Longevity Questions

Transhumanism in a Distant City, [03.05.2025 01:20]
A well-formulated question is a half-found solution. Let's formulate questions, the solution of which will bring us closer to victory over aging and death. I'll start with general ones, but you can also publish seemingly insignificant ones. This thread will be very strictly moderated. Please, at least format your lists of questions properly.

It's interesting to see the entire problem space. I'll start with fairly abstract ones:

1. What ideas guide us?
2. How do we make decisions?
3. How do we prioritize?
4. How do we choose axioms?
5. How do we get the data we need?
6. What does our picture of reality look like?
7. How do we work with hypotheses?
8. How can we attract geniuses to the fight against death?
9. What can AI do best right now to extend life?
10. Which question is the most cost-effective to answer?

Transhumanism in a distant city, [03.05.2025 02:20]
To answer the question of how to rejuvenate the extracellular matrix, Gemini suggests answering the following questions (I chose the topic with elastin):

1. How to ensure the correct assembly and integration of new elastic matrix fibers?

2. Which specific chaperones and proteins of the extracellular matrix (e.g. fibrillins 1/2, fibulins 4/5, EMILIN-1, MAGP-1/2, LTBP family proteins) are absolutely necessary for the initiation, direction and stabilization of elastic fiber assembly in vivo?

3. Is the expression level and functional activity of these accessory proteins sufficient in aging target tissues, or is their deficiency/dysfunction the main limiting factor?

4. Does successful elastogenesis require simultaneous therapeutic delivery of not only the elastin gene (ELN), but also genes for key accessory proteins?

5. What is the optimal activity and localization of the lysyl oxidase family of enzymes (LOX, LOXL1-4) required to form covalent crosslinks that give elastin its strength and elasticity?

6. How can this activity be ensured in aging tissue, given possible cofactor deficiencies (e.g. copper) or inhibitors?

7. Does therapeutic overexpression of tropoelastin result in correct crosslinking, or does it result in abnormal/incomplete crosslinks?

8. To what extent is the existing microfibrillar scaffold (fibrillin backbone) damaged or fragmented in aging tissue, and can it still serve as an adequate "backbone" for new tropoelastin deposition?

9. Is it possible to restore or "repair" the microfibrillar scaffold itself before or during stimulation of elastin synthesis?

10. How does new elastin interact with existing, possibly degraded, scaffold components?

11. Do conditions in aging tissue (e.g. pH, ionic strength, presence of AGEs) affect the coacervation process (phase separation) of tropoelastin, which is the initial step in assembly?

12. Can post-translational modifications of tropoelastin synthesized by therapeutic overexpression differ from the native protein and affect its ability to self-assemble?

13. What are the precise mechanisms of incorporation of new elastic fibers into the already densely packed and often fibrotic/rigid matrix of old tissue?

14. How to avoid spatial conflicts, mechanical stress or disruption of the overall tissue architecture when adding new material?

15. Is new elastin able to functionally interact with old collagen fibers and other ECM components?

16. How do cells (e.g. fibroblasts) control the spatial organization of elastogenesis so that fibers are formed in the right places and with the right orientation?

17. How do cellular senescence and changes in cellular mechanics affect the ability of cells to control this complex process?

18. Is it possible to pharmacologically or genetically "rejuvenate" producer cells so that they are better able to assemble elastin?

19. How does chronic low-grade inflammation ("inflammaging"), characteristic of aging, affect the activity of assembly enzymes (LOX) and the stability of accessory proteins?

20. Can accumulated advanced glycation end products (AGEs) on old matrix components interfere with the integration or proper assembly of new elastin?