Mitochondrial DNA Fragments in Blood Could Be Important Biomarkers for Aging and Inflammation

Chronic inflammation has been proven to lead to frailty symptoms, memory loss, and other cognitive declines over time. High levels of circulating cell-free genomic DNA (ccf-gDNA), or DNA fragments created due to cell death, in the blood, have been linked with chronic inflammation and frailty. Earlier studies primarily considered ccf-gDNA as a potential biomarker for the cognitive and physical decline associated with aging. Comparable to ccf-gDNA, mitochondrial DNA (ccf-mtDNA) — DNA that is inherited maternally — can be located in cell organelles and is often referred to as the "power plants" within the cells of humans, other animals, plants, and most organisms. Upon natural programmed cell death (apoptosis), mitochondrial DNA is fragmented and left to circulate in the blood, similar to genomic DNA. Large fragments of mitochondrial DNA can trigger chronic inflammation — an immune response similar to the body's reaction to bacteria and viruses — if a traumatic event such as injury, interrupted blood flow, or disease causes cell death. A novel study has now further correlated levels of circulating cell-free DNA in the blood with chronic inflammation and frailty by focusing on mitochondrial DNA rather than solely genomic DNA.

The new findings by researchers at Johns Hopkins Medicine (Baltimore, MD, USA) support the notion that relatively high levels of DNA fragments in routine blood samples could serve as precise and valuable biomarkers, or indicators, for a broad spectrum of cognitive and physical declines. The analysis also discovered relationships between these DNA fragments and the presence of other established aging biomarkers, such as cytokine proteins, tumor necrosis factors (proteins produced by the immune system in response to tumor growth), and proteins generated by the liver during inflammation. For this study, the research team analyzed blood samples taken from 672 community-dwelling men and women in the mid-1990s, who had an average age of 80 at the start of the study period. These participants were selected from three cohort studies.

All the participants underwent annual physical and cognitive testing at the time of each blood draw, which included memory, perception, and physical tests for grip strength, gait, fatigue, and motor function. The researchers then compared levels of long and short CCF-mtDNA fragments against four established biomarkers of inflammation: cytokine proteins, two types of tumor necrosis factors, and inflammatory liver proteins. The results revealed significant correlations between these four biomarkers and increased levels of CCF-mtDNA. For instance, if a patient's blood sample had high levels of one or more of these known inflammation biomarkers, the sample also had high levels of CCF-mtDNA. Additionally, the researchers found that while high levels of circulating genomic DNA were associated with cognitive and physical decline, high levels of mitochondrial DNA were more strongly linked to physical decline only. The researchers plan to extend their studies to younger adults in order to determine the earliest time these cell-free DNA fragments become significant in blood samples. Moreover, they aim to decipher precisely how these DNA fragments contribute to inflammation and explore possible interventions before they precipitate cognitive and physical decline.

“By expanding the types of DNA screened for in the blood, the new research has expanded efforts to better understand and predict physical and cognitive declines that come with aging,” says Peter Abadir, M.D., associate professor of geriatric medicine and gerontology at the Johns Hopkins University School of Medicine.

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