1011 plasmalogen drug.
Next steps.
We are taking pre-orders of Prodrome-Neuro Plasmalogen Oil as we complete regulatory requirements to offer Prodrome-Neuro for personal use; it is currently available for research use only. Several studies are ongoing to support dosing and demonstrate tissue levels and safety.
Enrollment begins in 2020 for a clinical trial funded by the Alzheimer’s Association to use Prodrome-Neuro Plasmalogen Oil in Alzheimer’s patients. Our goal is to expand the clinical trial to Parkinson’s disease and multiple sclerosis patients.
It’s clear.
While we continue to advance research on plasmalogens to answer important questions about the use in disease management, one thing is clear today: plasmalogens are an essential brain nutrient you do not want to be low on. Our scientifically designed, natural plasmalogen supplement ensures there is an adequate amount of plasmalogens in the blood supply for health.
Visit the pre-order page to learn more about our Prodrome-Neuro Plasmalogen Oil supplement, or visit the Prodrome Sciences website to learn more.
Prodrome Sciences
Temecula, CA
1-951-296-3130
erika@prodromesciences.com
www.prodromesciences.com
Follow us on social media to keep up to date:
Start experimenting today! Our product is available for research use only and the more research supporting plasmalogens the better. Contact us for more information.
And most importantly, help us spread the word about plasmalogens so this dangerous deficiency is no longer off the radar of health professionals!
References:
- Hall C, Hamalainen M, Goodenowe D, Hodges B, Kapahi P, Perrott K. Tracking the human metabolome, proteome, and transcriptome in aging users with genetic risks. Presented At: Bay Area Aging Meeting, Buck Institute for Research on Aging, Novato, CA.
- Han X. Lipid alterations in the earliest clinically recognizable stage of Alzheimer’s disease: implication of the role of lipids in the pathogenesis of Alzheimer’s disease. Curr Alzheimer Res. 2005 Jan;2(1):65-77. Review. PubMed PMID: 15977990.
https://www.ncbi.nlm.nih.gov/pubmed/15977990 - Senanayake V, Goodenowe DB. Plasmalogen deficiency and neuropathology in Alzheimer’s disease: Causation or coincidence? Alzheimers Dement (N Y). 2019 Oct 4;5:524-532. doi: 10.1016/j.trci.2019.08.003. eCollection 2019.Review. PubMed: 31650009; PubMed Central PMCID: PMC6804645.
https://www.ncbi.nlm.nih.gov/pubmed/31650009 - Rouser G, Yamamoto A. Curvilinear regression course of human brain lipid composition changes with age. Lipids. 1968 May;3(3):284-7. PubMed PMID: 17805871.
https://www.ncbi.nlm.nih.gov/pubmed/17805871 - Goodenowe D, Naseri M, Senanayake V. 2016. APOE Genotype, Serum Plasmalogens, Cognition and Mortality. Presented At: Alzheimer’s Association International Conference, Toronto, Canada.
- Goodenowe DB, Cook LL, Liu J, Lu Y, Jayasinghe DA, Ahiahonu PW, Heath D, Yamazaki Y, Flax J, Krenitsky KF, Sparks DL, Lerner A, Friedland RP, Kudo T, Kamino K, Morihara T, Takeda M, Wood PL. Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer’s disease and dementia. J Lipid Res. 2007 Nov;48(11):2485-98. Epub 2007 Jul 30. PubMed PMID: 17664527.
https://www.ncbi.nlm.nih.gov/pubmed/17664527 - Goodenowe DB, Senanayake V. Relation of Serum Plasmalogens and APOE Genotype to Cognition and Dementia in Older Persons in a Cross-Sectional Study. Brain Sci. 2019 Apr 24;9(4). pii: E92. doi: 10.3390/brainsci9040092. PubMed PMID: 31022959; PubMed Central PMCID: PMC6523320.
https://www.ncbi.nlm.nih.gov/pubmed/31022959 - Jenkins CM, Yang K, Liu G, Moon SH, Dilthey BG, Gross RW. Cytochrome c is an oxidative stress-activated plasmalogenase that cleaves plasmenylcholine and plasmenylethanolamine at the sn-1 vinyl ether linkage. J Biol Chem. 2018 Jun1;293(22):8693-8709. doi: 10.1074/jbc.RA117.001629. Epub 2018 Mar 12. PubMed PMID: 29530984.
https://www.ncbi.nlm.nih.gov/pubmed/29530984 - Terlecky SR, Koepke JI, Walton PA. Peroxisomes and aging. Biochim Biophys Acta. 2006 Dec;1763(12):1749-54. Epub 2006 Aug 23. Review. PubMed PMID: 17027095.
https://www.ncbi.nlm.nih.gov/pubmed/17027095 - Braverman NE, Moser AB. Functions of plasmalogen lipids in health and disease. Biochim Biophys Acta. 2012 Sep;1822(9):1442-52. doi: 10.1016/j.bbadis.2012.05.008. Epub 2012 May 22. Review. PubMed PMID: 22627108.
https://www.ncbi.nlm.nih.gov/pubmed/22627108 - Su XQ, Wang J, Sinclair AJ. Plasmalogens and Alzheimer’s disease: a review. Lipids Health Dis. 2019 Apr 16;18(1):100. doi: 10.1186/s12944-019-1044-1. Review. PubMed PMID: 30992016.
https://www.ncbi.nlm.nih.gov/pubmed/30992016 - Miville-Godbout E, Bourque M, Morissette M, Al-Sweidi S, Smith T, Mochizuki A, Senanayake V, Jayasinghe D, Wang L, Goodenowe D, Di Paolo T. Plasmalogen Augmentation Reverses Striatal Dopamine Loss in MPTP Mice. PLoS One. 2016 Mar 9;11(3):e0151020. doi: 10.1371/journal.pone.0151020. eCollection 2016. PubMed PMID: 26959819.
https://www.ncbi.nlm.nih.gov/pubmed/26959819 - Nadeau J, Smith T, Lamontagne-Proulx J, Bourque M, Al Sweidi S, Jayasinghe D, Ritchie S, Di Paolo T, Soulet D. Neuroprotection and immunomodulation in the gut of parkinsonian mice with a plasmalogen precursor. Brain Res. 2019 Dec 15;1725:146460. doi: 10.1016/j.brainres.2019.146460. Epub 2019 Sep 13. PubMed PMID: 31525350.
https://www.ncbi.nlm.nih.gov/pubmed/31525350 - Bourque M, Grégoire L, Di Paolo T. The plasmalogen precursor analog PPI-1011 reduces the development of L-DOPA-induced dyskinesias in de novo MPTP monkeys. Behav Brain Res. 2018 Jan 30;337:183-185. doi: 10.1016/j.bbr.2017.09.023. Epub 2017 Sep 14. PubMed PMID: 28917506.
https://www.ncbi.nlm.nih.gov/pubmed/28917506 - Miville-Godbout E, Bourque M, Morissette M, Al-Sweidi S, Smith T, Jayasinghe D, Ritchie S, Di Paolo T. Plasmalogen precursor mitigates striatal dopamine loss in MPTP mice. Brain Res. 2017 Nov 1;1674:70-76. doi: 10.1016/j.brainres.2017.08.020. Epub 2017 Aug 19. PubMed PMID: 28830769.
https://www.ncbi.nlm.nih.gov/pubmed/28830769 - Grégoire L, Smith T, Senanayake V, Mochizuki A, Miville-Godbout E, Goodenowe D, Di Paolo T. Plasmalogen precursor analog treatment reduces levodopa-induced dyskinesias in parkinsonian monkeys. Behav Brain Res. 2015 Jun 1;286:328-37. doi: 10.1016/j.bbr.2015.03.012. Epub 2015 Mar 11. PubMed PMID: 25771209.
https://www.ncbi.nlm.nih.gov/pubmed/25771209
Dr. Dayan Goodenowe
Founder and CEO, Prodrome Sciences
PhD, Medicine
PhD, Medicine
Dr. Goodenowe invented a technology platform in 1999 that has been used to analyze thousands of human samples from around the world. Through collaborations with international researchers and doctors, Dr. Goodenowe has become an expert on the biochemical basis of neurological diseases including Alzheimer’s, Parkinson’s, multiple sclerosis, autism, bipolar disorder, and schizophrenia. Prodrome Sciences uses Dr. Goodenowe’s technology and discoveries to develop blood tests and dietary supplements for the early detection and prevention of disease.
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While this is interesting, the study sited suggests 50mg/Kg. Yet this company sells a product that states the dose is 900mg per day. For a 200 lbs American (the new normal) the studies does would be in excess of 4500mg per day. Can the author help us understand this discrepancy?
Thanks, DrS we will reach out for a response-
DrKF
Hello Dr S,
Plasmalogens have been used in several animal studies at various dosages ranging from 10-200mg/kg. You are correct that in some animal studies, the lowest dose used was 50mg/kg. As a dietary supplement, 10mg/kg is sufficient to raise blood levels, as demonstrated in published papers (see figure 5: https://www.ncbi.nlm.nih.gov/pubmed/22142382) and we have preliminary confirmation in humans with further studies planned.
In a mouse model of Parkinson’s, 10mg/kg and 50mg/kg were both able to prevent MPTP’s neurotoxic effects when given only for five days prior (https://www.ncbi.nlm.nih.gov/pubmed/26959819) making a lower dose of 10mg/kg (about 900mg) suitable for preventative dietary supplement purposes.
In the same study, when the plasmalogen was administered after the neurotoxin MPTP, only the higher 50mg/kg dose prevented effects within 5 days. What remains unanswered is what effect the lower dose (10mg/kg) would have had when given for a longer duration after MPTP – at a lower dose it takes longer for levels to increase. We anticipate that health practitioners will have to determine a loading dose phase for individuals already suffering from neurodegeneration that could later be reduced to a regular maintenance dose. Further studies are needed.
What about measuring blood levels in the clinical setting? Are you aware of a lab offering such testing outside of research? We routinely measure the major fatty acid classes: PUFA3 PUFA6, MUFA, SFA. As you suggest, looking at phospholipid subclasses could be useful. DrKF
We hope to have our plasmalogen test available for clinical use by September 2020 as it is only available for research use right now. Unfortunately there are no labs that test for plasmalogens.
Very interesting idea. While it’s clear this is a vital nutrient to maintain, this is somehow reminiscent of vitamin D, or cholesterol… We see disease states with associated serum increases and decreases; we have agents to lower/raise levels, but the actual disease progression/prevention seems less affected. Is there actual human evidence showing that if we exogenously raise these plasmalogens, we can expect a reversal/prevention of disease state?
Hi Jack, the short answer to your question is that no, there is no human evidence on exogenously raising plasmalogens and disease prevention/reversal. There is no evidence because there have been no studies – the only plasmalogen supplements available until now have been very low dose (0.5-15mg compared to our 900mg) and have not been shown to actually raise blood plasmalogens. Our Prodrome-Neuro plasmalogen supplement has only been available for a couple of months and it will enter a clinical trial in Alzheimer’s patients in 2020 funded by the Alzheimer’s Association.
Your question is a very good one because it strikes at the heart of all intervention-based science: How do you scientifically go from a disease-biomarker association to the treatment or prevention of disease? There are 3 steps in this process:
1) The first step is to fully understand the association and to make sure that the association is real and not an artifact of some other biomarker association.
2) The second step is to identify the precise biochemical mechanisms to explain the clinical observations. For plasmalogens there are three well documented mechanisms that explain the human observations. Lower brain amyloid levels in persons with high plasmalogens is due to increased amyloid precursor processing through the non-amyloidogenic alpha-secretase pathway; the increased HDL levels in persons with high plasmalogens is due to increased cholesterol esterification and export via increased sterol-O-acetyltransferase activity; the increased cognition in persons with high brain plasmalogens is due to increased membrane fusion.
3) The final step is to either remove or enhance plasmalogen levels and measure the effect of these interventions. In humans, there is a rare disease called Rhizomelic Chondrodysplasia Punctata. Children born with this disease have a genetic mutation that specifically impairs the ability of a key enzyme responsible for the production of plasmalogens. These children have severe neurological impairments and a dramatically reduced lifespan. The prognosis of the disease is correlated to the amount of residual plasmalogen production in the patient. Clearly the body needs plasmalogens and they cannot be replaced by other phospholipids. In animal models of neurodegeneration, normal plasmalogen levels are insufficient to prevent demyelination in mice exposed to cuprizone or degeneration of neurons in mice exposed to MPTP. However, if the normal levels of plasmalogens in these mice are elevated using a plasmalogen precursor, the mice are protected from neurodegeneration. So, mice with exogenously elevated plasmalogens experience reduced neurodegeneration the same way that humans with naturally high levels of plasmalogens experience reduced neurodegeneration.
We have designed Prodrome-Neuro as a natural and safe dietary supplement such that direct evidence regarding the effects of elevating blood plasmalogens on multiple human diseases can proceed in both controlled and open (observational) clinical trial settings. Our goal is to provide a safe and economical supplement that can reproducibly and unambiguously elevate blood plasmalogen levels so that individuals and clinical researchers can perform the scientific studies needed to more fully understand the roles of plasmalogens in human health and longevity.
Can anyone please advise whether Plasmalogen interacts in a negative way with Epilim(sodium valproate). My wife has dementia and epilepsy. We have juts started to take Plasmalogen oil and she had a seizure after 3 years of being seizure free. Is it juts a coincidence or could it be brought on by the Plasmalogen?
I cannot comment specifically because of the limited data on drug interactions with Plasmalogen therapy and its composition we wouldn’t expect an interaction. But because of Epilim’s narrow therapeutic window, there might be an indirect impact. It’s challenging to say for sure, and I can’t rule out coincidence or possibly other factors either.