When aging and inflammation are mentioned, the term "SASP (Senescence-Associated Secretory Phenotype)" likely comes to mind. For a long time, we attributed age-related chronic inflammation to these "zombie cells" (senescent cells), which continuously release SASP to spread inflammation throughout body tissues, disrupting our internal environment.
This explains what spreads inflammation—but! What forces these senescent cells to release SASP? Is this secretion the root cause of inflammaging (inflammatory aging), or just a symptom?
Just yesterday, a study published in Nature provided a key clue, pointing the origin of inflammaging directly to dysregulated stability of mitochondrial DNA (mtDNA)!
1. The Out-of-Control "Heirloom"
First, let’s talk about a "key player" in cells—the mitochondrion. Known as the "energy factory," it produces ATP to power life activities and serves as a critical hub for metabolic regulation and signal transduction.
But the mitochondrion’s most unique feature lies in its unusual evolutionary origin: it was once an independent bacterium! It was engulfed and "domesticated" by our cellular ancestors, becoming a permanent symbiont within cells [2].
Figure Note: Two hypotheses for the origin of eukaryotic cells and mitochondria: 1. Primitive eukaryotic cells formed first, then engulfed bacteria that evolved into mitochondria (red arrow); 2. Archaea and bacteria fused in a single event, forming both eukaryotic cells and mitochondria (purple arrow).
Thanks to this origin, mitochondria still carry an "ancient heirloom": mitochondrial DNA (mtDNA). This small circular genome, independent of the cell nucleus, encodes multiple key proteins essential for the respiratory chain (the core of energy production).
Figure Note: Schematic of cell nucleus and mitochondria, highlighting mitochondrial DNA.
However, this precious mtDNA is surprisingly fragile in the face of aging. Studies have found that in senescent cells and tissues of old mice, large amounts of mtDNA—normally strictly confined inside mitochondria—escape into the cytoplasm as fragmented pieces, a region where mtDNA should never be.
Figure Note: Red = mitochondria, green = mtDNA. In Mgme1⁻/⁻ cells (Mgme1 maintains mitochondrial genome stability), green DNA (indicated by arrows) escapes mitochondrial confinement in large quantities and scatters in the cytoplasm. Left graph: Percentage of cells with mtDNA leakage; Right graph: Number of cytoplasmic mtDNA foci per leaking cell.
This is an extremely dangerous signal. Under normal physiological conditions, there is almost no free DNA in the cytoplasm. If free DNA appears, the cell’s innate immune system immediately recognizes it as a sign of foreign invaders (e.g., viruses or bacteria) and activates defense mechanisms.
But mtDNA fragments leaking into the cytoplasm are just a symptom of aging. What happens earlier, before the leakage, to trigger this process? To uncover the truth, we need to start with the two fundamentals of genetic information: DNA and RNA.
2. "Shoddy Workmanship" in the Body
DNA and RNA are like "brothers" in the nucleic acid family, but their basic building blocks differ drastically: DNA uses highly stable deoxyribonucleotides, while RNA uses more chemically reactive ribonucleotides. The only difference—a single hydroxyl group—fundamentally determines that DNA is suited for long-term genetic storage, while RNA only acts as a short-term messenger.
Figure Note: A nucleotide consists of a phosphate group + (deoxy)ribose + nitrogenous base. Left: Ribose (for RNA); Right: Deoxyribose (for DNA).
Now, imagine this: if an rNTP (ribonucleoside triphosphate), which belongs to RNA, mistakenly "wanders" into a DNA strand during replication, it plants a fatal seed for DNA breakage. Worse, this is not a rare event—with aging, such mistakes occur in bulk in our bodies, and their frequency increases.
Data shows that in senescent cells and tissues of old mice, the activity of ribonucleotide reductase (RNR)—a key enzyme that converts rNTPs to dNTPs (deoxyribonucleoside triphosphates)—decreases significantly. This directly leads to a severe shortage of correct dNTPs, a large backlog of rNTPs, a sharp rise in the rNTP/dNTP ratio, and a severe imbalance in the cellular nucleotide pool.
Figure Note: Left 4 graphs: In Mgme1⁻/⁻ cells, the levels of the four core dNTPs (for DNA synthesis) are severely depleted (P<0.0001 for key comparisons). Right 4 graphs: This shortage disrupts the balance between dNTPs (DNA building blocks) and rNTPs (RNA building blocks), leading to a sharp increase in their ratios (P<0.0001).
This imbalance poses a major risk to mtDNA replication. It’s like building a wall with too few quality bricks (dNTPs) and too many inferior ones (rNTPs)—DNA polymerase makes far more mistakes, inserting incorrect rNTPs into the growing mtDNA strand more frequently.
Figure Note: Under strongly alkaline conditions, mtDNA from normal cells (orange curve) remains structurally intact, forming a clear band. However, mtDNA from gene-knockout cells (blue curve), which has incorporated large numbers of incorrect rNTPs, is filled with weak points and breaks into countless small fragments under the same stress, forming a long, blurry tail.
Each incorrectly inserted rNTP creates a chemically unstable break in the DNA backbone due to its extra hydroxyl group. This makes mtDNA extremely fragile, prone to breakage under replication stress or chemical stress—leading to mtDNA fragmentation and leakage.
Figure Note: Aging is a universal cause of mtDNA fragility. mtDNA from senescent cells (blue curve, Sen(IR)) becomes vulnerable under strongly alkaline conditions, breaking into countless small fragments and forming a long, blurry tail (Left graph).
But the damage doesn’t end there: this leakage directly activates a classic cellular immune pathway—the cGAS-STING pathway [3]. This is the main surveillance mechanism for cytoplasmic DNA; once it detects DNA molecules in the cytoplasm (where they don’t belong), the system immediately activates to eliminate potential threats.
Figure Note: Workflow of the cGAS-STING pathway: Recognition of "invaders" → Cell produces messenger molecules (cGAMP) → Activation of STING → Launch of immune response. Specific steps: Damaged mtDNA (or bacterial/nuclear DNA) is recognized; cGAS binds to DNA and synthesizes cGAMP using ATP/GTP; cGAMP activates STING on the endoplasmic reticulum (ER); STING moves to the Golgi apparatus, activates TBK1, and ultimately triggers interferon (IFN) production and immune response.
When fragile mtDNA fragments leak from mitochondria into the cytoplasm, they become targets of the cGAS-STING pathway, which indiscriminately recognizes them as danger signals. cGAS binds to these DNA fragments, activating the downstream adapter protein STING, igniting inflammatory signals, and triggering the expression of a series of pro-inflammatory genes.
Figure Note: (Slide to view) Left heatmap: In Mgme1-deficient mice (Mgme1 maintains mitochondrial genome stability), the expression of numerous inflammation-related genes increases. However, when STING is also knocked out, their expression levels almost fully return to normal (blue regions).
With continuous mtDNA leakage on one side and long-term cGAS-STING activation on the other, cells continuously produce and release inflammatory factors—initiating and maintaining the low-grade, persistent chronic inflammation known as "inflammaging." Finally, we have found a evidence-based origin for this once vague concept!
Can We Reverse This Process?
If the lack of dNTPs is the true starting point, can supplementing dNTPs reverse the aging process and repair all damage? Scientists directly supplemented senescent cells with the deficient deoxyribonucleosides (dNTPs). The results were immediate:
As dNTP supply was restored, the replication accuracy and structural integrity of mtDNA improved, mtDNA fragment leakage stopped, and the cGAS-STING immune system returned to quiescence. Ultimately, the expression of senescence-associated inflammatory phenotypes (SASP) driven by this pathway was successfully inhibited.
Figure Note: Senescent cells (solid red bars) express high levels of inflammatory factors (e.g., CXCL1, IL8), entering a state of chronic inflammation. However, after dNTP supplementation (striped red bars), the expression of these inflammatory factors decreases significantly (P<0.0001 for key comparisons). Young cells (solid blue bars) and young cells + dNTPs (striped blue bars) serve as controls.
In summary, this study shows that age-related inflammatory pathways can theoretically be "turned off" through targeted intervention! Inflammaging, once seen as a complex phenotype driven by multiple factors, may now be recognized as a causal event with clear molecular logic—driven by upstream metabolic imbalance.
References
[1] Bahat, A., Milenkovic, D., Cors, E., et al. (2025). Ribonucleotide incorporation into mitochondrial DNA drives inflammation. Nature. https://doi.org/10.1038/s41586-025-09541-7[2] Gray, M.W., Burger, G., & Lang, B.F. (1999). Mitochondrial evolution. Science, 283(5407), 1476–1481. https://doi.org/10.1126/science.283.5407.1476[3] Wang, R., Lan, C., Benlagha, K., et al. (2024). The interaction of innate immune and adaptive immune system. MedComm (2020), 5(10), e714. https://doi.org/10.1002/mco2.714