Memory

Plasmalogens Week #6 – Health and Diseases, Part 2

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Continuing Part 1 with three 2025 papers, starting with a rodent study of dietary mussel plasmalogens’ effects on atherosclerosis:

“The purpose of this study was to clarify the underlying mechanisms of Mytilus edulis-derived plasmalogens (Pls) against atherosclerosis (AS) in ApoE−/− mice induced by a high-fat diet (HFD), through a comprehensive analysis of hepatic metabolomics and aortic transcriptomics data. Besides Pls role as the storage pool of n-3 PUFAs, the structural feature of vinyl ether bond at sn-1 position confers multiple advantages upon Pls compared to their diacyl counterparts, including enhanced antioxidant capacity, increased membrane fluidity, as well as improved stability and stability of biomembranes.

The C57BL/6 mouse strain is susceptible to high-fat diet (HFD)-induced AS lesions, and ApoE knockout accelerates AS development. Molecular mechanisms by which Pls ameliorate AS were investigated through a comprehensive analysis of hepatic metabolomics and aortic transcriptome profiles, focusing on changes in gene related to the p38 mitogen-activated protein kinase (MAPK) signaling pathway and the downstream inflammatory response.

The concentration of Pls in mussel tissues is 32 μgmg−1 (dry weight), and the obtained Pls contains 49.53% of phosphatidylethanolamine-Pls, 35.87% of phosphatidylcholine-Pls, and 14.60% of phosphatidylserine-Pls. The main fatty acid compositions of Pls are presented in Supplementary Table 1, which indicates that EPA accounts for 45.82% and the n-3/n-6 ratio is 3.84.

Pls inhibited aortic lipid accumulation, prevented thickening of the aortic wall, and suppressed collagen accumulation at the aortic-heart junction. Pls inhibited HFD-induced loosening of hepatocyte arrangement, vacuolization, and accumulation of lipid droplets.

Although several key components of MAPK signaling pathway were suppressed at both the transcriptional and protein levels in Pls-treated mice, no significant changes in phosphorylated p38 protein were observed among the experimental groups in our study. Further research is needed to elucidate the overall inhibitory mechanism of Pls on p38 protein and the MAPK signaling pathway.”

https://www.nature.com/articles/s41538-025-00546-0 “Effects of Mytilus edulis derived plasmalogens against atherosclerosis via lipid metabolism and MAPK signaling pathway”

A rodent / human cell study investigated effects of plasmalogens in innate immune system macrophages on atherosclerosis:

“We demonstrate that simultaneous inactivation of two key enzymes involved in macrophage polyunsaturated fatty acid (PUFA) metabolism—ELOVL5, which elongates long-chain PUFAs, and LPCAT3, which incorporates them into phospholipids—disrupts membrane organization by promoting the formation of cholesterol-enriched domains. This increases macrophage sensitivity to cytotoxic oxysterols and leads to more vulnerable atherosclerotic plaques with enlarged necrotic cores in a mouse model of atherosclerosis.

We identified ELOVL5 as one elongase facilitating the conversion of C20 to C22 PUFA. In humans, analysis of 187 carotid plaques reveals a positive correlation between LPCAT3/ELOVL5-generated phospholipids—including arachidonate (C20:4 n-6)-containing ether lipids—and more stable plaque profiles. Additionally, Mendelian randomization analysis supports a causal relationship between LPCAT3 expression and reduced risk of ischemic stroke.

Potentially beneficial effects we observed in mice and in human atheroma plaques were mainly associated with PLs enriched in omega-6, particularly in AA. Although omega-6 FAs are often considered as pro-inflammatory, their role is undergoing reconsideration, with markers linked to the intake of omega-6 appearing beneficial in the context of cardiovascular diseases. In this context, it is worth to note that AA-containing plasmalogens have been previously identified as markers of healthy obesity.

Our findings uncover a regulatory circuit essential for PUFA-containing phospholipid generation in macrophages, positioning PUFA-containing ether lipids as promising biomarkers and therapeutic targets.”

https://www.sciencedirect.com/science/article/pii/S2666379125002046 “Plasmalogen remodeling modulates macrophage response to cytotoxic oxysterols and atherosclerotic plaque”

A human study included plasmalogens in investigating associations among people with mental illness and their lipid profiles:

“Plasma lipidomic profiles of 623 individuals (188 schizophrenia (SCZ), 243 bipolar disorder (BD), 192 healthy controls) belonging to the PsyCourse Study were assessed using liquid chromatography and untargeted mass spectrometry. Exact etiology of these major mental health disorders is yet unknown and while their symptoms overlap, their diagnostic criteria are based on clinical evaluations of symptoms without objective markers.

Cognitive dysfunction is among the most disabling symptoms of SCZ and BD, and is difficult to treat with the commonly used pharmacologic regimes. Consequently, it has important impacts on long-term functional outcomes.

We aimed to answer the question, whether specific lipid species or classes were associated with differential performance across various cognitive domains, including psychomotor and processing speed, executive function, short-term and working memory and crystalized intelligence and whether these associations were affected by diagnoses.

Lipids belonging to the phosphatidylethanolamine plasmalogen (PE-P) class emerged as the main lipid class associated negatively with DG-SYM test performance, representative of processing and psychomotor speed. Our findings showed that higher levels of PE-P 42:5, PE-P 40:4, PE-P 40:5, and ceramide 38:1 in plasma samples of our study are significantly associated with poorer DG-SYM test performance. The DG-SYM test mainly measures processing speed, the amount of time required to complete a series of cognitive tasks. Enrichment analysis also showed significant associations between other lipid classes and various cognitive tests.

Our findings suggest a link between lipids and cognitive performance independent of mental health disorders. Independent replication is warranted to better understand if phosphatidylethanolamines could represent an actionable pharmacologic target to tackle cognitive dysfunction, an important unmet clinical need that affects long-term functional outcomes in individuals with severe mental health disorders.”

https://www.nature.com/articles/s41398-025-03323-5 “Investigating the association of the plasma lipidomic profile with cognitive performance and genetic risk in the PsyCourse study”

It was apparently beyond these researchers’ expertise to offer informed discussion on this study’s associative link between enrichment of these three phosphatidyl ethanolamine plasmalogens and cognitive dysfunction. Grok countered that their depletion was associated with neurodegenerative diseases (Alzheimer’s, Parkinson’s, multiple sclerosis), cardiovascular risk / oxidized-LDL burden, and chronic fatigue / post-viral syndromes.

Plasmalogens Week #3 – Aging

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Continuing Plasmalogens Week with two 2025 papers, starting with a rodent study of plasmalogens’ effects on mitigating cognitive decline:

“We evaluated beneficial effects of plasmalogens (PLS), phosphatidylcholine (PC), and phosphatidylserine (PS) on age-associated cognitive decline. We established a mouse model of aging-associated cognitive impairment using the subcutaneous injection of d-galactose (D-gal) at a dosage of 400 mg/kg/day.

We randomly divided six-week-old female mice into nine groups: control, model, high-dose PLS (0.3 mg/kg/day), low-dose PLS (0.09 mg/kg/day), high-dose PC (200 mg/kg/day), low-dose PC (50 mg/kg/day), high-dose PS (200 mg/kg/day), low-dose PS (50 mg/kg/day), AMC-Plas (120 mg/kg/day; and functional component PLS (0.252 mg/kg/day).

We administered PLS, PC, and PS separately by oral gavage once daily. We extracted PLS from scallops according to the literature. AMC-Plas is a commercially available health supplement known for its neuroprotective properties and memory-enhancing effects. In this study, we included AMC-Plas as a positive control group to evaluate the effects of different phospholipids.

Synaptophysin (SYP), synapsin-1 (SYN-1), postsynaptic density protein 95 (PSD-95), and brain-derived neurotrophic factor (BDNF) play important roles in synapse formation and synaptic plasticity. Synaptic function alterations or losses are key pathological mechanisms that underlie development of cognitive impairment. Therapeutic strategies that attempt to restore synaptic function or promote synaptic remodeling are considered to be increasingly promising strategies to mitigate cognitive decline.

Results showed that:

  • PLS improved spatial memory performance by 44% and object recognition by 80% in D-galactose-induced cognitively impaired mice.
  • PLS significantly decreased glial fibrillary acidic protein (GFAP)-positive cells (an indicator of astrocyte activation) in the dentate gyrus (DG) of the hippocampus, an important result because the DG is a crucial neurogenesis region.
  • PLS alleviated neuronal damage and protected against synaptic injury, verified by a 228.01% increase in PSD-95 expression in the hippocampus.
  • PLS showed a more prominent role for the mitigation of age-related cognitive impairment compared with PC and PS.

In conclusion, the evaluation of PLS using both behavioral and neuropathological assessments in cognitively impaired mice highlighted its exceptional efficacy compared with other phospholipids. PLS at a remarkably low effective dose significantly ameliorated cognitive deficits in cognitively impaired mice. This result further emphasized its potential relevance in neurodegenerative disease research.

We found that PLS alleviated cognitive impairment potentially by improving synaptic function; however, the molecular mechanisms that underlie its effects on synaptic function warrant further investigation.”

https://www.sciencedirect.com/science/article/pii/S175646462500132X “Mitigating effects of plasmalogens on age-related cognitive impairment”

There was no disclosed chemical analysis of the PLS scallop extract’s plasmalogen types or other contents. Despite its name, I didn’t see that the AMC-Plas product contained plasmalogens or plasmalogen precursors.

A fruit fly study investigated plasmalogen effects on mitochondria during aging:

“We identify plasmalogens—endogenous ether-linked phospholipids—as key regulators of age-associated mitochondrial fission in Drosophila melanogaster. Loss of Kua (also known as plasmanylethanolamine desaturase (PEDS) / TMEM189 in mammals), the enzyme essential for plasmalogen biosynthesis, leads to inhibition of mitochondrial fission and impaired recruitment of the fission protein Drp1, similar to what is observed during aging.

Mitochondrial dynamics, comprising balanced cycles of fission and fusion, are essential for preserving organelle quality, metabolic flexibility, and cellular homeostasis throughout life. Aging disrupts this balance, with multiple studies reporting a decline in mitochondrial fission that contributes to the accumulation of enlarged and dysfunctional mitochondria.

These morphological changes are linked to impaired mitophagy, altered energy production, and tissue dysfunction. Midlife induction of Drp1—the dynamin-related GTPase that drives mitochondrial division—has been shown to reverse age-related mitochondrial defects and prolong lifespan in Drosophila.

To determine whether plasmalogen biosynthesis is essential for mitochondrial fission, we used KuaMI04999, a hypomorphic allele. Western blot analysis revealed significantly reduced Kua protein levels in KuaMI04999/+ heterozygotes compared to wild-type controls.

Our findings reveal a previously unrecognized lipid-based mechanism that controls mitochondrial fission during aging and position plasmalogens as key effectors linking membrane composition to mitochondrial homeostasis. It is not merely expression or stability of Drp1 that is affected, but rather its recruitment to the mitochondrial surface, which is a critical activation step for fission.

While our study highlights the requirement of plasmalogen biosynthesis for Drp1 recruitment, further work is needed to understand how plasmalogens mechanistically facilitate this interaction.”

https://www.researchsquare.com/article/rs-7330024/v1 “Plasmalogen Biosynthesis Controls Mitochondrial Fission via Drp1 Recruitment during Aging”

This study didn’t analyze or characterize specific plasmalogens.

Ancient DNA fragments enable adult neurogenesis

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A 2025 rodent study investigated mechanisms by which erythropoietin (EPO) enables adult neurogenesis and cognitive function:

“We mapped epigenomic and transcriptional landscapes of adult mouse hippocampus under recombinant human EPO (rhEPO) treatment. We discovered significant lineage-specific remodelling of chromatin accessibility predominantly in newly formed pyramidal neurons, highlighting a robust EPO-driven neurogenic response. Notably, transposable elements (TEs), particularly ancient LINEs and SINEs, emerged as critical cis-regulatory elements (cCREs).

EPO is known to be upregulated in the brain under hypoxic or injury conditions, and it has been considered a natural neuroprotective agent. We demonstrated that EPO, a traditionally hematopoietic hormone, can profoundly reprogram the adult neural epigenome to drive neurogenesis.

EPO may activate a specific subclass of dormant regulatory elements to drive nearby genes. Such a mechanism would represent a previously unappreciated mode of gene regulation: the de novo recruitment of ancient genomic elements to drive a contemporary cellular response.

Our data support the model that EPO drives differentiation of progenitors rather than inducing widespread cell division. The net effect is an enrichment of pyramidal neurons at the cost of interneurons. Pyramidal neurons integrate in the hippocampal circuitry, leading to potential implications for mood, memory, cognitive enhancement, and recovery from brain injury.

We propose a conserved evolutionary mechanism at play: ancient TEs embedded in the genome have been repurposed as cCREs in neural cells, and during an EPO-induced neurogenic stimulus, the brain taps into this reservoir of regulatory elements to rapidly reshape gene expression. In evolutionary terms, this represents an efficient strategy.”

https://www.biorxiv.org/content/10.1101/2025.10.13.682070v1.full “Transposable Element-Mediated Epigenomic Remodeling Drives Erythropoietin-Induced Neurogenesis in the Adult Hippocampus”

Get a little stress into your life, Part 2

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A 2025 reply to a letter to the editor cited 56 references to elaborate on Part 1 and related topics:

“A positive effect does not necessarily mean benefit, and positive effects on individual organisms may mean adverse effects on other coexisting organisms. However, a vast literature shows that hormetic stimulation can result in benefits depending on the context, for instance, clear growth, yield, and survival improvement.

There is some energetic cost to support hormetic stimulation, with a likely positive energy budget, which might also have negative consequences if there is insufficient energy substrate, especially under concurrent severe environmental challenges. Moreover, hormetic preconditioning could be particularly costly when there is a mismatch between the predicted environment and the actual environment the same individuals or their offspring might face in the future.

Hormesis should not be unilaterally linked to positive and beneficial effects without considering dose levels. For any research to answer the question of whether a stimulation represents hormesis and whether it is beneficial, robust dose–response evaluations are needed, which should be designed a priori for this purpose, meeting the requirements of the proper number, increment, and range of doses.

Both additivity and synergism are possible in the hormetic stimulatory zone, depending also on the duration of exposure and the relative ratio of different components. This might happen, for example, when a chemical primes stress pathways (e.g., heat shock proteins and antioxidants), thus enabling another chemical to trigger hormesis (defense cross-activation) and/or because combined low subtoxicity may modulate receptors (e.g., aryl hydrocarbon receptor and nuclear factor erythroid 2-related factor 2) differently than individual exposures (receptor binding synergy).

Moreover, even when stimulation occurs in the presence of individual components, stimulation may no longer be present when combined, and therefore, effects of mixtures cannot be accurately predicted based on the effects of individual components. There may be hormesis trade-offs; hormesis should be judged based on fitness-critical end points.

While often modeled mathematically, hormesis is fundamentally a dynamic biological process and should not be seen as a purely mathematical function, certainly not a linear one. Much remains to be learned about the role of hormesis in global environmental change, and an open mind is needed to not miss the forest for the trees.”

https://pubs.acs.org/doi/10.1021/acs.est.5c05892 “Correspondence on ‘Hormesis as a Hidden Hand in Global Environmental Change?’ A Reply”

Reference 38 was a 2024 paper cited for:

“Hormetic-based interventions, particularly priming (or preconditioning), do not weaken organisms but strengthen them, enhancing their performance and health under different environmental challenges, which are often more massive than the priming exposure.

The catabolic aspect of hormesis is primarily protective whereas the anabolic aspect promotes growth, and their integration could optimize performance and health. The concept of preconditioning has also gained widespread attention in biomedical sciences.”

https://www.sciencedirect.com/science/article/abs/pii/S1568163724004069 “The catabolic – anabolic cycling hormesis model of health and resilience” (not freely available)

Reference 40 was a 2021 review that characterized hormesis as a hallmark of health:

“Health is usually defined as the absence of pathology. Here, we endeavor to define health as a compendium of organizational and dynamic features that maintain physiology.

Biological causes or hallmarks of health include features of:

  • Spatial compartmentalization (integrity of barriers and containment of local perturbations),
  • Maintenance of homeostasis over time (recycling and turnover, integration of circuitries, and rhythmic oscillations), and
  • An array of adequate responses to stress (homeostatic resilience, hormetic regulation, and repair and regeneration).

Disruption of any of these interlocked features is broadly pathogenic, causing an acute or progressive derailment of the system.

A future ‘medicine of health’ might detect perilous trajectories to intercept them by targeted interventions well before the traditional ‘medicine of disease’ comes into action.”

https://www.sciencedirect.com/science/article/pii/S0092867420316068 “Hallmarks of Health”

Sulforaphane as a senotherapy, Part 2

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A 2025 rodent study by the same group as Part 1 investigated similar subjects from a different experimental angle of senotherapy effects on brain and behavior rather than cardioprotective effects of dasatinib / quercetin (a senolytic combination) and sulforaphane (senomorphic):

“This is the first study to analyze the effect of senotherapy in the brain of a model of chronic obesity in middle-aged female rats. D + Q reduced the pro-inflammatory cytokines evaluated in the obesity model. It did not improve memory and learning nor the expression of molecules associated with the maintenance of synapses.

In contrast, sulforaphane (SFN), which without eliminating senescent cells, decreased pro-inflammatory factors, increased IL-10, as well as brain-derived neurotrophic factor BDNF, synaptophysin (SYP), and postsynaptic density protein 95 (PSD-95), which, in turn, were associated with an improvement in behavioral tests in obese rats. This suggests that modulating the senescence-associated secretory phenotype (SASP), rather than eliminating senescent cells, might have better effects.”

https://www.sciencedirect.com/science/article/pii/S0014488625001955 “Senotherapy as a multitarget intervention in chronic obesity: Modulation of senescence, neuroinflammation, dysbiosis, and synaptic integrity in middle-aged female Wistar rats”

Activate Nrf2 with far-infrared light

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A 2025 rodent study investigated effects of far-infrared light on Alzheimer’s disease models. I’ll focus on its Nrf2 findings:

“Far-infrared radiation (FIR) is commonly utilized as a complementary treatment of a range of disease, for example, insomnia and rheumatoid arthritis. In this research, we explored how FIR light impacts cognitive functions of TgCRND8 AD mice and elucidated its underlying molecular mechanism.

Infrared radiation is a form of electromagnetic energy that has wavelengths between 750 nm and 1000 μm, which are longer than visible light. International Commission on Illumination categorizes infrared light as three sub-divisions according to the wavelength: (1) near-infrared radiation (0.7–1.4 μm), (2) middle infrared radiation (1.4–3.0 μm), and (3) far-infrared radiation (3.0–1000 μm).

Nrf-2/ HO-1 signaling, a key endogenous antioxidant system, helps mitigate oxidative stress and enhances expression of various endogenous genes. Activation of HO-1 during inflammatory conditions may serve as an adaptive response to reduce cytotoxicity through various mechanisms.

In this study, we applied EFFIT LITE® as the FIR spectrum transmitter which stably radiates an FIR spectrum with a wavelength of 4–20 μm, and the device was put within 1 cm directly above the head of the 3-month-old TgCRND8 mice for 30 min exposure once every day. FIR light notably enhanced cognitive function and spatial memory of TgCRND8 mice after 28-days consecutive treatment.

Underlying molecular mechanisms involve suppression of Aβ deposition, hyperphosphorylation of tau, and neuroinflammation through modulating Jak-2/Stat3 and Nrf-2/HO-1 pathways. Our current experimental findings amply indicate that FIR light is a potential non-pharmacological therapy for AD.”

https://link.springer.com/article/10.1007/s12017-025-08860-2“Far-Infrared Radiation Ameliorates the Cognitive Dysfunction in an Alzheimer’s Disease Transgenic Mouse via Modulating Jak-2/Stat3 and Nrf-2/HO-1 Pathways”

This study measured Nrf2 and its quickly-induced downstream enzyme HO-1 effects of daily far-infrared light exposure for 30 minutes. We’d have to see measurements of Nrf2’s more-slowly induced and longer-lasting downstream xenobiotic detoxifying enzyme NQO1 to compare far-infrared light Nrf2 activation effects with those of natural plant compounds.

Betaine as an exercise mimetic

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A 2025 human study investigated effects of long-term exercise:

“Exercise has well-established health benefits, yet its molecular underpinnings remain incompletely understood. We conducted an integrated multi-omics analysis to compare effects of acute vs. long-term exercise in healthy males.

Acute exercise induced transient responses, whereas repeated exercise triggered adaptive changes, notably reducing cellular senescence and inflammation and enhancing betaine metabolism. Exercise-driven betaine enrichment, partly mediated by renal biosynthesis, exerts geroprotective effects and rescues age-related health decline in mice.

Betaine binds to and inhibits TANK-binding kinase 1 (TBK1), retarding the kinetics of aging.

Betaine effectively alleviated senescence phenotypes by reduced senescence-associated β-galactosidase (SA-β-Gal)-positive cells, decreased p21 expression, lowered DNA damage indicator γ-H2A.X, and elevated heterochromatin mark H3K9me3. Betaine treatment also enhanced cellular antioxidant capacity, as evidenced by increased NRF2 phosphorylation and reduced ROS accumulation.

These findings systematically elucidate the molecular benefits of exercise, and position betaine as an exercise mimetic for healthy aging.”

https://doi.org/10.1016/j.cell.2025.06.001 “Systematic profiling reveals betaine as an exercise mimetic for geroprotection” (not freely available) Thanks to Dr. Weimin Ci for providing a copy.

Practice what you preach, or shut up

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A 2025 review subject was sulforaphane and brain health. This paper was the latest in a sequence where the retired lead author self-aggrandized his career by citing previous research.

He apparently doesn’t personally do what these research findings suggest people do. The lead author is a few weeks older than I am, and has completely white hair per an interview (Week 34 comments). I’ve had dark hair growing in (last week a barber said my dark hair was 90%) since Week 8 of eating broccoli sprouts every day, which is a side effect of ameliorating system-wide inflammation and oxidative stress.

If the lead author followed up with what his research investigated, he’d have dark hair, too. Unpigmented white hair and colored hair are both results of epigenetics.

Contrast this lack of personal follow-through of research findings with Dr. Goodenowe’s protocol where he compared extremely detailed personal brain measurements at 17 months and again at 31 months. He believes enough in his research findings to personally act on them, and demonstrate to others how personal agency can enhance a person’s life.

It’s every human’s choice whether or not we take responsibility for our own one precious life. I’ve read and curated on this blog many of this paper’s references. Five years ago for example:

So do more with their information than just read.

https://www.mdpi.com/2072-6643/17/8/1353 “Sulforaphane and Brain Health: From Pathways of Action to Effects on Specific Disorders”

Year Five of Changing to a youthful phenotype with sprouts

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1. I’ve continued daily practices from Year Four to experience another year without being sick! I’ll get a set of Labcorp tests in a week to see if anything is sneaking up on me.

Really think that Brassica clinical trials should last years, not weeks. Once people get over the fact that broccoli, red cabbage, and mustard sprouts will never taste good because their compounds are plants’ defenses against predators, they’ll overlook that in favor of health benefits. Avena sativa oat sprouts don’t have a palatability problem.

2. Daily supplements have changed a little:

  • Started taking a quercetin supplement suggested in a comment to Year One as helpful for seasonal allergies (it doesn’t do that for me). Repeatedly rinsing and soaking the salt out of capers for quercetin content became too much of a nuisance, and the results didn’t always taste right;
  • Stopped taking Prodrome supplements because of unsustainable high costs;
  • Started taking Ovega 3 algae oil DHA 420 mg/EPA 140 mg twice a day in their place;
  • Substituted flax oil 1400 mg once a day for Balance oil;
  • Started taking 2 g magnesium L-threonate;
  • Upped taurine intake from 5 to 6 grams;
  • Upped D3 by 25 mcg to a daily 4400 IU;
  • Reduced chondroitin sulfate by 1.8 g since my joints are doing fine;
  • Stopped soy lecithin in favor of eating three raw eggs.

3. I injured my left shoulder in May 2024 by overdoing upper body exercises, and stopped seven months to recover. Gained thirty pounds during that layoff, and have worked off ten pounds with new routines since then.

I’m no longer dogmatic about aerobic exercise / beach walks. I’ll go over to the beach before sunrise when it isn’t raining or windy, or wait until the afternoon for weather to improve, rather than walk 30 minutes a day irregardless.

2025 α-ketoglutarate research

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I haven’t mentioned α-ketoglutarate for a while, although I’ve taken it twice a day for several years. Here are four 2025 papers on α-ketoglutarate, starting with a review of its role in bone health:

“α-Ketoglutarate (α-KG) serves as a pivotal intermediate in various metabolic pathways in mammals, significantly contributing to cellular energy metabolism, amino acid metabolism, and other physiological processes. α-KG may be a therapeutic target for a variety of bone-related diseases, such as osteoporosis, osteoarthritis, and rheumatoid arthritis, because of its role in maintaining metabolic balance of bone.

α-KG, as a rate-determining mitochondrial intermediate, is crucial in cell energy metabolism because it connects intracellular carbon and nitrogen metabolism between isocitrate and succinyl coenzyme A. Additionally, α-KG is closely involved in the amino acid cycle. As a precursor of amino acids such as glutamine and glutamic acid, α-KG plays a direct role in energy production and a wide range of cellular chemical reactions. α-KG provides an energy source, stimulating protein synthesis, inhibiting protein degradation in muscle, and serving as a significant metabolic fuel for gastrointestinal cells.

α-KG promotes osteogenic differentiation of stem cells, increases activity of osteoblasts to promote osteogenesis, and inhibits bone resorption activity of osteoclasts. α-KG in articular cartilage promotes differentiation and maturation of chondrocytes and formation of a cartilage matrix. The protective effect of α-KG on bone has practical value in treatment of abnormal bone loss symptoms in various bone tissue diseases.”

https://www.sciengine.com/ABBS/doi/10.3724/abbs.2025020 “Essential role of the metabolite α-ketoglutarate in bone tissue and bone-related diseases”

A rodent study explored adding α-KG to osteoarthritis treatment:

“Mesenchymal stem cell (MSC) therapy represents a promising treatment strategy for osteoarthritis (OA). Nevertheless, the therapeutic efficacy of MSCs may be attenuated under conditions of cellular senescence or when the available clinical quantity is insufficient. α-Ketoglutarate (AKG) exerts beneficial effects on skeletal tissues and activity of stem cells. The present study was designed to explore the potential of AKG in augmenting viability of MSCs and the potential of their combined utilization in treatment of OA.

AKG plays a crucial role in multiple biological processes. It is involved in regulating stem cell differentiation, exerts anti-apoptotic effects, modulates the body’s immune and inflammatory responses, contributes to muscle and bone development, and is essential for maintaining stability of the cartilage matrix.

Platelet-rich plasma (PRP) has been demonstrated to have protective effects on chondrocytes and can effectively repair damaged cartilage in OA. However, PRP has intractable problems in terms of product quality control and allogeneic application, and its long-term therapeutic effect gradually weakens.

Combining AKG’s regulation of cellular metabolism with the multi-directional differentiation and immunomodulatory functions of MSCs is likely to generate a synergistic effect. This combined treatment modality targets the complex pathological processes of OA, including cartilage damage, inflammatory responses, and extracellular matrix imbalance, in a more comprehensive manner than a single therapy.”

https://www.sciencedirect.com/science/article/pii/S2707368825000032 “The repair effect of α-ketoglutarate combined with mesenchymal stem cells on osteoarthritis via the hedgehog protein pathway”

A rodent study investigated whether α-KG has a role in determining frailty:

“Frailty is an age-related geriatric syndrome, for which the mechanisms remain largely unknown. We performed a longitudinal study of aging female (n = 40) and male (n = 47) C57BL/6NIA mice, measured frailty index, and derived metabolomics data from plasma samples.

We find that frailty related metabolites are enriched for amino acid metabolism and metabolism of cofactors and vitamins, include ergothioneine, tryptophan, and alpha-ketoglutarate, and present sex dimorphism. We identify B vitamin metabolism related flavin adenine dinucleotide and pyridoxate as female-specific frailty biomarkers, and lipid metabolism related sphingomyelins, glycerophosphoethanolamine and glycerophosphocholine as male-specific frailty biomarkers.

We were interested to observe whether metabolite abundance at any specific timepoint was associated with frailty at a future timepoint. Unfortunately, we didn’t observe any metabolites that showed an overall significant association with future FI (FIf) or future devFI (devFIf). When focusing only on the abundance of metabolites at the baseline time point (∼400 days), we found a single metabolite, alpha-ketoglutarate, was negatively associated with both FIf and devFIf.”

https://www.biorxiv.org/content/10.1101/2025.01.22.634160v1.full “Metabolomics biomarkers of frailty: a longitudinal study of aging female and male mice”

Wrapping up with a rodent study adding α-KG to exercise for its effects on depression and learning:

“aKG acts as a prophylactic and antidepressant to effectively counteract social avoidance behaviors by modulating BDNF levels in the hippocampus and nucleus accumbens. Exercise increases aKG levels in the circulation.

In mice, aKG supplementation prolongs lifespan and reduces aging-associated frailty. aKG supplementation also reverses aging in humans as measured by DNA methylation patterns.

aKG functions as a co-factor for epigenetic enzymes. Changes in the intracellular αKG/succinate ratio regulates chromatin modifications, including H3K27me3 and ten-eleven translocation (Tet)-dependent DNA demethylation. The ability of aKG to influence epigenetic status of cells may explain both its prophylactic and anti-depressant effects since transcriptional dysregulation and aberrant epigenetic regulation are unifying themes in psychiatric disorders. This may also explain its ability to differentially regulate BDNF expression in the hippocampus and NAc.

If exercise mediates its effects through aKG, aKG may be a pivotal component of an exercise pill along with lactate and BHB that can serve as both a prophylactic and antidepressant treatment for depression.”

https://www.sciencedirect.com/science/article/pii/S266717432500031X “α-ketoglutarate (aKG) is a circulatory exercise factor that promotes learning and memory recall and has antidepressant properties

Vitamin K2 and your brain

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A 2025 review linked Vitamin K2‘s effects on vascular health with cognitive function:

“Cardiovascular disease (CVD) is negatively correlated with cognitive health. Arterial stiffness, in particular, appears to be a critical factor in the functional and structural brain changes associated with aging. We review the association between vitamin K and cerebral function, discussing novel developments regarding its therapeutic role in arterial stiffness and cognitive health.

Among the non-invasive measures of vascular stiffness, pulse wave velocity (PWV) is considered the gold standard. PWV measures arterial stiffness along the entire aortic pathway, providing a reliable, feasible, and accurate assessment of vascular health. Arterial stiffness, as measured by PWV, is negatively associated with total brain volume, brain atrophy, and cognitive function. Pathogenic mechanisms responsible for vascular stiffness recently shifted from collagen and elastin to the differentiation of vascular smooth muscle cells to osteoblastic phenotype, which is triggered by oxidative stress and inflammation, membrane mechanotransduction, lipid metabolism, genetic factors, and epigenetics.

Vitamin K-dependent proteins (VKDPs) rely on vitamin K to undergo γ-glutamylcarboxylation, a modification essential for their biological activity. This family of proteins includes hepatic VKDPs such as prothrombin, FVII, FIX, and FX, protein S and protein C as well as extrahepatic VKDPs such as matrix Gla-protein (MGP), which is involved in inhibiting vascular calcification, and osteocalcin, which plays a role in bone mineralization.

Structural differences between K1 and K2 influence their bioavailability, absorption, bioactivity, and distribution within tissues. Compared to vitamin K1, the K2 subtype menaquinone-7 (MK-7) has a significantly longer half-life, accumulates more effectively in blood, and exhibits greater biological activity, particularly in facilitating the carboxylation of extrahepatic VKDPs. Circulating dephosphorylated, uncarboxylated Matrix Gla protein (dp-ucMGP), a marker of extrahepatic vitamin K deficiency, could represent a novel therapeutic target for mitigating both arterial stiffness and cognitive decline.

Vascular calcification and arterial stiffness may represent pathophysiological mechanisms underlying the onset and progression of cognitive decline. Vitamin K deficiency is a key determinant of arterial health and, by extension, may influence cognitive function in the elderly.

To elucidate potential therapeutic benefits of MK-7 supplementation on cognitive function, future randomized controlled trials (RCTs) are needed. These trials should focus on using optimal dosages (>500 μg/day), ensuring long follow-up periods, and utilizing the most bioactive form of vitamin K (MK-7).”

https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2024.1527535/full “The role of vitamin K2 in cognitive impairment: linking vascular health to brain health”

A coauthor Dr. Katarzyna Maresz took time on her weekend to answer a few questions:

1. Regarding the second paper of Part 2 of Vitamin K2 – What can it do?:

Hello Dr. Maresz. Did this trial ever happen? “Effects of Combined Vitamin K2 and Vitamin D3 Supplementation on Na[18F]F PET/MRI in Patients with Carotid Artery Disease: The INTRICATE Rationale and Trial Design” I haven’t seen a followup mention of it since 2021.

“Hello. The study never started. The capsules were produced for the study, but the research center experienced delays. Unfortunately, I’m afraid it won’t proceed. Regarding studies on aortic stenosis and vitamin K2, BASIC II has been completed, and the data from this pilot study are currently under analysis. (https://pubmed.ncbi.nlm.nih.gov/29561783/). There is also published study with K1: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.116.027011

2. Thank you! In your recent review of cognitive function and K2 (above), what influenced the heuristic that a >500 mcg K2 dose should be pursued in future RCTs?

“The optimal vitamin K dosage depends on the target population. Research in kidney patients has shown that 460 mcg daily was insufficient, that is why have hypothesis that at least 500 mcg should be used. The ongoing VIKIPEDIA study is using 1,000 mcg daily in peritoneal dialysis patients. In healthy young individuals, 180-360 mcg was effective in improving vitamin K status (British Journal of Nutrition (2012), 108, 1652–1657) . However, a one-year clinical study found that 180 mcg daily was sufficient for women but not for men. Additionally, older adults and individuals with metabolic disorders may require higher doses for optimal benefits. So it is pretty complicated situation. We do not have good marker of extrahepatic K status. dp-ucMGP seems to be valuable from CV perspective.”

3. Regarding Fat-soluble vitamin competition:

Thank you again Dr. Maresz! Would any consideration be given to dosing K2 separately from dosing another fat-soluble vitamin? A 2015 in vitro study found that vitamins D, A, and E outcompeted K1 intake when simultaneously dosed. I inferred from the one capsule of D3-K2 produced for the canceled trial that isn’t that much of a problem with K2?

“You are right, the key findings suggest that vitamin D, E, and K share common absorption pathways, leading to competitive interactions during uptake. However, I’m afraid we do not have human data. The majority of studies have focused on vitamin K2 alone. Recent research combining K2 and D3 showed an improvement in vitamin K status. Example: https://pubmed.ncbi.nlm.nih.gov/35465686/ or increase in D level: https://pubmed.ncbi.nlm.nih.gov/39861434/. We do not know if VKDP activation or absorption of D would be more effective if K2 were not supplemented with D3 at the same time. Unfortunately, I doubt anyone will fund such a study, as clinical trials are very expensive. In vitro data will always raise questions regarding their relevance to human physiology. In my opinion, for patients to fully benefit from optimal vitamin K status, vitamin D levels should also be optimized, as both have synergistic effects.”

Epigenetic clock analysis of a clinical trial

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Memory, Stress , , ,

A 2025 paper performed post-hoc epigenetic clock analyses of a supplement and exercise clinical trial completed earlier this decade:

“We report results of a post hoc analysis among 777 participants of the DO-HEALTH trial on the effect of vitamin D (2,000 IU per day) and/or omega-3 (1 g (330 mg EPA plus 660 mg DHA from marine algae) per day) and/or a home exercise program (a strength-training exercise program performed for 30 min three times per week) on four next-generation DNA methylation (DNAm) measures of biological aging (PhenoAge, GrimAge, GrimAge2 and DunedinPACE) over 3 years. Omega-3 alone slowed the DNAm clocks PhenoAge, GrimAge2 and DunedinPACE, and all three treatments had additive benefits on PhenoAge.

Inclusion criteria were age 70 years and older, living at home, having no major health events (no cancer or myocardial infarction) in the 5 years before enrollment, having sufficient mobility to visit the study centers without help and having good cognitive function with a Mini-Mental State Examination score of at least 24. 777 provided consent for these analyses and had samples available after the application of the exclusion criteria. This group of individuals formed our analysis sample, which had the following characteristics: 59% were women; the mean age at baseline was 75 years; 30% had 25-hydroxyvitamin D (25(OH)D) levels of <20 ng ml−1; 53% were healthy agers as defined in the Nurses’ Health Study (free of major chronic diseases, disabilities, cognitive impairments and mental health limitations); and 88% were physically active (29% were active one to three times per week, and 59% were active more than three times per week). The Swiss participant subgroup represents a healthier and more active subgroup within the total DO-HEALTH population.

Overall, from baseline to year 3, standardized effects ranged from 0.16 to 0.32 units (2.9–3.8 months). In summary, our trial indicates a small protective effect of omega-3 treatment on slowing biological aging over 3 years across several clocks, with an additive protective effect of omega-3, vitamin D, and exercise based on PhenoAge.”

https://www.nature.com/articles/s43587-024-00793-y “Individual and additive effects of vitamin D, omega-3 and exercise on DNA methylation clocks of biological aging in older adults from the DO-HEALTH trial”

These epigenetic clock measurements of a subset of trial subjects was interesting, although I didn’t find it particularly relevant to what I do. I take twice as much Vitamin D and omega-3s everyday, do resistance exercises once or twice a week whenever I’ve recovered from the previous session, walk a few miles on the beach if the weather is nice, and other things.

I don’t bother with epigenetic clock measurements anymore because the free one (PhenoAge) is too variable to be personally accurate. For other clocks, it would be meaningless if all I got was a 2-3 month improvement over a three year period like this trial. Studies usually find that the most deficient subjects at the beginning are the ones that show the greatest improvements with effective treatments. Unhealthiness on any epigenetic clock parameter probably wouldn’t be my starting point, so I may not show even a one-month improvement over three years.

Dr. Goodenowe offered his opinion on the paper:

“DHA is a polyunsaturated fatty acid that is essential for maintaining youthful fluidity of the body’s membranes. While our bodies can make DHA from the essential omega-3 dietary fatty acid, as we get older, our ability to make DHA decreases and oxidative stress on our bodies increases. These two factors contribute to our membranes becoming stiffer and less pliable as we age, in other words, ‘older.’

Because getting older and losing function appear to go hand in hand, we equate aging with a loss of function. As such, we think that aging causes this loss of function, like a disease. Instead, the opposite is true, and it’s the loss of function that causes aging. To slow aging you need to focus on maintaining function.”

https://www.prevention.com/health/a63850396/vitamin-exercise-boost-longeivty-study/ “Scientists Find Taking This Vitamin Boosts Longevity, Add Years to Your Life”

Prevention magazine’s editors need to better proof their writers’ work before it gets published. Unlike the headline, the trial had nothing to do with adding years to human lifespan.

Too dangerous to investigate?

gettingwell4 0-1 star Wasted resources, Hippocampus, Immune system, Limbic system, Memory , ,

This blog’s 1100th curation is a clinical trial of ergothioneine’s effects on cognitive decline:

“We recruited participants aged between 60–90 years of age, from three study cohorts diagnosed with mild cognitive impairment (MCI) and provided them with ergothioneine (ET)  (25 mg capsules administered orally three times a week) or placebo in a double-blinded and randomized manner. Blood samples were collected at baseline and quarterly (visits 1, 4, 7, 10, 14) for clinical safety assessment and biomarker analyses). Neuro-cognitive assessments were conducted biannually (visits 7 and 14).

Following ET intake, an increase in Z-scores was observed in the Rey Auditory Verbal Learning Test (RAVLT) (immediate and delayed recalls), which evaluates learning ability and memory.

ravlt

wbc

Participants in both ET and placebo groups recorded a lower total white blood cell count compared to baseline at visit 7, both of which recovered subsequently. The reasons for this anomaly are unclear but values were all still within the expected range for their age.”

https://journals.sagepub.com/doi/epub/10.1177/13872877241291253 “Investigating the efficacy of ergothioneine to delay cognitive decline in mild cognitively impaired subjects: A pilot study”

I rated this study a waste of time and money for the researchers’ incurious lack of following where their data led. Significant WBC signals of both treatment and placebo subjects’ immune system responses were shrugged off with an “expected range” non-explanation.

Polyphenol Nrf2 activators

gettingwell4 2-3 stars Required further work, Acetylcholine, Amygdala, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Oxytocin, Serotonin, Stress, Vasopressin , , , , ,

Two 2024 reviews by the same group that published Sulforaphane in the Goldilocks zone investigated dietary polyphenols’ effects as “hormetic nutrients”:

“Polyphenols display biphasic dose–response effects by activating at a low dose the Nrf2 pathway resulting in the upregulation of antioxidant vitagenes [see diagram]. We aimed to discuss hormetic nutrients, including polyphenols and/or probiotics, targeting the Nrf2 pathway and vitagenes for the development of promising neuroprotective and therapeutic strategies to suppress oxidative stress, inflammation and microbiota deregulation, and consequently improve cognitive performance and brain health.

antioxidants-13-00484-g001

Hormetic nutrition through polyphenols and/or probiotics targeting the antioxidant Nrf2 pathway and stress resilient vitagenes to inhibit oxidative stress and inflammatory pathways, as well as ferroptosis, could represent an effective therapy to manipulate alterations in the gut microbiome leading to brain dysfunction in order to prevent or slow the onset of major cognitive disorders. Notably, hormetic nutrients can stimulate the vagus nerve as a means of directly modulating microbiota-brain interactions for therapeutic purposes to mitigate or reverse the pathophysiological process, restoring gut and brain homeostasis, as reported by extensive preclinical and clinical studies.”

https://www.mdpi.com/2076-3921/13/4/484 “Hormetic Nutrition and Redox Regulation in Gut–Brain Axis Disorders”

I’m not onboard with this study’s probiotic assertions because most of the cited studies contained unacknowledged measurement errors. Measuring gut microbiota, Part 2 found:

“The fecal microbiome does not represent the overall composition of the gut microbiome. Despite significant roles of gut microbiome in various phenotypes and diseases of its host, causative microbes for such characteristics identified by one research fail to be reproduced in others.

Since fecal microbiome is a result of the gut microbiome rather than the representative microbiome of the GI tract of the host, there is a limitation in identifying causative intestinal microbes related to these phenotypes and diseases by studying fecal microbiome.”

These researchers also erroneously equated isothiocyanate sulforaphane’s Nrf2-activating mechanisms with polyphenols activating Nrf2.

This research group did better in clarifying polyphenols’ mechanisms in a review of hormetic dose-response effects of the polyphenol rosmarinic acid:

“This article evaluates whether rosmarinic acid may act as a hormetic agent, mediating its chemoprotective effects as has been shown for similar agents, such as caffeic acid, a derivative of rosmarinic acid.

Rosmarinic acid enhanced memory in institute of cancer research male mice in the Morris water maze (escape latency).

untitled

Of importance in the evaluation of rosmarinic acid are its bioavailability, metabolism, and tissue distribution (including the capacity to affect and/or cross the BBB and its distribution and half-life within the brain). In the case of polyphenols, including rosmarinic acid, they are typically delivered at low doses in the diet and, in most instances, they do not escape first-pass metabolism, with the prominent chemical forms being conjugates of glucuronides and sulfates, with or without methylation.

These conjugated metabolites are chemically distinct from the parent compound, showing considerable differences in size, polarity, and ionic form. Their biological actions are quite different from the parent compound.

Bioavailability studies reveal that maximum concentrations in plasma typically do not exceed 1 µM following consumption of 10–100 mg of a single phenolic compound, with the maximum concentration occurring typically less than 2 h after ingestion, then dropping quickly thereafter. In the case of the in vitro studies assessed herein, and with few exceptions, most of the studies employed concentrations >10 µM with some studies involving concentrations in the several hundred µM range, with the duration of exposure typically in the range of 24–72 h, far longer duration than the very short time interval of a few minutes to several hours in human in vivo situations.

We strongly recommend that all experiments using in vitro models to study biological responses to dietary polyphenols use only physiologically relevant flavonoids and their conjugates at appropriate concentrations, provide evidence to support their use, and justify any conclusions generated. When authors fail to do this, referees and editors must act to ensure that data obtained in vitro are relevant to what might occur in vivo.”

https://www.degruyter.com/document/doi/10.1515/med-2024-1065/html “The chemoprotective hormetic effects of rosmarinic acid”

Failed aging paradigms

gettingwell4 2-3 stars Required further work, Brain development, Epigenetics, Memory , , , ,

A 2024 paper with 81 coauthors presented different views of aging:

“This article highlights the lack of consensus among aging researchers on fundamental questions such as the definition, causes, and onset of aging as well as the nature of rejuvenation. Our survey revealed broad disagreement and no majority opinion on these issues.

We obtained 103 responses (∼20% of which were submitted anonymously). The respondents included 29.8% professors, 25% postdoctoral fellows, 22.1% graduate students, 13.5% industry professionals, and 9.6% representing other categories (a total of eight additional groups).

When does aging begin? At 20 years (22%), gastrulation (18%), conception (16.5%), gametogenesis (13%), 25 years (11%), birth (8%), 13 years (5%), and 9 years (4%). Nobody chose the only remaining option (30 years).

m_pgae499f3

It is clear from responses that aging remains an unsolved problem in biology. While most scientists think they understand the nature of aging, apparently their understanding differs. Where some may stress the importance of targeting underlying mechanisms, others focus on ameliorating the phenotypes.”

https://academic.oup.com/pnasnexus/article/3/12/pgae499/7913315?login=false “Disagreement on foundational principles of biological aging”

I’ll assert that these researchers were unable to incorporate information outside of their chosen paradigm. This would explain why only 18% understood the embryonic stage of gastrulation as aging’s start, although the 2022 paper Epigenetic profiling and incidence of disrupted development point to gastrulation as aging ground zero in Xenopus laevis provided epigenetic clock evidence that:

“It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life.”

I’ve cited Josh Mitteldorf’s work about aging a few times. His paradigm of aging is in his 2017 book Cracking the Aging Code: The New Science of Growing Old – And What It Means for Staying Young that:

“Aging has an evolutionary purpose: to stabilize populations and ecosystems.”

However, there isn’t evidence of such causal inheritance mechanisms that would begin an organism’s aging during embryogenesis, i.e., that an embryo’s development of aging elements at gastrulation is causally affected by population and ecosystem factors.

Dr. Goodenowe recently had a casual conversation Episode 8 – Perpetual Health, Exploring The Science Behind Immortality where he asserted items such as:

“What we’re all fighting is entropy. Entropy is the tendency of all things to reach a level of randomness. Aging is not a disease. It’s just apathy and entropy. The body just doesn’t care – people don’t pay attention.

This notion that we are programmed for death is wrong. We’re not programmed to die. We actually teach ourselves to die. The body learns how to die, so as your function decreases, it adjusts. It appears to be programmed because of the association with chronological age.”

I haven’t seen any of his papers that put these and his other assertions up for review. For example, I doubt the entropy-caused randomness assertion would survive peer review per Stochastic methylation clocks?:

“Entropic theories of aging have never been coherent, but they are nevertheless experiencing a resurgence in recent years, primarily because neo-Darwinist theories of aging are all failing. I find this ironic, because the neo-Darwinist theories arose precisely because scientists realized that the Second Law of Thermodynamics does not apply to living systems.”

The funny thing about failed aging paradigms is that quite a few of their treatments improve healthspan, but not lifespan. If they don’t “target aging underlying mechanisms” they “ameliorate aging phenotypes.” None so far have positively affected both human healthspan and lifespan.

PXL_20241129_174732711.MP~2