Scientists have discovered that errors in mitochondrial DNA (mtDNA) replication may contribute to a type of inflammation called “inflammaging.” This occurs in healthy aging tissue. The process involves the incorrect incorporation of RNA building blocks (rNTPs) into mtDNA during replication. This happens due to a relative scarcity of DNA building blocks (dNTPs).
The imbalance in building blocks leads to a fragile mitochondrial genome. This creates fragments that trigger an immune response. Mitochondria are the energy-producing organelles in cells.
They are believed to have originated from bacteria that entered ancient cells. Due to their bacterial origins, mtDNA leaking into the cytoplasm can provoke an immune response. The immune system mistakes it for bacterial DNA.
This immune response contributes to inflammaging. Inflammaging is a sterile inflammation that is harmful to cells and tissues. It is increasingly seen with aging.
Researchers used mice lacking the MGME1 enzyme, which is necessary for proper mtDNA replication. These mice showed mtDNA fragment accumulation and innate immune activation in their kidneys. This indicated a causal relationship.
Blocking the inflammatory pathway reduced inflammation and improved kidney health. Further research revealed that active mtDNA copying is essential for this inflammatory effect.
MtDNA errors and aging inflammation
Interrupting mtDNA replication decreased the inflammatory response. This implies the issue lies with breaks during replication rather than existing damaged DNA. Deep sequencing of mtDNA showed numerous aborted replication attempts causing fragmentation.
The study also involved human fibroblasts, which mimic senescent cell behavior. Reducing the rNTP:dNTP ratio in these cells lessened cytosolic mtDNA presence and toxicity. However, it did not reverse senescence.
Instead, it reduced the secretion of pro-inflammatory molecules associated with senescence. These findings were consistent in older, healthy mouse tissues. This suggests that the mechanism is characteristic of normal aging. Prof.
Thomas Langer, who led the study, said these insights open new strategies for anti-aging interventions. They do this by addressing metabolic disturbances leading to inflammation. Dr.
David Sinclair, a Harvard geroscientist, endorsed the study. He indicated its potential to explain how cell stress and aging lead to inflammaging. This happens by incorporating incorrect bases into replicating mtDNA.
This research points towards possible future therapies. However, more studies are needed to see if existing treatments for some mitochondrial diseases could reduce age-related inflammation.
