#21

So … if those are elevated, addressing the cause is the primary focus.

For most of us, we have normal levels, so the liver health part of this isn’t the benefit - the question is on the neurocognitive component, which I wish we had more evidence for.

Now for @John_Hemming who enjoys his ethanol … might be another mitigating action in addition to the citrate.

On UDCA seems like Vera-Health has much more to say, and many more references
Ursodeoxycholic acid (UDCA) has shown potential in addressing neurodegeneration through various mechanisms. UDCA is a bile acid that has been studied for its neuroprotective properties in several neurodegenerative diseases. It is known to cross the blood-brain barrier, making it a promising candidate for treating central nervous system disorders.

In Parkinson’s disease (PD), UDCA has been investigated for its ability to rescue mitochondrial function, a key factor in neurodegeneration. A study demonstrated that high-dose UDCA was safe and well-tolerated in early PD, with evidence of improved ATP hydrolysis in the midbrain, suggesting potential neuroprotective effects
7
.

UDCA has also been studied in the context of GM2 gangliosidosis, a neurodegenerative disorder. It was found to diminish neurite atrophy and decrease pro-apoptotic signaling, indicating its role in alleviating endoplasmic reticulum stress and promoting neuronal survival
8
.

Furthermore, UDCA and its derivative, tauroursodeoxycholic acid (TUDCA), have been shown to reduce prion protein conversion and neuronal loss in prion disease models. These compounds demonstrated neuroprotective effects by reducing astrocytosis and prolonging survival in prion-infected mice, highlighting their potential in treating protein misfolding diseases
1
.

The modulation of apoptosis through the p53 pathway is another mechanism by which UDCA exerts its effects. It has been suggested that UDCA can modulate p53-triggered apoptosis, which is relevant in various neurodegenerative conditions
1
.

Overall, UDCA shows promise as a therapeutic agent in neurodegenerative diseases due to its ability to modulate mitochondrial function, reduce protein misfolding, and influence apoptotic pathways. However, further research and larger clinical trials are needed to fully establish its efficacy and safety in these conditions.

References

  1. Solving neurodegeneration: common mechanisms and strategies for new treatments
    Molecular Neurodegeneration
    Wareham et al.
    121 citations
    2022
    Major areas of mechanistic overlap between neurodegenerative diseases of the central nervous system: neuroinflammation, bioenergetics and metabolism, genetic contributions, and neurovascular interactions are discussed.

Open Access
Highly Influential Journal
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2. The Q/R editing site of AMPA receptor GluA2 subunit acts as an epigenetic switch regulating dendritic spines, neurodegeneration and cognitive deficits in Alzheimer’s disease
Molecular Neurodegeneration
Wright et al.
9 citations
2023
Eliminating unedited GluA2(Q) expression in AD mice prevented dendritic spine loss and hippocampal CA1 neurodegeneration as well as improved working and reference memory in the radial arm maze and revealed increased spine density in non-AD mice with exonically encoded Glu a2(R) as compared to their wild-type littermates, suggesting an unexpected and previously unknown role for un edited GLUA2 (Q) in regulating dendrites.

Open Access
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3. BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia
Molecular Neurodegeneration
Sudwarts et al.
39 citations
2022
The consensus from in vitro and in vivo findings showed that loss of Bin1 impaired the ability of microglia to mount type 1 interferon responses to proinflammatory challenge, particularly the upregulation of a critical type 1 immune response gene, Ifitm3 .

Open Access
Highly Influential Journal
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4. Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration
Molecular Neurodegeneration
Querfurth et al.
131 citations
2021
Beyond rapamycin; an mTOR inhibitor, there are rapalogs having greater tolerability and micro delivery modes, that hold promise in arresting these age dependent conditions.

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5. cGAS-STING triggers inflammaging-associated neurodegeneration
Molecular Neurodegeneration
Izquierdo et al.
0 citations
2023
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Highly Influential Journal
6. Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration
Translational Neurodegeneration
Verma et al.
169 citations
2022
Evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and Huntington’s disease is reviewed and strategies for normalizing the flux of calcium into and out of the mitochondrial matrix are discussed, thereby preventing excitotoxic dendritic loss.

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7. A Double-Blind, Randomized, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson’s Disease.
Movement Disorders
Payne et al.
14 citations
2023
High-dose UDCA is safe and well tolerated in early PD and midbrain 31 P-MRS demonstrated an increase in both Gibbs free energy and inorganic phosphate levels in the UDCA treatment group compared to placebo, reflecting improved ATP hydrolysis.

Open Access
Influential Journal
Show more
8. Ursodeoxycholic Acid Binds PERK and Ameliorates Neurite Atrophy in a Cellular Model of GM2 Gangliosidosis
International Journal of Molecular Sciences
Morales et al.
2 citations
2023
It is found that UDCA significantly diminished the neurite atrophy induced by GM2 accumulation in primary neuron cultures, suggesting a direct interaction between UDCA and the cytosolic domain of PERK, which promotes kinase phosphorylation and dimerization.

Open Access
Influential Journal
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9. Glycoursodeoxycholic Acid Reduces Matrix Metalloproteinase-9 and Caspase-9 Activation in a Cellular Model of Superoxide Dismutase-1 Neurodegeneration
Molecular Neurobiology
Vaz et al.
53 citations
2014
Data highlight caspase-9 and MMP-9 activation as key pathomechanisms in ALS and GUDCA as a promising therapeutic strategy for slowing disease onset and progression.

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10. The role of p53 in apoptosis.
Discover medicine
Amaral et al.
347 citations
2010
It is suggested that the finely tuned, complex control of p53 by Mdm-2 (mouse double minute-2, an oncoprotein) is a key step in UDCA modulation of p52-triggered apoptosis, with particular emphasis on potential benefits of UDCA.

Show more
11. Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease
Journal of Virology
Cortez et al.
49 citations
2015
It is demonstrated that TUDCA and UDCA substantially reduced PrP conversion in cell-free aggregation assays, as well as in chronically and acutely infected cell cultures, and this effect occurs in prion disease, with an added mechanistic target of upstream prion seeding.

Open Access
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12. Targeting the p53 pathway of apoptosis.
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Amaral et al.
62 citations
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Recent developments of p53-induced apoptosis in human diseases are highlighted, and controversies arising from the double-edge sword of targeting p53 in disease are discussed.

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13. Role of neuroinflammation in neurodegeneration development
Signal Transduction and Targeted Therapy
Zhang et al.
259 citations
2023
The factors affecting neuroinflammation and the major inflammatory signaling pathways involved in the pathogenicity of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Amyotrophic lateral sclerosis are reviewed.

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3 Likes
#22

Rapamycin definitely pushes up GGT.

These are all my GGT figures since 2021 (only started weekly part into 2022) you can see the high dose Rapamycin pushing it up at the and it is only slowly coming down. One reason I may hold back on Rapamycin after 8th December is to see what happens with GGT.

43		37		32		28		34		34		28		29		30		30		31.89		26		34.94		28		36.71		37.6		30		24.68		27.96				29		35		30		28						30.2				31.15				23.7				23.5		23.99		27		22.73		24		23		22.12				26		27		23		28		29		32				27		28		30		30		27.9		27		27				23		25		24.7				25		26.1				22		33.4		25		25.5				25		38.8				36.9				29.9		28		32.3		32.16		25		24		28		32		27.7					26		29.8		28		27.8		28		32.6		32		26		33.1		28		28		32.5		33		26		28		32		31		31		30				29.2		28		35.7		30		32.4		32		32.5		31		41		32		27.2		34		33.1		36.8		33		27.4						35				35		43.3		37				40		39.4				48		43.8		46		38.9		39		44		16.8		50.6		56.3		55.8		58		56.3		57.4		49.8		49		51		56		58		59		56

GGT is just at the top end of the normal range, but it was a lot lower.

2 Likes
#23

The man is convinced C. Diff. is what causes Alzheimer’s so that sounds a bit cooky on the surface but he presents his clinical evidence which suggests to me that infections of all sorts can cause Alzheimer’s if they make it into the brain. It’s probably a subset of causes.

3 Likes
#24

Vaccines of all kinds seem to be associated with reduction in neurodegenerative disease. Assuming that this is due to a reduction in infections and not some other effect of vaccines would seem to imply that infection burden is possibly a causal factor for neurodegenerative disease. If we take that assumption, CDiff could very well be contributing to neurodegenerative disease.

Search vaccines on this forum for more info, eg Shingles vaccine had a significantly lower risk of developing dementia within 6 years of vaccination

3 Likes
#25

Low level infection increases inflammation, which is a known neuro problem.

Plus many bacterial and viral infections leave a mark on the immune system as a way to avoid complete clearance. Once you get a staph infection you become more susceptible due to the way staph modifies your immune system to hide.

These hidden reservoirs of past infections are quite the thing and cause a variety of seemingly unrelated illnesses.

Covid is a significant modifier of the immune system.

#26

I’m interested in this concept. Broadly speaking it seems like a mental safety barrier that people could use to avoid marketing driven wishful thinking.

The whole concept of “marginal gains” whereby lots of little benefits could add up to big improvements seems foolish when talking about a biological system we don’t understand. In addition, the wishful thinking associated with taking stuff that is “good for you” can remove the motivation to make real lifestyle change that would really drive improvement in healthspan outcomes. Taking a pill is so easy to do… it’s an attractive nuisance I’m fighting to avoid.

3 Likes
#27

Just checked the half-life: 4 days for UDCA but 3 hours for TUDCA!

#28

I’m starting ~400 mg TUDCA and 10 mg Ezetimibe. Not taking any other medication right now. Hoping to lower ALP and ApoB. ALP already decreased a bit from 108 U/L with I think vitamin D supplementation. I took a few other blood tests. We’ll see…

ALT 26 U/L
AST 20 U/L
ALP 102 U/L
GGT 14 U/L
Bilirubin 0.9 mg/dL
ApoB 60 mg/dL
Triglycerides 64 mg/dL
CRP 0.7 mg/L

2 Likes
#29

Thank you! I was wondering re the source…

#30

I think I got heartburn from this but might be confounding as N=1 so I’m quitting this for now…

2 Likes
#31

However, it appears that TUDCA is metabolised into UDCA.

1 Like
#32

This is an interesting paper to add to this topic

Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with Either Sporadic or Familial Alzheimer’s Disease

https://www.sciencedirect.com/science/article/pii/S0022283618309872?via%3Dihub

2 Likes
#33

The author, Heather Mortiboys, is leading the UDCA trial in PD: The UP Study results - Cure Parkinson's

And she’s now fast testing 100 promising compounds (including rapamycin, empagliflozin, lithium, terazosin, Theracurmin, telmisartan, omega 3, NAC, UDCA, etc.) in human cells for PD: Prioritising the most promising drugs for Parkinson’s: our new drug screening project - Cure Parkinson's

5 Likes
#35

Most interesting to me in delineating all the ways in which apoE4 carriers’ mitochondria are fucked. I had already gathered as much, but not the bit that mitochondrial impairments seem to extend to all cell types in the body. Only knew of brain and muscle cells for sure. I’d have to think it’s a good idea to double down on all known agents for improving mitochondrial function and biogenesis.

2 Likes
#36

Can’t think of anything better than exercise, I wonder if it would be a good idea to look at what PED’s (performance enhancing drugs) are banned for endurance athletes or other sports directly dependent on mitochondria. E.g AICAR just showed up in a perplexity search for me:

1 Like
#37

I tried AICAR 2 years ago when I did a lot of running, it does something, it’s a simular result / feeling to injectable carnitine 1g plus. For mitochondrial function during exercise I suspect that high dose methylene blue (20mg) is more cost efficient than AICAR

2 Likes
#38

Well, if it’s banned it probably works, is my reasoning, at least on the performance enhancing aspect, whether it’s safe is another question.

3 Likes
#39
2 Likes
#40

One more interesting datapoint for TUDCA: Tauroursodeoxycholic acid regulates macrophage/monocyte distribution and improves spinal microenvironment to promote nerve regeneration through inhibiting NF-κB signaling pathway in spinal cord injury 2025

:warning: Preprint + China :warning:

We found TUDCA restored spinal NSCs migration and proliferation and reduced spinal NSCs and neurons apoptosis and axon degeneration by regulating inflammatory response in vitro. TUDCA treatment promoted wound healing, down-regulated genes related to inflammatory response, and up-regulated genes related to spinal cord development in SCI mice. Our study provided evidence that TUDCA treatment regulated monocyte/macrophage distribution and improved the microenvironment to promote nerve regeneration in SCI mice.

4 Likes
#41

Tauroursodeoxycholic Acid Confers Protection Against Oxidative Stress via Autophagy Induction in Retinal Pigment Epithelial Cells 2025

Tauroursodeoxycholic acid (TUDCA) has been shown to protect against oxidative damage in retinal pigment epithelial (RPE) cells. However, the mechanisms by which it mediates these protective effects have not been thoroughly investigated in the context of age-related macular degeneration (AMD) disease onset and progression. We measured LC3-II and p62 expression via Western blot and immunohistochemistry in RPE cells treated with H2O2, TUDCA, or a combination of both to measure autophagy induction. To determine autophagy flux, we measured the expression of LC3-II/LC3-I in RPE cells in the presence of bafilomycin via Western blot. To determine the mechanistic pathways of TUDCA-induced autophagy, we measured the protein expression of autophagy regulators (Atg5, Beclin-1, S6, AMPK, and Akt) via Western blot. We show that TUDCA-mediated autophagy induction confers protection of RPE cells against oxidative damage via mTORC1/mTORC2 independent pathways but depends on Atg5. Our work adds to the overall understanding of RPE cell homeostasis and highlights the role of TUDCA in maintaining RPE health.
Our studies show that TUDCA’s cytoprotective effect in RPE cells is AMPK-independent. The activation of the Akt pathway by TUDCA in the presence of OS has significant implications for both cytoprotection and autophagy induction. Akt can phosphorylate and inhibit several pro-apoptotic factors, thereby enhancing cell survival under stress conditions. Akt activation can also induce autophagy. While Akt is typically associated with the mTOR pathway, which inhibits autophagy, there are situations where Akt activation can promote autophagy indirectly. For instance, Akt can modulate the activity of transcription factors like FOXO [61], which can upregulate autophagy-related genes. In summary, TUDCA activation of Akt in the presence of oxidative stress could enhance cytoprotection by inhibiting apoptotic pathways and potentially promoting autophagy through alternative signaling routes. Thus, it is crucial to consider that the specific cellular context, the type of stressor, and the duration of TUDCA treatment can diversely influence these signaling pathways.
We investigated whether RPE autophagy induction was seen with other bile acids. The lack of change in LC3-II levels in cells treated with TCA or TCDCA alone suggests that these treatments do not significantly affect autophagosome formation or the autophagic process under the conditions tested. The increase in LC3-II levels with the combined treatments of H2O2 and TCA or TCDCA indicates an accumulation of autophagosomes. This accumulation could be due to increased autophagosome formation or a blockage in autophagosome–lysosome fusion, leading to their accumulation. However, the concurrent increase in p62 levels indicates that these autophagosomes are not efficiently degraded, indicating impairment in autophagic flux. We cannot be sure of this conclusion without repeating an autophagy flux experiment with TCA and TCDCA, which is a limitation of this study. The lack of conclusive evidence could be a relevant next step in determining if autophagy induction is unique to TUDCA or can be seen with other bile acids.

@John_Hemming fyi