Abstract
Background
As the population ages, a rising mortality burden is attributed to deaths in older adults, particularly deaths from inflammation-related chronic non-communicable diseases. The synergism between aging and inflammation remains unclear. Here, we conducted a study to examine whether a decrease in leukocyte mitochondrial DNA copy number (mtDNACN) with age modifies the association between inflammation and the mortality risk in older adults.
Methods
A total of 3520 adults (mean [SD] age, 67.6 [7.4] years) underwent serial leukocyte mtDNACN and serum high-sensitivity C-reactive protein (hs-CRP) measurements and ascertainment of subsequent all-cause and cardiovascular diseases (CVD) deaths. Mortality risks were estimated using Cox proportional hazards models.
Results
Compared to participants with both a sustainedly low serum hs-CRP and change in leukocyte mtDNACN at the highest tertile, the adjusted hazard ratios (95% CI) of all-cause and CVD death are 3.20 (2.20-4.66) and 5.77 (2.72-12.21) for those with both increased serum hs-CRP and change in leukocyte mtDNACN at the lowest tertile, 1.48 (0.93-2.38) and 1.24 (0.44-3.53) for those with increased serum hs-CRP alone, and 1.29 (0.93-1.81) and 1.44 (0.70-2.97) for those with a change in leukocyte mtDNACN at the lowest tertile alone. The relative excess risks due to interaction (95% CI) for all-cause and CVD death are 1.42 (0.19-2.65) and 4.08 (0.21-7.96). Similar results are observed for those with a change in leukocyte mtDNACN at the middle tertile and in sensitivity analyses.
Conclusions
We demonstrate super-additive interactions between decreases in leukocyte mtDNACN and inflammation on the mortality risk in older adults, indicating underlying synergism.
Plain language summary
Increasing mortality is attributed to deaths in older adults, particularly those due to inflammation-related chronic non-communicable diseases. Through unclear mechanisms, aging is thought to elevate the risk of death in the presence of stressors. It is known that the amount of DNA in the mitochondria of white blood cells changes with age. Here, we investigated whether changes in this DNA over time impact the risk of death with inflammation. We conducted a study in which we tracked the amount of this DNA and a marker of inflammation among older adults. We showed that, among participants with a loss of this DNA over time, an increase in inflammation confers the highest risk of all-cause death and death from cardiovascular diseases. Our results suggest aging, signaled by a decrease in mitochondrial DNA in white blood cells with age, may elevate the death risk in the presence of inflammation.
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Data availability
The data that support the findings of this study are available from the National Health Research Institutes, but restrictions apply to the availability of these data, which were used under regulations and licenses for the current study imposed by the agencies, and so are not publicly available. Please contact the corresponding author for data availability.
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Acknowledgements
We thank all participating men and women in the HALST study; and all members of the HALST study group. This work was supported by the National Health Research Institutes (project nos. BS-097-SP-04, PH-098-SP-02, PH-099-SP-01, PH-100-SP-01, PH-101-SP-01, PH-102-SP-01, PH-103-SP-01, PH-104-SP-01, PH-105-SP-01, PH-106-SP-01, PH-107-SP-01, PH-107-PP-22, PH-108-SP-01, PH-108-PP-22, PH-109-SP-01, PH-109- PP-22, PH-110-SP-01, PH-110- PP-17, PH-111-SP-01, PH-111-PP-15, PH-112-PP-15, PH-113- PP-15, PH-114-PP-16) and National Science and Technology Council (project no. MOST 109-2314-B-400-026) in Taiwan. The sponsors had no roles in the design and conduct of the study; collections and analysis of the data; preparation and approval of the manuscript.
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I.C.W., P.F.C. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. I.C.W. conceived and designed the study. I.C.W., C.S.L., W.L.C., and T.T.L. contributed to the data acquisition. I.C.W., H.L.C., and P.F.C. contributed to the data curation. I.C.W., P.F.C., contributed to the data analysis. I.C.W. drafted the manuscript. All authors contributed to the critical revision of the manuscript for important intellectual content and approved the final manuscript.
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Wu, IC., Liu, CS., Cheng, WL. et al. Association of leukocyte mitochondrial DNA copy number and inflammation with mortality among older adults. Commun Med (2026). https://doi.org/10.1038/s43856-026-01531-8
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DOI: https://doi.org/10.1038/s43856-026-01531-8
