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[南尧说生]

This paper proposes and systematically elaborates on the hypothesis of 'Comprehensive Decoding of Aging Pathways,' which defines mitochondrial dysfunction as the 'primary cause' of aging. Mitochondrial dysfunction is not a passive damage but an active driver that initiates the aging process. It triggers a series of cascade reactions by affecting cellular energy metabolism, redox balance, and signal transduction, including metabolic disorders of sugar and lipids (secondary cause), decline of the GH-IGF-1 axis (tertiary cause), collapse of the antioxidant network (quaternary cause), immune collapse caused by imbalance of the inflammation-glucocorticoid axis (quinary cause), and accumulation and clearance of damaged senescent cells (sixth cause). These factors are interrelated, forming a self-reinforcing locking mechanism that leads to continuous decline in bodily functions. The article also deeply analyzes key regulatory networks, such as interactions between genes and pathways like PPARα, AMPK, PGC-1α, NRF1/NRF2, as well as the roles of blood oxygen supply, vitamin metabolism, and calcium signaling in aging. Based on this model, potential anti-aging strategies are proposed, such as high-protein ketogenic diet, time-restricted fasting, and systemic interventions, aiming to reverse mitochondrial dysfunction from the upstream. Finally, the authors review the theoretical development process, from the initial focus on mTOR to ultimately tracing back to mitochondrial dysfunction, emphasizing the core role of mitochondrial function in anti-aging research.

 

A Note on the Text:
Please be aware that this paper has been translated from its original language into English with the assistance of AI. While I have strived for accuracy, I am not a native English speaker. Therefore, if you encounter passages that seem logically weak or unclear, it may be due to a loss of nuance or precision in the translation process, rather than a flaw in the underlying theory itself. I welcome any questions for clarification.

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Edited by 南尧说生, 14 October 2025 - 02:18 PM.

[南尧说生]

Subject: Major Update to "The First Cause of Aging" Hypothesis - Now at Version 89

Hello everyone,

I'm excited to share a significant update to my integrative theory of aging, which positions mitochondrial functional decline as the programmed "First Cause" driving the body's systemic collapse.

The PDF currently available on Zenodo (DOI: 10.5281/zenodo.17356371) is an outdated V1 snapshot. The theory has since undergone extensive refinement and is now at Version 89.

Key Evolutions from V1 to V89:

• From Description to Mechanism: The model now details the core regulatory network (PPARα-AMPK-PGC1α) and introduces the concept of "Epigenetic Inertia" to explain how key genes get locked in a low-expression state.

• The Self-Reinforcing "Lock-In" Mechanism: A fully articulated cascade explains how the "First Cause" sequentially triggers metabolic derangement, hormonal axis decline, antioxidant network collapse, and immune surveillance failure, forming a positive feedback loop that accelerates aging.

• Novel Molecular Pathways: The model now integrates critical mechanisms like the CD38-NAD+-AMPK axis as a universal cellular inflammation reversal pathway and the ketone/lactate antagonism that determines senescent cell fate.

• Actionable, Multi-Pronged Intervention Strategies: Based on the model's logic, a coherent framework for intervention is proposed, combining circadian-aligned metabolic interventions (e.g., high-protein ketogenesis) with systemic support (e.g., optimized oxygenation, antioxidant network support).

This is no longer just a hypothesis but a dynamic, testable, and predictive framework that unifies hallmarks of aging into a causal hierarchy.

I am sharing this to solicit critical feedback from the community. Does this refined model resonate with your understanding? What are its strongest points and most glaring weaknesses?

The core concepts and the logical structure are stable. Your insights are invaluable for guiding the next iterations.

You can access the outdated V1 here for reference: https://doi.org/10.5...zenodo.17356371

I look forward to a stimulating discussion.

[南尧说生]

[Update Announcement · 93rd Edition]

Dear colleagues

The comprehensive decoding hypothesis of the aging pathway has been iterated to its 93rd edition and is officially archived in Zenodo today (DOI: 10.5281/zenodo. 17371217). This upgrade is the most significant expansion and calibration of the theoretical framework to date, with the following core highlights:

Add a complete causal chain for "epigenetic disorder"

For the first time, the "genomic ghost" of calcium oscillation collapse → AKG deficiency → TET/histone demethylase inactivation → ERK disinhibition was fully incorporated into the model to explain the autoimmune storm at the end of aging.

Introducing the 'first cause self-locking mechanism'

Elucidate how the two core circuits of PPAR α - NRF2 and AMPK mTOR are locked in the pathological region through competitive antagonism, leading to a decline in mitochondrial function as the starting point.

https://doi.org/10.5...zenodo.17371217

 

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•  译文_衰⽼路径全⾯破译假说第93版-3.pdf   18.1MB   1 downloads

Edited by 南尧说生, 16 October 2025 - 06:14 PM.

[南尧说生]

This version simplifies the process of the four axis model and eight variables to ensure clearer theoretical understanding. At the same time, the citation semantics of key parts of the entire text have been improved. The current version has achieved the highest theoretical description, clear architecture, and entered a state where content cannot be updated. There may be some paths that need further description, but these are no longer the main update content. The next update will focus on academic language optimization, which will take a long time as I am not really good at writing papers.

If you feel that there are any logical issues with this theory, please feel free to raise them at any time. I will conduct a certain degree of self verification, improvement, and error correction. This is a theoretical advancement and also a progress in anti-aging. Readers who have read this article are welcome to provide feedback and suggestions. When manpower is limited, I am alone, so it is not easy to generalize like this. I must have some omissions. I am very aware of this, but I will definitely find it difficult to discover.

From the first edition to this edition, although I have been able to constantly overturn previous theories, making them clearer and the mechanisms more complete, I believe that if more people join in, we can decipher aging faster.

This update provides a large amount of literature to support this theory.

https://doi.org/10.5...zenodo.17389294

 

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•  97.pdf   802.98KB   5 downloads

Edited by 南尧说生, 23 October 2025 - 02:21 PM.