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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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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Ok 
Looking forward to something substantive when you have it.
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.
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
As long as I don’t have to live in one of Dr Barts bubbles
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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.
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.
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.
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.
If you’re interested, I can:
- Dive into specific splicing factors known to regulate elastin and how acetylation may modulate them.
- Explore 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.
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.
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.
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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Merz Pharma (Merz Aesthetics) claims that their injectable implant Radiesse stimulates collagen and elastin production through its unique composition and mechanism of action. Radiesse contains microspheres of CaHA, a biocompatible substance also found in bones. Over time, the CaHA particles act as a scaffold, stimulating fibroblasts (skin cells) to produce collagen and elastin. The collagen production can last up to a year, while elastin stimulation typically lasts for several months.
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Interestingly if you ask chatGPT to answer the question not broken down into steps it does not get the correct answer. (or perhaps moreso misses out a key component)
You said:
to what extent is elastin production dependent on the mitochondrial membrane potential
ChatGPT said:
Great question! The relationship between elastin production and mitochondrial membrane potential (ΔΨm) is indirect but important, especially in the context of cellular metabolism, oxidative stress, and overall cell health.
1. Basic Connection Between Mitochondria and Protein Synthesis (like Elastin)
- Mitochondrial membrane potential (ΔΨm) is essential for ATP production via oxidative phosphorylation.
- ATP is required for protein synthesis, including elastin, which is a major extracellular matrix (ECM) protein important for tissue elasticity (e.g., skin, lungs, vasculature).
- If ΔΨm is disrupted, ATP levels drop, leading to impaired general protein synthesis, including elastin.
2. Mitochondrial ROS and ECM Regulation
- Mitochondrial dysfunction and ΔΨm depolarization often increase reactive oxygen species (ROS).
- High ROS levels can damage signaling pathways and proteins directly or indirectly regulate elastin gene (ELN) expression.
- Oxidative stress can downregulate elastin synthesis and promote ECM degradation (via MMPs—matrix metalloproteinases).
3. Mitochondrial-Dependent Signaling Pathways
- Mitochondrial health (reflected in ΔΨm) affects TGF-β, Notch, and other pathways that modulate elastin gene expression.
- For example, TGF-β signaling, crucial in elastogenesis, is sensitive to mitochondrial ROS and ATP levels.
4. Cell Types and Context Dependence
- Fibroblasts, vascular smooth muscle cells, and other elastin-producing cells rely on mitochondrial function.
- In diseases like COPD, vascular diseases, and aging, impaired mitochondria (low ΔΨm) correlate with reduced elastin content and increased tissue stiffness.
Summary:
Elastin production is dependent on mitochondrial membrane potential indirectly, via:
- ATP production needed for synthesis.
- Regulation of ROS that can damage elastin or suppress its gene expression.
- Impact on signaling pathways that govern ECM remodeling and elastin synthesis.
When ΔΨm is compromised, elastin synthesis is typically reduced, and ECM degradation is enhanced — contributing to diseases involving tissue elasticity loss.
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I’m not terribly concerned about the skin aspect. That is not where the lack of elastin is going to kill you.
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That implant is not about skin only, it’s distributed in all tissues and adds so needed collagen and elastin. Skin, our biggest organ, is very important for general health but often is undervalued.
Last week I had a very unique experience with meeting a woman who’s 102 years old. It was the first time in my life that I interacted with such an old person in real life. What amazed me was her skin. It didn’t have any blemishes, growths, rough spots, etc. it was all even and clean, with almost no wrinkles. She did have dementia, but besides that, she didn’t have major health issues. Good skin is a sign of good health and good genes imo.
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Do they specifically die because they lack elastin or are other factors at play here?
Without enough functional elastin, lungs fail, the heart fails, arteries fail.
One can have perfect markers, triglycerides perfect, heart rate perfect, strength perfect but that is not enough without perfect elastin.
https://journals.physiology.org/doi/full/10.1152/japplphysiol.90563.2008
Other functional aspects become irreversibly impaired as well. This is easy to see in aging people who are athletic. Their stride changes as elastin is lost, their range of motion is reduced due to loss of flexibility, tendons and ligaments require elastin for flexibility and the essential rebound it provides. As people age they don’t “bounce” like younger people with more elastin. This is the visible and irreversible effect of loss of elastin.
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If you understand the elastin problem, then you will know the maximum human life span is 120 regardless of living in a bubble.
OK, so now we are up to 140 years old as potential maximum human life span, that’s progress !
I think a person with good genetics, lifestyle from birth that can slow down aging to 0.5 (so immaculate diet, exercise, sleep, stress reduction, excellent dental care, social support), living in a relatively isolated community so they could avoid CMV/EBV/HPV and other DNA based viruses, worst forms of influenzae, coronavirus and other infectious agents, avoid excessive Sun and other environmental toxic hazards and lots of luck - could live to 140 years old.
And that’s without pharmaceuticals, supplements and worked out Yamanaka factor therapy.
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Do you know how important it is for the CNS/brain?
From Nick Norwitz.
The Key To SLOWING Aging? $1 Omega-3 vs. $2M Anti-Aging Protocol
6:45 - Omega 3 (1 g/day) improved scores on Phenoage, Grimage2, and DunedinPace
7:20 - Omega 3 alone at 1g/da was lowering the DunedinPACE estimated rate of aging to 0.69, close to Bryan Johnson’s scores.
9:00 Who looks younger? Bryan Johnson (22 August 1977)? Or Tom Brady (3 August 1977)?
Nick’s source paper is linked below.
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
Sample size is 777.
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Good question. The brain like all our other organs requires a variety of fluid flows. Blood and CSF are the 2 fluids that come to mind.
Loss of elastin affects circulation as the arteries lose their elasticity.
Elastases and elastokines: elastin degradation and its significance in health and disease
https://www.tandfonline.com/doi/full/10.1080/10409238.2020.1768208
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I was just trying to give you some hope
120 is still the upper limit for lifespan, 140 is highly speculative but people don’t want to deal with the clock winding down.
Speaking of clocks, they deceive us and give us false hope. As an analogue clock runs in never ending circles, and a digital clock constantly repeating numbers, even the sun and the stars offer false hope. These are never ending indicators of time and life passing.
If humans were born with an hour glass in their chest that they could see and watch the very limited sands of their life running out, they might do things a bit differently. Or they may not. When that hour glass is new, and full to the brim it may seem unlimited. But we know it’s not.
Many of us on this forum are at the age where our peers are passing. When I see people 50, 60, 70 passing and I think about being in my 70th year at the age of 69, I often wonder how much time I have left. Will I hit the stat average of 81?, if that is my fate, I have 12 years left.
Is it now time for me to “retire” and sit back in my rocking chair or to engage more fully in the life I have left?
I’m going for the engaged approach, as all the members of this forum have also chosen
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Again, there is no solid evidence for that, it’s all just speculations based on some theories and few case studies, so basically scraping the bottom of the scientific barrel.
I’m going for the engaged approach
I agree with all that, I am not sure what has to do with making blanket statements about the upper limit for human lifespan ? I would feel very lucky to live with mostly intact cognition to the age of 100.
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Not a very strong argument for your position LoL!
The elastin problem has been studied extensively and is very well understood by people much smarter than me. We know how elastin is lost, we know how long it takes to run out of it, we know it’s not replaceable systemically, those are scientific facts. As far as how elastin affects lifespan, it’s pretty simple logic, we die without it. Period, end of story.
So until there is a solution to the elasitin problem, human lifespan is rate limited to 120 years by this one factor. You can disagree with that all you want but you have not brought anything to the discussion that changes the established facts on elastin.
There are many other factors that limit how long humans can live, elastin is probably the hardest one to solve. When this problem is solved, this may allow for life to be longer than 120 years. Until then increasing health span is the only thing we can do.
I hope you do reach the century mark, it’s a good goal.
In the mid 90’s I was at a SNF in the SeaTac area, taking pictures of bedsores and saw a “leader board” with 6 people 100 and up, the oldest was 104. This was a Japanese only facility and very well run. The staff were very proud of their centenarians. I got to meet 2 of them.
I’ve been in over 200 SNF’s and had never seen a “leader board” like that. It was very cool
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I don’t have a position on max age limit. Some scientists don’t believe there is a limit. There is as scant evidence for 140 as there is for 120.
In medieval England life expectancy was 31 years, once you made it to 25 then average became about 51 years old. The records were very poor back then but living in to 80’s was rare. Maximal lifespan was probably around 90. Now 600 years later, same place average age is 80’s and maximal lifespan recorded was 115. So that’s about 25-30 year shift. All mostly due to proper nutrition and sanitation.
What makes you think that we achieved maximal life span in 21 century when medicine is still in its toddler stage? We cannot cure most diseases, we can only manage or lessen the impact of most of them.
The elastin problem has been studied extensively and is very well understood by people much smarter than me. We know how elastin is lost, we know how long it takes to run out of it, we know it’s not replaceable systemically, those are scientific facts.
I am NOT discounting your research of the elastin pathophysiology but I would be careful with this dogmatic approach. Science is full of dogmas and myths that were disproven. We used to think neurons cannot regenerate once they are set in place in humans. There may be simple a solution for the elastin problem that we maybe already have implemented. Just like sanitation prevented millions of deaths or fluoride increased dental health. Again, unless you have a controlled human study, you cannot be certain.
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