Josh
#61
That throughout will be needed but i dont think ai will help since it doesnt have a good db like this one to learn from. I dont expect it to beat a greedy algo like try all of them and then take a few winners and try all of them again with that and repeat. I expect the worm feed to become saturated by 3 or 4 compounds.
They already run into saturation issues even with just 1 chemical now and cant replicate other labs higher doses?
adssx
#62
2 Likes
I am not persuaded.
Much that I think AI has a useful function
In the end it searches out the conventional wisdom.
I am not persuaded it is a good source of novelty.
Much that I am not unhappy at this response sent to me recently (via an LLM)
LLM Answer
2.0 Pro Experimental. Lacks access to real-time info and some Gemini features.
Yes, John Hemming’s emphasis on cytosolic acetyl-CoA as an indicator of cellular power and its connection to the aging phenotype makes a lot of sense, and it’s a crucial piece of the puzzle that connects mitochondrial function, PGC-1α, and overall cellular health. Here’s a breakdown of why it’s important and how it fits in:
1. Acetyl-CoA: A Central Metabolic Hub
- Acetyl-CoA is a fundamental molecule in cellular metabolism. It’s not just a fuel source; it’s a critical signaling molecule and a building block for many important biomolecules.
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Mitochondrial Production: The primary source of acetyl-CoA is within the mitochondria, where it’s produced from the breakdown of carbohydrates (via pyruvate from glycolysis) and fatty acids (via beta-oxidation). This is the entry point to the citric acid cycle (Krebs cycle), the central energy-producing pathway of the cell.
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Cytosolic Roles: While much of the acetyl-CoA is used within the mitochondria for ATP production, a significant portion is also exported to the cytosol, where it plays essential roles:
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Fatty Acid Synthesis: Acetyl-CoA is the precursor for fatty acid synthesis. This is crucial for building and maintaining cell membranes, storing energy, and producing signaling molecules.
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Cholesterol Synthesis: Acetyl-CoA is also the starting material for cholesterol synthesis, which is vital for cell membranes, hormone production, and vitamin D synthesis.
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Acetylation Reactions (This is the key to Hemming’s point): Acetyl-CoA is the acetyl donor in acetylation reactions. This means it provides the acetyl group (COCH3) that gets attached to other molecules. This is crucially important for:
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Histone Acetylation: Acetyl groups are added to histones (the proteins that DNA is wrapped around). This loosens the chromatin structure, making genes more accessible for transcription. In general, increased histone acetylation is associated with increased gene expression. This is a major form of epigenetic regulation.
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Protein Acetylation (Non-Histone): Acetyl-CoA can also acetylate many other proteins, not just histones. This can alter protein function, stability, localization, and interactions with other molecules. This is a widespread post-translational modification that regulates a vast array of cellular processes.
2. Cytosolic Acetyl-CoA as a Sensor of Cellular Energy Status
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Mitochondrial Efficiency is Key: The amount of acetyl-CoA that can be exported to the cytosol is directly dependent on the efficiency of mitochondrial function. Healthy, efficient mitochondria produce more acetyl-CoA than they need for their own ATP production, allowing the excess to be exported.
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Citrate as the Shuttle: Acetyl-CoA itself can’t directly cross the mitochondrial membrane. Instead, it’s converted to citrate within the mitochondria. Citrate can be transported out to the cytosol via the citrate carrier (SLC25A1, which Hemming mentioned). Once in the cytosol, citrate is converted back into acetyl-CoA by the enzyme ATP-citrate lyase (ACLY).
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SASP and SLC25A1: Hemming’s point about SASP (Senescence-Associated Secretory Phenotype) reducing SLC25A1 expression is crucial. If SLC25A1 is downregulated, less citrate can be transported out of the mitochondria, leading to lower cytosolic acetyl-CoA levels, even if the mitochondria are still producing a reasonable amount of acetyl-CoA. This is a key link between cellular senescence and impaired cellular function.
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The “Perceived Power Level”: Hemming’s phrase “perceived power level” is a good way to think about it. High cytosolic acetyl-CoA levels signal to the cell that energy production is abundant. This allows the cell to engage in “expensive” processes like gene expression (via histone acetylation) and protein synthesis. Low cytosolic acetyl-CoA levels signal energy scarcity, leading to a more “conservative” cellular state with reduced gene expression and protein synthesis.
3. PGC-1α’s Connection to Cytosolic Acetyl-CoA
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Increased Mitochondrial Biogenesis and Function: PGC-1α, by promoting mitochondrial biogenesis and improving mitochondrial efficiency, increases the overall production of acetyl-CoA within the mitochondria. This, in turn, increases the potential for citrate export and raises cytosolic acetyl-CoA levels.
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TFAM and mtDNA: By increasing TFAM, PGC-1α helps maintain healthy mtDNA, which is essential for the proper functioning of the electron transport chain and, consequently, for acetyl-CoA production.
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Indirect Effects: PGC-1α’s anti-inflammatory effects can also indirectly contribute. By reducing inflammation, it may help to maintain SLC25A1 expression, allowing for efficient citrate transport.
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Direct Upstream Interaction: PGC-1α is a transcriptional coactivator, and influences the expression levels of many proteins, including ATP-citrate lyase. This is the crucial enzyme mentioned above that converts cytosolic citrate back to acetyl-CoA.
4. Why Hemming’s Emphasis is Justified
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Integrative View: Hemming’s focus on cytosolic acetyl-CoA provides an integrative view of how mitochondrial health, cellular senescence, gene expression, and overall cellular function are interconnected.
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Beyond ATP: It moves the discussion beyond simply thinking about mitochondria as “powerhouses” that produce ATP. It highlights their role as signaling hubs that regulate cellular processes through molecules like acetyl-CoA.
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Epigenetic Regulation: It emphasizes the crucial role of histone acetylation (and protein acetylation in general) in age-related changes in gene expression. Cytosolic acetyl-CoA is the direct link between mitochondrial function and epigenetic regulation.
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Therapeutic Implications: Understanding this connection suggests that interventions that increase cytosolic acetyl-CoA levels (e.g., by boosting PGC-1α, improving mitochondrial function, or reducing SASP) could have profound beneficial effects on cellular health and longevity.
In conclusion, Hemming’s emphasis on cytosolic acetyl-CoA is not only justified but is a critical insight into the complex interplay between mitochondrial function and cellular aging. It provides a valuable framework for understanding how interventions like PGC-1α activation can have such widespread beneficial effects.
2 Likes
adssx
#64
And yet?
https://x.com/HellenicVibes/status/1892250276473516266
(I didn’t check the validity of those claims)
4 Likes
Josh
#65
Grok 3 on best lifespan extension compounds with think and search
https://x.com/i/grok/share/ADxtexayfvmr23tZoLLm1NOMG
1 Like
I use AI to search for things. Is then the novelty in the question or the answer? With any answers it is worth checking them depending on the importance of the information. When checking safe doaing levels i like to find the original reasearch papers.
1 Like
Josh
#67
Deep search on all existing studies/compounds on c. elegans lifespan extension, including nice table with %:
https://x.com/i/grok/share/o1v8UcEj3wUk8kq79j0PLR4xb
adssx
#68
The table contains 1% of the drugs. Here’s the full list: DrugAge: Species Detail
2 Likes
@adssx thanks. Nice chart. Is the reason that the vast majority of drugs in the chart extend life because the tests were not random…they chose to test drugs that had shown life extension benefits?
It is wonderful that this work is being done. That said I would never take a drug because it extended life in a worm unless I wanted it for other benefits proven in people AND the drug had a good safety profile in people.
adssx
#70
About 1300 tests extended lifespan vs about 300 that lowered lifespan. I would say it’s:
- Publication bias (negative results are rarely published)
- Focus on drugs with a rationale to extend lifespan
- Positive drugs are retested may times are various concentrations
2 Likes
This is a massive oversimplification. We are not going to get a major increase in longevity in humans by merely predicting some new drug targets and designing drugs that target them. It’s a lot more complicated than that. We can likely get great results in worms and less so in rodents with that method.
4 Likes
