Introduction
The current theory of static aging defines the essence of aging as static wear and tear, but it is difficult to explain three core paradoxes: inter-individual heterogeneity, non-linear acceleration, and cliff-like senescence are the three main paradoxes of aging. These three phenomena themselves constitute the falsification of single-causation models.
In this paper, dynamic aging theory is constructed based on metabolic flux homeostasis, and its framework has three explanatory powers: Firstly, through the multi-parameter phase space of metabolic flux homeostasis, Computationally explain the diversity of aging: the set-point bias of AMPK-mTOR-PGC-1α-PPARα in different individuals determines the emergence of differential pathological phenotypes; Second, multi-factorial convergence to the critical node of mitochondrial functional decline is used to account for phenotypic convergence in aging; Finally, by revealing the mechanism by which the dominant factors of aging switch with the phase transitions of metabolic homeostasis, the nonlinear dynamic nature of accelerated aging and cliff aging is explained.
金, . 英杰 . (2026). Comprehensive decoding of aging pathways: hypothesis of metabolic homeostasis cascade collapse convergence and re-drive model(V112). Zenodo. https://doi.org/10.5...zenodo.19249525
the English version is translated for non-native speakers, there may be inaccuracies, distortions, or misalignments in conceptual frameworks. If any framework is ambiguous, please refer to the Chinese version below for clarification.
金, . 英杰 . (2026). 衰⽼路径全⾯破译:代谢稳态级联崩塌收敛再驱动模型假说(V112). Zenodo. https://doi.org/10.5...zenodo.19246452
Here is the English translation:
Note to non-native English readers: As this English version was AI-translated, there may be inaccuracies, distortions, or misaligned conceptual frameworks. If any framework appears ambiguous, please refer to the Chinese version above for clarification.
In this 112 update and correction, I have falsified the replicative senescence theory and proposed a new theoretical framework. Citing original text section 5.7: 5.7 The Field Damage Theory of rDNA Shortening and Recovery Mechanisms.
As stated in reference [269], rRNA constitutes the structural and functional core of ribosomes. ROS can affect RNA through multiple pathways [34,35,36,37], including chemical modifications of bases and sugar moieties, generation of abasic sites, and strand breaks. Guanine is the most susceptible nucleobase to oxidation and has been most extensively studied in this regard. One oxidized form of guanine, 8-hydroxyguanine (8-oxoguanine; 8-oxo-G; 8-oxo-G), is a ubiquitous oxidative lesion readily detectable in cellular nucleic acids. When 8-oxo-G is present in mRNA, it interferes with decoding, potentially forming Hoogsteen pairs with adenine when the base rotates around the N-glycosidic bond. The altered base-pairing capability of 8-oxo-G also perturbs RNA folding. A recent study revealed multiple outcomes when 8-oxo-G was incorporated into model RNA substrates, ranging from stabilization of existing structural motifs to their destabilization and rearrangement into new structures. Since ribosome translation activity depends on numerous precisely tuned conformational changes and movements within its rRNA framework, oxidation of critical bases essential for maintaining correct rRNA structure may impair ribosomal function. Therefore, the requirement to tolerate certain levels of oxidation was likely a factor shaping ribosomal evolution. Many guanines are significantly eliminated from mitochondrial rRNA, accompanied by overall reduction in RNA content.
As stated in reference [270], the muscle regeneration process comprises four interconnected stages: necrosis, inflammation, activation and differentiation of satellite cells, maturation of newly formed myofibrils, and muscle remodeling. During the inflammatory phase, which occurs during muscle injury repair, reactive oxygen species (ROS) are massively produced, primarily present in neutrophils and M2 macrophages. Furthermore, MAPK (mitogen-activated protein kinase), NFκB (nuclear factor kappa B), and AP-1 (activator protein 1) activated by ROS induce protective responses in injured muscle through ROS activation. Additionally, antioxidant enzymes such as superoxide dismutase 2, glutathione peroxidase, and catalase increase during the initial days after injury. Thus, ROS activate important signaling pathways for muscle repair. However, impaired oxidative stress may cause secondary damage to uninjured fibers.
As stated in reference [271], resistance exercise training (RET) can be effectively applied to increase muscle mass and function in older adults aged 65-75 years. However, there has been speculation that individuals over 85 years respond less favorably to RET benefits. This study compared the effects of RET on muscle mass and function between healthy older adults aged 65-75 years and those aged 85 years and above. We examined 17 healthy older adults aged 65-75 years (65-75 years, n=13/4 [female/male]; 68±2 years; 26.9±2.3 kg/m²) and 12 healthy older adults aged 85+ years (85+ years, n=7/5 [female/male]; 87±3 years; 26.0±3.6 kg/m²) undergoing 12 weeks of whole-body RET (three times per week). Before and after 6 and 12 weeks of training, we assessed quadriceps and lumbar level 3 muscle cross-sectional area (computed tomography), whole-body lean mass (dual-energy X-ray absorptiometry), strength (one-repetition maximum test), and physical performance (Timed Up and Go and Short Physical Performance Battery). Twelve weeks of RET increased quadriceps cross-sectional area by 10%±4% and 11%±5% respectively (from 46.5±10.7 to 51.1±12.1 cm², and from 38.9±6.1 to 43.1±8.0 cm²; p<.001; η² = 0.67); whole-body lean mass increased by 2%±3% and 2%±3% (p=.001; η²=.22); one-repetition maximum leg extension strength improved by 38%±20% and 46%±14% respectively in the old 65-75 and old 85+ groups (p<0.001; η² = 0.77). RET responses did not differ between groups (time×group, all p>0.60; all η²≤0.012). Short Physical Performance Battery and Timed Up and Go physical performance both improved (all p < 0.01; η² ≥ 0.22), with no between-group differences (time×group, p > 0.015; η² ≤ 0.07). Extended RET increases muscle mass, strength, and physical performance in aging populations, with no significant differences between 65-75 year-olds and 85+ year-olds.
As stated in reference [272], this study demonstrates that resistance training significantly increases muscle stem cell content... In older adults, satellite cell number significantly increased after 12 weeks of resistance training. Resistance training significantly increased satellite cell number in Type II muscle fibers in older adults... This systematic review and meta-analysis shows that resistance training in older adults can significantly increase muscle stem cells.
Based on the above four articles, it can be inferred that the current replicative senescence theory has boundary limitations in its application scope. Replicative senescence is a typical wear-and-tear theory of aging, within whose theoretical framework there is no concept of recovery—unidirectional, irreversible wear constitutes its core definition of aging. However, this is merely an erroneous extrapolation that overgeneralizes the in vitro passage model to in vivo contexts.
Oxidative stress damages rDNA, leading to loss of rDNA array copies. If we follow the replicative senescence path推演 [deduction], human exercise would trigger free radical formation and oxidative stress; this oxidative signal drives muscle growth, while simultaneously these free radicals would damage rDNA arrays. However, this logical deduction is falsified by resistance exercise—faced with empirical cases where individuals maintaining regular long-term resistance exercise preserve greater muscle mass, this argument cannot hold. For if long-term resistance exercise were maintained, ROS would damage rDNA arrays and inhibit self-renewal of muscle satellite stem cells; during aging, excessive exercise should lead to severe rDNA array copy loss, preventing muscle satellite stem cells from maintaining appropriate numbers and causing muscle atrophy. Yet reality shows the opposite, indicating either that oxidative stress cannot drive rDNA array copy number loss, or that human stem cells possess rDNA array recovery mechanisms.
Given that oxidative stress-driven rDNA array copy number loss has been confirmed, human stem cells must necessarily possess rDNA array recovery mechanisms; otherwise, the anti-aging benefits of resistance exercise and other forms of exercise would not exist.
As stated in reference [273], unequal sister chromatid exchange (USCE) allows cells to restore rDNA copy number on one sister chromatid at the expense of the other. This phenomenon specifically occurs in Drosophila male germline stem cells (GSCs)—these cells undergo asymmetric division to produce one self-renewing stem cell and one daughter cell entering the differentiation program, during which the chromatid with restored rDNA copy number is preferentially retained in the stem cell lineage, while the copy-damaged one enters the differentiated daughter cell.
As stated in reference [274], in Saccharomyces cerevisiae, rDNA copy number (CN) maintenance depends on competitive occupancy between the Pol I-UAF complex and the Sir2-UAF complex. When CN is high, Pol I-UAF binds rDNA promoters, blocking further copy number expansion through transcription-replication coupled negative feedback; when CN decreases due to oxidative stress or recombination, the Sir2-UAF complex relieves inhibition of the bidirectional promoter E-pro, necessarily initiating intra-array homologous recombination (intra-array HR), driving rDNA gene conversion and amplification to achieve copy number recovery. This "high-suppression, low-amplification" bidirectional homeostatic switch enables rDNA arrays to actively count and self-recover, rather than undergoing telomere-like unidirectional depletion.
As stated in reference [275], when rDNA undergoes double-strand breaks (DSBs), a specialized nucleolar DNA damage response (n-DDR) is activated; upon activation of this response, rDNA migrates from the nucleolar interior to the nucleolar periphery to form "nucleolar caps," within this subnuclear structure dedicated homologous recombination (HR) repair occurs. In this process, BLM (Bloom syndrome) helicase plays a critical function, promoting recombination repair by unwinding DNA double-strand structures—BLM-deficient cells exhibit rDNA recombination rates exceeding 10%, proving this enzyme is a core regulatory factor for human rDNA genomic stability maintenance, ensuring rDNA array integrity through promoting the HR pathway.
Through the above literature, it can be inferred that rDNA recovery mechanisms exist in both humans and animals. Combined with the phenomenon of resistance exercise effectiveness and the phenomenon of oxidative damage to rDNA, we can propose the Inhibitory Field Theory of Dynamic rDNA Copy Number Recovery. "Field" refers to different interfering factors producing interfering effects on a single target. As previously mentioned, genomic instability can inhibit rDNA through p53, and oxidative stress directly damages rDNA, confirming that rDNA copy number loss is multi-source inhibition, while rDNA itself possesses repair mechanisms; the intersection of these two forms a phenomenon of dynamic recovery and depletion.
However, this depletion is not irreversible—simply removing inhibitory factors or strengthening recovery factors may restore stem cell rDNA arrays to normal levels.
References
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