#537

And really it doesn’t matter because the maximum lifespan ever achieved was only 122 years (excluding myths like the 2XX year old Chinese man or biblical figures).

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#538

You had to deal with a lot of infectious disease in the past though from water, living quarters, food, etc. Inhibiting mTOR via gene mutations doesn’t help with that.

Tangentially related:

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#539

The same when he said he has the cleanest plasma in world… Last friday when I donate mine the nurse was happy about the color and texture of it. It was fat-free and “really beautiful” she said. I like Bryan Johnson be he definitely have an ego problem. Bro is not a god.

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#540

I don’t think he does. His testing regimen is very extensive, this is just one that is easy to share and gamifies the process. Not only that but it’s readily accessible and it’s a managed process for all who want to participate. Gives people an apples to apples thing :slight_smile:

The $2M he supposedly spends annually is mostly on testing and since the D_Pace done quarterly is about $1k a year, his other tests are providing the “real” guidance.

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#541

If we could ever do an life time closed lab experiment where we have a small human community living in biosphere type of sterile environment, where we can control the air quality, water quality, food etc and choose human subjects with genetic longevity predisposition and observe their offspring from birth to death. And somehow offset the mental issues associated with captivity. Maybe then we could figure out the true human lifespan. Lab mice live almost twice as long as wild mice, so it is possible than under right conditions we could get higher numbers for humans.

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#542

If you understand the elastin problem, then you will know the maximum human life span is 120 regardless of living in a bubble.

Until that puzzle is solved everything being done is about health span, not lifespan.

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#543

I think the ECM can be maintained

#544

I think it’s just marketing, to be honest. Bold claims to get attention.

As for epigenetic tests, it’s a super interesting concept to have an actual biomarker that we can track, but right now I personally put little weight in them. Maybe in the next 10 years we’ll have something which is more reliable.

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#545

The ECM is not 1 thing, elastin is one of the components.

Collagens, Elastin, Fibronectin, Laminins, Tenascins, Growth factors, and MMPs

All the other factors in the ECM are or seem to be addressable.

The extracellular matrix: Structure, composition, age-related differences, tools for analysis and applications for tissue engineering - PMC .

On top of that elastin is present in organs and structures that cannot function without elastin.

Elastin is an extracellular matrix protein and is most abundant in tissues where elasticity is of major importance, such as blood vessels (50% of dry weight), elastic ligaments (70% of dry weight), lungs (30% of dry weight) and skin (2–4% of dry weight)

Role of elastic fiber degradation in disease pathogenesis

https://www.sciencedirect.com/science/article/pii/S0925443923000728

Elastin is complex and the mechanism that makes it shuts off at puberty. Elastin has a 70 year half-life and if it was made continually we would be a ball of rubber :slight_smile:

Repair of elastin is a challenging problem. One cannot just add elastin to a tissue and hope for improvement, as the precise structure, amount, and interactions with other components of the extracellular matrix are all important. The only realistic approach is to guide cells into performing the same work of elastic depositition that occurred in early life. This is not a solved problem, as it is quite possible to trigger behavior that leads to unhelpful or even harmful elastin deposition, in which the structure and amounts are incorrect. Regulatory networks must be clearly identified and then manipulated in the right ways.

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#546

I think the ECM can be maintained including elastin.

#547

The science seems to disagree with that idea.

If you do figure out how to restore elastin and can prove it, you will be a billionaire in no time :slight_smile: Let me know when you can provide the solution as I’d be one of your first investors :slight_smile:

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#548

Whatever research was done on elastin, it was NOT done in a controlled setting in humans. You cannot establish the actual in-vivo half life of Elastin WITHOUT controlled human studies and since we cannot put humans in a lab for the entire life we just don’t know. History of science is full of premature absolutist statements that were disproven later.

The earth is flat… Copernicus… not really.
The Newtonian laws of physics are absolute and cannot be broken… Einstein… well, it’s more complicated than that.

#549

Here is one company working on this problem.

https://elastin-biosciences.com/

#550

Elastin has been studied extensively and the half life is not in dispute in any of the papers I’ve read. How it’s formed, when it’s formed, what breaks it down, how to protect it, why there is currently no solution to this problem are also well established. I’ve provided a number of references related to this problem.

This is not an unknown issue, it’s been studied for 70 plus years. There are hundreds of papers on it.

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#551

The ecm depends on elastin, collagen, hyalronic acid and some others in order to suppress cancer formation. The question is, at what levels does the lack of elastin no longer support life? At the age of 140 you should only have 25% elastin left but can you survive on less?

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#552

Again, how many of the life-span studies on Elastin were in-vivo studies in humans in a controlled laboratory setting ?

This is not an unknown issue, it’s been studied for 70 plus years. There are hundreds of papers on it.

That’s a poor argument. Alzheimer’s dementia was studied for 124 years and there are thousands of papers on it… and the scientists still don’t know what is causing it…(it’s not amyloid plaques).

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#553

Ok :slight_smile:

Looking forward to something substantive when you have it.

#554

Maybe when humans establish a base on the moon or mars. That may resemble the closest thing to a laboratory study, although the varying gravity force may be a huge factor.

#555

Since few people live past 100 fewer still past 120, it appears that the range of 120 to 140 is the life span that is supported by our diminishing elastin. Being healthy and active to that age is my goal :slight_smile:

As long as I don’t have to live in one of Dr Barts bubbles :slight_smile:

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#556

to what extent is elastin production dependent upon mRNA splicing

ChatGPT said:

Great question! Elastin production is highly dependent on mRNA splicing, and this step plays a crucial role in determining the amount and functionality of elastin produced. Here’s a breakdown of how and to what extent mRNA splicing is involved:

1. Elastin Gene and Pre-mRNA

  • The ELN gene encodes elastin. Like many other genes, ELN is first transcribed into a pre-mRNA, which contains both exons (coding regions) and introns (non-coding regions).
  • For elastin to be properly synthesized, this pre-mRNA must undergo splicing to remove introns and join exons into a mature mRNA that can be translated into tropoelastin (the soluble precursor of elastin).

2. Alternative Splicing and Elastin Variants

  • Alternative splicing of elastin pre-mRNA can produce multiple isoforms of elastin, which may differ in their properties and tissue-specific functions.
  • This means that splicing is not just a yes/no step — how elastin is spliced affects the final elastin protein’s structure and elasticity.

3. Regulation of Elastin Expression via Splicing

  • Elastin production is regulated at the level of splicing. For example:
    • Developmental stages: In embryonic and neonatal stages, elastin is highly expressed, and splicing is tightly regulated to ensure high production.
    • Adult tissues: Elastin production decreases, and changes in splicing contribute to this downregulation.
  • Defects or mutations affecting the splicing sites or machinery can lead to improper splicing, resulting in reduced elastin or non-functional proteins, contributing to diseases like supravalvular aortic stenosis (SVAS) or cutis laxa.

4. Splicing Factors and External Influences

  • Various splicing factors (proteins that assist in splicing) influence elastin mRNA processing.
  • External factors such as oxidative stress, aging, and inflammatory signals can alter splicing factor activity, thereby affecting elastin levels and contributing to age-related loss of tissue elasticity.

:white_check_mark: Summary: To What Extent?

Elastin production critically depends on mRNA splicing — both in quantity (how much functional mRNA is produced) and in quality (which isoforms are generated). Defects in splicing can significantly reduce elastin production or produce dysfunctional elastin, leading to severe physiological consequences.

If you want, I can dive into specific splicing factors or mutations that impact elastin splicing. Let me know!

You said:

to what extent is the splicing of elastin variants dependent upon cytosolic acetyl-CoA levels

ChatGPT said:

Excellent follow-up! You’re diving into a nuanced and emerging area — the intersection of cellular metabolism (e.g., acetyl-CoA levels) and gene regulation via splicing. Let’s unpack this carefully.

:key: Core Idea: Linking Acetyl-CoA to mRNA Splicing

1. Acetyl-CoA as a Central Metabolic Hub

  • Acetyl-CoA is a key metabolite involved in energy production, lipid synthesis, and protein acetylation.
  • In the nucleus and cytosol, acetyl-CoA serves as a donor for acetylation reactions, including the acetylation of histones and splicing factors.

2. Acetylation and Splicing Regulation

  • The acetylation status of splicing regulatory proteins (SR proteins, hnRNPs) affects their ability to bind RNA and influence splice site selection.
  • Histone acetylation can also indirectly influence splicing by altering chromatin structure and making certain exons more or less accessible to the splicing machinery.
  • Since cytosolic acetyl-CoA is a key acetyl group donor, its availability directly impacts protein acetylation, including of splicing regulators.

3. Evidence of Acetyl-CoA Impact on Elastin Splicing (Indirect but Plausible)

  • While direct studies specifically linking cytosolic acetyl-CoA levels to elastin splicing variants are limited, indirect evidence suggests that:
    • Changes in acetyl-CoA can modulate the activity of splicing factors known to regulate alternative splicing of many genes, possibly including ELN (elastin).
    • During aging and metabolic shifts, acetyl-CoA levels decline, coinciding with reduced elastin production and altered extracellular matrix composition — suggesting a potential metabolic control over elastin splicing.

4. Splicing Factors Potentially Affected by Acetyl-CoA

  • Splicing regulators like SR proteins (e.g., SRSF1, SRSF2) and hnRNP family members, which have been shown in other contexts to be regulated by acetylation, may influence elastin alternative splicing.
  • If acetyl-CoA levels fall:
    • Reduced acetylation of these factors could impair their splicing activity, possibly altering the inclusion/exclusion of specific exons in elastin mRNA.
    • This could explain age-related shifts in elastin isoforms or reduced elastin synthesis.

:white_check_mark: Summary Answer: To What Extent?

  • The splicing of elastin is likely indirectly dependent on cytosolic acetyl-CoA levels, through acetylation of splicing factors and chromatin modifications.
  • Exact quantification of this dependence (e.g., dose-response of acetyl-CoA to elastin splice variants) has not been fully elucidated in current research.
  • However, given acetyl-CoA’s central role in regulating protein acetylation, chromatin state, and RNA processing, it’s reasonable to infer a significant modulatory effect, especially under conditions like aging, metabolic disease, or oxidative stress, where acetyl-CoA pools are altered.

:gear: If you’re interested, I can:

  • Dive into specific splicing factors known to regulate elastin and how acetylation may modulate them.
  • 探索 experimental data (if any) on metabolic control of elastin synthesis.
  • Suggest experimental approaches to test this hypothesis in a research setting.

Let me know!

You said:

to what extent are cytosolic acetyl-CoA levels dependent upon mitochondrial membrane potential

ChatGPT said:

Fantastic — this is a deep biochemical question that touches on the integration of mitochondrial function, metabolism, and gene regulation. Let’s break it down carefully and precisely.

:key: Short Answer:

Cytosolic acetyl-CoA levels are highly dependent on mitochondrial membrane potential (ΔΨm), because ΔΨm is essential for mitochondrial ATP production and for the export of citrate, which is the main precursor for cytosolic acetyl-CoA synthesis. Disruption of ΔΨm limits acetyl-CoA availability in the cytosol and nucleus, impacting processes like histone and protein acetylation and potentially mRNA splicing regulation.

:white_check_mark: Detailed Explanation:

1. Mitochondrial Membrane Potential (ΔΨm): What is it?

  • ΔΨm is the electrochemical gradient across the inner mitochondrial membrane, generated by the electron transport chain (ETC).
  • It drives ATP synthesis and metabolite transport into and out of mitochondria.
  • Sufficient ΔΨm is essential for normal mitochondrial and cellular function.

2. Cytosolic Acetyl-CoA: Where Does It Come From?

The main source of cytosolic acetyl-CoA is mitochondrial-derived citrate, exported via the citrate shuttle, then cleaved by ATP-citrate lyase (ACLY) in the cytosol:

Citrate+ATP via ACLY Acetyl-CoA+Oxaloacetate+ADP+Pi

Thus, citrate export from mitochondria is key to cytosolic acetyl-CoA production.

3. How is Citrate Export Dependent on Mitochondrial Membrane Potential?

  • Citrate production in mitochondria depends on TCA cycle activity, which is powered by oxidative metabolism — and this is highly dependent on ΔΨm.
  • ΔΨm is essential for ATP production, which powers various mitochondrial enzymes and transport processes.
  • Citrate export to the cytosol is mediated by the mitochondrial citrate carrier (SLC25A1) — this transport is indirectly dependent on ΔΨm because without sufficient ΔΨm, TCA cycle flux drops, and citrate levels fall.

4. Consequences of Collapsing Mitochondrial Membrane Potential:

If ΔΨm is lost or impaired (e.g., by toxins, oxidative stress, aging, mitochondrial dysfunction):

  • TCA cycle slows → less citrate produced.
  • Less citrate exported → reduced substrate for cytosolic acetyl-CoA synthesis.
  • Less acetyl-CoA available for:
    • Lipid synthesis.
    • Protein acetylation (including histones and splicing factors).
    • Epigenetic regulation of gene expression and splicing.

Thus, mitochondrial dysfunction leads to a drop in acetyl-CoA pools, affecting gene expression, splicing, and cell function.

5. Experimental Evidence & Pathophysiological Relevance:

  • Mitochondrial inhibitors (e.g., FCCP, rotenone) that dissipate ΔΨm reduce cytosolic and nuclear acetyl-CoA and lower global acetylation.
  • Aging and degenerative diseases (with compromised ΔΨm) show reduced acetyl-CoA and altered gene expression patterns, including splicing.
  • In stem cells, mitochondrial activity (including ΔΨm) tightly regulates nuclear acetylation and gene programs via acetyl-CoA availability.

:white_check_mark: Summary Answer (Concise):

Cytosolic acetyl-CoA levels are strongly dependent on mitochondrial membrane potential (ΔΨm) because ΔΨm is crucial for the mitochondrial production and export of citrate — the main precursor for cytosolic acetyl-CoA synthesis via ACLY. When ΔΨm is reduced, citrate export drops, leading to lower cytosolic acetyl-CoA, which can impair lipid synthesis, histone acetylation, and splicing regulation.

Thus, any disruption of mitochondrial membrane potential can have downstream effects on nuclear processes like mRNA splicing, via acetyl-CoA shortage.

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