Date Published: December 16, 2018
Publisher: Impact Journals
Author(s): Meng-Wan Zhang, Peng Zhao, Wing-Ho Yung, Yuan Sheng, Ya Ke, Zhong-Ming Qian.
To test the hypothesis that iron accumulation in tissues with age is a key harmful factor for the development of aging, we established heterochronic parabiosis-pairings and investigated changes in serum iron, the expression of major iron transport proteins and iron contents, as well as telomerase reverse transcriptase (TERT), telomerase RNA component (TERC), and telomere length in the liver, kidney and heart of Y-O(O) (old pairing with young), Y-O(Y) (young pairing with old), O-O (pairings between two old) and Y-Y (pairings between two young) mice. We demonstrated that the reduced serum iron, increased iron and reduced expression of TERT and TERC in the tissues of aged mice are reversible by exposure to a younger mouse’s circulation. All of these measurements in young mice are reversible by exposure to an older mouse’s circulation. Correlation analysis showed that tissue iron is negatively correlated with TERT and TERC expression in the liver, kidney and heart of parabiotic mice. These findings provide new evidence for the key role of iron in aging and also imply the existence of rejuvenating factors in young serum with an anti-ageing role that act by reversing the impaired activity of iron metabolism in old mice.
Heterochronic parabiosis, which is the joining of the circulation systems of an aged mouse and a young mouse together, has been reported to have an anti-ageing effect. Studies of heterochronic parabiosis show that beneficial factors derived from the young systemic environment are able to activate molecular signaling pathways in hepatic, muscle or neural stem cells of the old parabiont, leading to increased tissue regeneration . On the other hand, studies have also demonstrated that with age, the composition of the circulatory milieu changes in ways that broadly inhibit tissue regenerative capacities , suggesting the existence of certain harmful factors in the older organisms that trigger aging, thus preventing the rejuvenation process [2,3]. Currently, the beneficial or harmful factors involved in rejuvenation or aging and the relevant mechanisms are not completely understood, although chemokine CCL11 (eotaxin) , growth differentiation factor 11 (GDF11, a member of the TGF-β superfamily) [5–7], oxytocin , β-catenin , pro-inflammatory cytokines (most notably interleukin-6, IL-6)  and β2-microglobulin (B2M)  have been identified as some beneficial or harmful factors that are in part responsible for rejuvenating or aging effects.
One of the major objectives of the present study was to find out whether exposure to a younger mouse’s serum is able to reduce iron contents in tissues and produce an anti-ageing effect in old mice. We demonstrated for the first time that heterochronic parabiosis (an old mouse sharing the same circulatory system with a young mouse) significantly reduced the contents of iron, Ft-H and Ft-L in the liver, kidney and heart, and up-regulated serum iron level in old mice. Also, heterochronic parabiosis up-regulated the expression of TERC and TERT mRNAs in the liver, kidney and heart in old mice. Furthermore, correlation analysis showed that tissue iron contents are negatively correlated with TERC or TERT mRNA expression in heterochronic parabiotic mice. These findings, plus the existing knowledge on the connection between iron and genome stability , iron-induced oxidative stress and telomere shortening or telomerase activity [18–20] and ageing  support the hypothesis that the accumulated iron in tissues with age is one of the key harmful factors in the development of aging, whereas reducing iron contents in tissues via exposure to a younger mouse’s serum produces an anti-ageing effect in old mice. Our results imply that there are beneficial factors in younger mice’s serum with an anti-ageing role that act by reversing impaired activity of iron metabolism in older mice.