Research finds that while excess stored iron may speed up aging through oxidative stress, higher blood iron and transferrin saturation are associated with slower epigenetic aging.

Study: Association Between Body Iron Status and Biological Aging. Image Credit: Anas Sarfraz / Shutterstock.com

A recent study published in Nutrients examines the role of blood iron levels in DNA methylation-based measurements of biological aging.

The physiology of iron

Iron is an essential element that plays a crucial role in various cellular processes including enzymatic activity, DNA repair, and oxygen transfer.

To determine an individual’s iron status, clinicians can measure ferritin, iron, or transferrin saturation levels within the serum. Whereas serum ferritin reflects iron store levels, serum iron provides information on the amount of circulating iron bound to transferrin. Transferrin saturation describes the percentage of iron that is bound to transferrin.

High iron levels can promote oxidative stress by producing reactive oxygen species (ROS), which induce damage to both cells and DNA. Hemochromatosis, for example, is a genetic that leads to iron overload, which increases the risk of liver disease, heart disease, and diabetes in affected individuals.

The role of iron in aging

Leukocyte telomere length decreases in a uniform manner with increasing age and, as a result, is the most widely used measurement to determine biological aging. Existing evidence suggests a correlation between leukocyte telomere length and ferritin levels; however, the mechanisms involved in this association remain unclear.

Serum transferrin saturation has also been linked to aging. However, in one of the two studies examining this association, results were skewed by the inclusion of participants with high iron levels or hemochromatosis.

Epigenetic clocks, which are based on DNA methylation profiles, are also used to determine the rate of biological aging. To date, few studies have examined the relationship between epigenetic clocks and excess iron levels.

About the study

The current study included 1,260 women with a mean age of 56 years and median body mass index (BMI) of 26 kg/m².

Serum ferritin, iron, transferrin saturation levels were measured and analyzed for their association with GrimAgeAccel, PhenoAgeAccel, and DunedinPACE, all of which are metrics of biological aging based on DNA methylation. Both crude and adjusted analyses of any observed association were performed.

Study findings

Serum iron levels were strongly associated with transferrin saturation; however, neither of these iron measurements were strongly associated with ferritin levels. After adjusting for factors like menopause, socioeconomic status, smoking and alcohol, exercise and diet, slower biological aging was associated with increased serum iron levels and higher transferrin saturation.

Serum iron was associated with a reduction of 0.02, 0.04 and 0.05 in GrimAgeAccel, PhenoAgeAccel, and DunedinPACE, respectively. Increased serum ferritin levels were associated with DunedinPACE.

Transferrin saturation was also associated with reductions in all aging metrics. PhenoAgeAccel and GrimAgeAccel were associated with serum iron and transferrin levels, the latter of which showed stronger associations.

After adjusting for possible confounding factors, all estimates suggested that transferrin saturation is not strongly linked to biological age, as estimated by DNA methylation. For example, transferrin saturation of 45% or greater did not change the positive direction of the association; however, this association did not exceed 0.03 standard deviations in any of the aging parameters.

Thus, the toxicity of iron at high levels was not reflected in the epigenetic clocks when comparing the highest to the lowest quartile. This might be due to the reduced transport of iron through transferrin that occurs during accelerated biological aging.

Conclusions

More rapid biological aging was associated with rising ferritin levels. This observation indicates that high iron levels promote oxidative stress, thereby accelerating biological aging.

The positive association with ferritin is consistent with the proposed role of oxidative stress in accelerated aging associated with high iron exposure.”

However, the current study also reported negative associations between aging and both serum iron and transferrin saturation. Since telomere length is not strongly associated with methylation-based epigenetic markers of aging, oxidative stress induced by excess iron may reflect reduced telomere length, rather than the epigenetic changes underlying biological aging.

Chronic inflammation causes anemia, which may also explain high ferritin but low serum iron and transferrin levels observed in chronic disease. In these cases, biological aging is the cause, rather than the result, of the anemia of inflammation that contributes to chronic disease.