Abstract
Aging is intricately linked to various diseases including cancers, neurodegenerative disorders, and metabolic irregularities. Copper (Cu) overexposure has been found to be linked to many diseases during aging, particularly neurodegenerative diseases. Meanwhile, as an essential element, Cu has been implicated in key processes associated with aging, raising questions about its role in age-related health issues. This study delves into the mechanisms behind the copper imbalance during aging. By analyzing blood copper concentrations of healthy individuals (including data from healthy subjects (26 ≤ age ≤ 90, n = 62) and publicly available data from the National Health and Nutrition Examination Survey (18 ≤ age < 80, n = 1624)) and employing C57BL/6N male mice models (n = 22), we reveal a consistent age-related increase in copper levels, particularly in plasma. Utilizing stable copper isotopic analysis, copper-associated protein analysis, and metabolomic analysis, we trace the sources of Cu imbalance associated with aging. Our findings reveal that aged mice had a higher copper concentrations and an enrichment of light copper isotope (63Cu) in plasma compared to controls. Additionally, copper reductases and copper transporters are upregulated in the intestine tract, associated with the AMPK and mTOR signaling pathways. We suggest that aged mice have an abnormally high copper intake requirement, probably due to deregulated nutrient sensing, leading to increased expression levels of copper reductases and copper transporters for extra copper absorption in the intestines. This research provides a copper-centric perspective on the connection between deregulated nutrient sensing and aging, thus shedding light on the aspect of aging and copper overexposure.