The guardian paradox: DNA damage response overactivation as an integrative driver of aging – a tumor suppressor–negative regulator framework (IMAGE)
Caption
Figure 4. Cross-axis synergy and feedback architecture. Four principal feedback loops interlock through shared nodes and converge on the senescence/inflammaging program. Loop ① (DDR–senescence–SASP amplification): chronic DDR activation stabilizes p53 and p21, driving senescence and a senescence-associated secretory phenotype (SASP) that propagates paracrine DDR to neighboring cells; candidate restoration nodes are MDM2, BMI-1, and SIRT1. Loop ② (NAD+–sirtuin–mitochondrial nexus): NAD+ depletion inactivates sirtuins, impairing mitochondrial function and generating reactive oxygen species that feedback as DNA damage (SIRT1, NAMPT, PGC-1α). Loop ③ (insulin/IGF-1–FOXO–mTOR network): reduced insulin/IGF-1 signaling activates FOXO3 and suppresses mTOR to sustain autophagy (PTEN, FOXO3, AMPK). Loop ④ (epigenetic aging cascade): SIRT1 decline and heterochromatin erosion derepress transposable elements and trigger cGAS–STING/interferon signaling (SIRT1, NRF2, DNMT3A). Shared nodes (DDR and SIRT1) couple the loops, which converge on the IL-6/TNF-α SASP program of senescence and inflammaging; a gut-barrier/dysbiosis input (LPS → TLR4/NF-κB) acts as an external, modifiable amplifier of the same program. All candidate restoration nodes are illustrative and non-validated.
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Copyright: © 2026 Sewell. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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