#1

As for the vitamin-B rich Buckwheet extract, B vitamins drive the methylation cycle, which drives up wide genome methylation as seen in this large elderly cohort study (7), potentially accelerating the aging-associated epigenetic changes. Furthermore, long-term B9 supplementation increased cancer incidence and all cause mortality, with the effect specifically correlated to the folate concentration in the blood (8).

#2

Are there any studies in mice showing that supplementing with moderate doses of folate causes a change in median and maximum lifespan? Or is this another mechanistic speculation that does not have any effect on an actual organism.

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#3

There have been studies showing that supplementing with folic acid leads to greater colon cancer incidence, but I think more recently that association was not confirmed:

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#4

I think the opposite. I think of epi-genetic aging as the result of gene promoters becoming less methylated and thus active when they shouldnā€™t be, causing the cell to be less effective at its job or even outright apoptosis ie random gene de-regulation. Folate contributes to the methylation process to keep gene promoters silenced when needed (which is the vast majority of promoters in a specialized cell) and likely has little effect on actively expressed genes.

#5

Bivalent promoters gain methylation with age (and the rate of their methylation gain is inverse to species life expectancy, see horvath paper)

PRC2 binding sites gain methylation with ageā€¦ (worse in shorter lived organisms). EZH2 is the active domain of PRC2ā€¦ [but doesnā€™t act equally on all genesā€¦]

histone methylase EZH2 is frequently dysregulated in melanoma and is associated with DNA methylation and silencing of genes involved in tumor suppression

This has effects on the ability of H3K27me3 to properly do what it does [need to fil this in later]

But bivalent promoters are also only a small fraction of the CpG sites that get overmethylated with age. I think there is still an overal average SMALL decrease in methylation with age, though you see this more in transposon sites that arenā€™t as easy to label as cpG sitesā€¦

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how is H3K27me3 involved in recruiting PRC2 complexes and spreading methylation marks

Hereā€™s how H3K27me3 and PRC2 interact in a self-reinforcing loop:

  1. Initial PRC2 Activity:
  • PRC2 methylates H3K27 to H3K27me3
  • Core components:
    • EZH2 (catalytic)
    • SUZ12
    • EED
    • RBBP4/7
  1. Recognition & Spreading:
  • EED recognizes H3K27me3
  • Binds existing marks
  • This binding:
    • Activates EZH2
    • Increases methylation activity
    • Promotes spreading
  1. Key Mechanisms:
  • Positive Feedback:
    • H3K27me3 recruits more PRC2
    • More PRC2 creates more H3K27me3
    • Leads to domain expansion
  • Spatial Spread:
    • Nucleosome to nucleosome
    • Creates repressive domains
    • Can spread over kilobases
  1. Regulation Factors:
  • Chromatin accessibility
  • Boundary elements
  • Competing modifications
  • Other protein complexes
  • DNA sequence elements
  1. Important Features:
  • Self-reinforcing loop
  • Epigenetic memory
  • Heritable silencing
  • Domain maintenance
  • Cellular memory

This creates a robust system for maintaining repressive chromatin states.

CopyRetry

AC

does overmethylation of cpg sites (eg from excess methyl donors) block prc2 from binding to h3k27me3 sites, causing negative feedback to increased methylation activity

This is a fascinating and complex question about potential negative feedback between DNA methylation and H3K27me3/PRC2. Hereā€™s what we know:

  1. CpG Methylation vs PRC2:
  • Dense CpG methylation often:
    • Can interfere with PRC2 binding
    • Affects chromatin accessibility
    • May compete for binding sites
  1. Known Interactions:
  • PRC2 preferentially binds:
    • Unmethylated CpG islands
    • H3K27me3-marked regions
    • Specific DNA sequences
  • DNA methylation can:
    • Reduce PRC2 recruitment
    • Affect chromatin structure
    • Change binding affinity
  1. Potential Feedback:
  • High methyl donor conditions:
    • Increased DNA methylation
    • Could reduce PRC2 binding
    • Might affect H3K27me3 spread
    • Potential negative feedback
  1. Complexities:
  • Multiple regulatory layers
  • Cell-type specific effects
  • Context-dependent outcomes
  • Dynamic equilibrium

However, I should note that:

  • Direct causation is complex
  • Research is still ongoing
  • Many factors involved
  • Specifics may vary by context

Would you like me to explore any particular aspect in more detail?

CopyRetry

AC

and prc2 activity decreases with age right

Yes, PRC2 activity generally decreases with age. Hereā€™s what we know:

  1. Age-Related PRC2 Changes:
  • Decreased EZH2 expression
  • Lower H3K27me3 levels
  • Reduced complex stability
  • Changed targeting patterns
  • Loss of repressive domains
  1. Contributing Factors:
  • Oxidative stress
  • DNA damage accumulation
  • Changed chromatin accessibility
  • Altered cofactor availability
  • Metabolic changes
  1. Consequences:
  • Loss of gene repression
  • Changed cell identity
  • Increased transcriptional noise
  • Dysregulated developmental genes
  • Cellular aging phenotypes
  1. Specific Patterns:
  • Bivalent domain disruption
  • Changed stem cell regulation
  • Cancer-related changes
  • Tissue-specific effects
  • Memory loss in aging
  1. Feedback Loops:
  • Age ā†’ ā†“PRC2 ā†’ ā†“H3K27me3
  • ā†“H3K27me3 ā†’ ā†“PRC2 recruitment
  • DNA methylation changes
  • Chromatin accessibility changes
  • Metabolic alterations

This creates a progressive decline in epigenetic regulation with aging.

Would you like me to elaborate on any of these aspects?

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#6

If folate can accelerate epigenetic aging (significantly) yet it does not affect lifespan in clinical trials, then I would argue that the epigenetic age is somewhat worthless.

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#7

To me the question to consider is what the function of methylation is.

I think of it like grass growing on a road that is not travelled. It arrives because the gene is less frequently transcribed. However, it has the effect of discouraging the genome from spending energy on transcribing the gene.

This means that if the transcription would fail part way through if the gene did start then it does not waste the energy on trying to transcribe it. Alternatively it slows down the transcription which has similar effects in terms of energy balance between transcription and translation.

1 Like
#8

Can someone tell me is there a relationship between folic acid and folate? I know folic acid makes people suicidal.

#9

This argument can also be used using the mice data. Rapmaycing accelerated epigenetic aging but it increases lifespan. Metformin the opposite.

1 Like
#10

Folic Acid is Folate plus I think 1 naked proton. (it may be more than 1)

#11

If I have to choose between a younger epigenetic age or a longer realized lifespan, I know what Iā€™ll choose.

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#12

Per Vera-Health.ai on this question ā€¦ they seem to think B Johnson might be wrong ā€¦

Current evidence suggests that folic acid supplementation does not increase mortality. In fact, it may offer protective benefits, particularly in certain populations. A recent meta-analysis involving 16 studies with 39,034 participants found that folic acid supplementation was associated with a statistically significant reduction in the risk of stroke and mortality
1
. This indicates that folic acid may have a protective effect rather than increasing mortality.

In patients with end-stage renal disease (ESRD), high serum homocysteine levels are linked to an increased risk of cardiovascular diseases. Folic acid supplementation has been shown to reduce these levels. A study using the Taiwan National Health Insurance Research Database found that among 55,636 stable incident hemodialysis patients, those receiving folic acid supplementation had improved all-cause and cardiovascular-related mortality rates compared to those who did not receive supplementation
2
. This suggests that folic acid supplementation may be particularly beneficial in reducing mortality in high-risk groups like hemodialysis patients.

However, the efficacy of folic acid in reducing cardiovascular disease risk in the general population remains controversial. The same meta-analysis found no statistically significant reduction in the risk of cardiovascular disease, coronary heart disease, or peripheral arterial disease
1
. This indicates that while folic acid supplementation may not significantly impact cardiovascular disease risk in the general population, it does not increase mortality.

In conclusion, current evidence supports that folic acid supplementation does not increase mortality and may provide benefits by lowering stroke risk and improving survival rates, especially in high-risk groups. Further research is needed to better understand the broader impact of folic acid on cardiovascular health across diverse populations.

References

  1. Abstract 4144952: A Meta-analysis of Folic Acid Supplementation Efficacy in Cardiovascular Diseases Prevention.
    Circulation
    Martinez et al.
    0 citations
    2024
    Folic acid supplementation showed efficacy in reducing the risk of stroke and mortality, however, future research is necessary to investigate homocysteineā€™s role in cardiovascular diseases and events.

Meta Analysis
Systematic Review
RCT
Highly Influential Journal
Show more
2. Folic acid supplementation in end-stage renal disease patients reduces total mortality rate.
JN. Journal of Nephrology (Milano. 1992)
Chien et al.
10 citations
2013
In adult hemodialysis patients, folic acid supplementation improves cardiovascular and all-cause mortality rates.

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#13

This appears to be the best approach. Look at ACM, all cause mortality. Epigenetics is hugely complicated subject so looking at how folate affects human epigenetics could lead to endless questions and speculation. Itā€™s certainly not clear that more or less DNA methylation is good for health and longevity. You need both occurring at the correct times. Itā€™s why epigenetic clocks arenā€™t reliable yet. Itā€™s complicated and they havenā€™t figured it out yet.
Does Bryan Johnsonā€™s team have any explanation for HOW folate accelerates epigenetic aging? Do they mean just by the TruDiagnostic clocks? (and thus not definitive for aging)
@AlexKChen , your lead article says:

Conclusions

Long-term supplementation with folic acid and vitamin B12 in elderly subjects with mildly elevated homocysteine levels resulted in changes in DNA methylation of several genes implicated in normal developmental processes and carcinogenesis. These findings may provide unique leads for further research unraveling the mechanisms underlying the effects of B-vitamins on health and disease during the life cycle.

Changes in DNA methylation are happening all the time - every day - that could be good or bad or normal.

And your post on H3K27me3, PRC2 is pretty obscure and the AI may be doing a bit of speculating. Iā€™ll look into it more. I do agree with this:

However, I should note that:

Direct causation is complex
Research is still ongoing
Many factors involved
Specifics may vary by context

So, the speculation is that supplemental folate is equivalent to aging here?

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#14

Could you elaborate on this? And maybe provide links to some studies?

#15

The problem is that methylation changes are generally poor predictors of changes in gene expression, which suggests that the causal role they play in age-associated loss of function is often minimal.

Other epigenetic clocks (based on histone modifications, for example) could better correlate with gene expression, and might be better predictors of health status.

I think the methylation data is just easier to acquire and the methylation clocks have been around longer so people are more familiar with them.

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#16

I donā€™t agree with this. Yes, histone modification is also involved but epigenetics looks at both. The problem is that there are over 28 million CpG sites and maybe 28,000 CpG islands in the human genome so it all depends on which ones you are looking at and how often they change. However, DNA methylation is widely considered an on-off switch for that gene. Whether thatā€™s a ā€œcausal roleā€ in aging is much more complicated. My guess is that for the right CpG site, at the right time, it would be causal and/or correlated to aging. Once the researchers pin that down, I think that an accurate, reliable Epigenetic Clock is very much possible. The question is whether a Proteomic Clock may be an easier (cheaper?) nut to crack.

#17

ā€¦.oh, the shock of it!

4 Likes
#18

Hereā€™s what AI saysā€¦

DNA methylation and histone modification are closely correlated, often working together to regulate gene expression by creating a repressive chromatin environment, where DNA methylation generally leads to long-term silencing while histone modifications can provide more dynamic control, with the two mechanisms often influencing each other through protein interactions and signaling pathways; essentially, DNA methylation can ā€œlock inā€ a repressed state established by histone modifications.

Histone modifications can direct where DNA methylation occurs, and conversely, DNA methylation can recruit proteins that modify histones, creating a feedback loop.

Certain histone modifications, like H3K9me and H3K27me3, are often associated with DNA methylation and are linked to gene repression.

image
image1029Ɨ189 6.79 KB

https://byjus.com/biology/difference-between-dna-methylation-and-histone-acetylation/#:~:text=DNA%20methylation%20is%20used%20to,chromatin%20and%20hence%20greater%20transcription.