**Advanced Age Is Associated with Iron Dyshomeostasis and Mitochondrial DNA Damage in Human Skeletal Muscle**

**Anna Picca 1,2, Robert T. Mankowski 3, George Kamenov 4, Stephen D. Anton 3, Todd M. Manini 3, Thomas W. Buford 5, Sunil K. Saini 3, Riccardo Calvani 1,2, Francesco Landi 1,2, Roberto Bernabei 1,2, Emanuele Marzetti 1,2,\* and Christiaan Leeuwenburgh 3**


Received: 21 October 2019; Accepted: 25 November 2019; Published: 27 November 2019

**Abstract:** Whether disruption of iron metabolism is implicated in human muscle aging is presently unclear. We explored the relationship among iron metabolism, muscle mitochondrial homeostasis, inflammation, and physical function in older adults and young controls. Eleven young and 23 older men and women were included. Older adults were classified into high–functioning (HF) and low–functioning (LF) groups according to their Short Physical Performance Battery score. Vastus lateralis muscle biopsies were assayed for total iron content, expression of 8-oxoguanine and DNA glycosylase (OGG1), 3-nitrotyrosine (3-NT) levels, and mitochondrial DNA (mtDNA) content and damage. Circulating ferritin and hepcidin levels were also quantified. Muscle iron levels were greater in the old group. Protein expression of transferrin receptor 1, Zrt-Irt-like protein (ZIP) 8, and ZIP14 were lower in old participants. Circulating levels of ferritin, hepcidin, interleukin 6 (IL6), and C-reactive protein were higher in the old group. Old participants showed lower mtDNA content and greater mtDNA damage. OGG1 protein expression declined with age, whereas 3-NT levels were greater in old participants. Finally, a negative correlation was determined between ZIP14 expression and circulating IL6 levels in LF older adults. None of assayed parameters di ffered between HF and LF participants. Our findings sugges<sup>t</sup> that muscle iron homeostasis is altered in old age, which might contribute to loss of mtDNA stability. Muscle iron metabolism may therefore represent a target for interventions against muscle aging.

**Keywords:** iron overload; hepcidin; transferrin; ferritin; ZIP; inflammation; mtDNA; mitochondrial dysfunction; muscle aging; physical performance
