Free iron: a forgotten target in skin aging prevention

1. Free iron: a forgotten target in skin aging prevention

2. Iron Iron is essential for aerobic life, oxygen transport, energy production, red blood cell function But (free) iron is also involved at various steps of the oxidation processes, increasing the production of the more toxic hydroxyl radicals .OH+ Fe3+ + -OH Fenton reaction: H2O2 + Fe2+ Haber-Weiss reaction: .OH+ -OH + O2 + Fe3+ H2O2 + O2.- + Fe2+

3. DNA Fe2+ O2 O2.- H2O2 .OH molecular oxygen superoxide anion hydrogen peroxide hydroxyl radical sugar glycation membrane lipids nucleus mitochondria strand breaks proteins dysfuntion of the respiratory chain lipid peroxidation functional alterations cellular senescence Damages induced by hydroxyl radical (Polla BS et al 2013)

4. Free iron also activates transcription factors involved at different steps of pro-inflammatory processes such as NFκB UV plays a role in the release of free iron from proteins to which iron is normally bound such as ferritin Iron

5. Iron and inflammation UV ferritin O2.- H2O2 .OH Fe2+ Fe3+ Fe2+ lysosomal enzyme Fe2+ Fe2+ cellular damages NF-κB activation Fe2+ Fe2+ ferritin inflammation lysosome fibroblast Lysosomal enzymes damage ferritin that releases free iron thus indirectly causing cellular damages (Polla BS et al 2013)

6. Iron -The aging process is accelerated by oxidation →iron increases oxidation damage → affects the aging process -The aging process is modulated by inflammation → iron modulates inflammation → affects the aging process

7. Haemochromatosis -0.3% of individuals: common metabolic disorder -genetically determined: HFE gene on chromosome 6 -this gene intervenes in the control of gastrointestinal iron absorption -spontaneous pathology of iron accumulation in the internal organs as well as in the skin

8. Haemochromatosis -skin has a gray appearance and presents accelerated signs of aging: role of iron in photoaging -iron levels in the circulation are generally higher than the binding capacity of iron to transferrin -publications on hemochromatosis and skin aging are however rare; skin histology appears to be missing

9. Haemochromatosis Picture: Cutaneous pigmentation in haemochromatosis (greyish hue and brown hue) (Hemochromatosis, Genetics, pathophysiology, diagnosis and treatment, Ed JC Barton and CQ Edwards, 2000)

10. Clinical / pathological models for iron overload and free iron excess -Haemochromatosis -UV exposure In both cases : -excess free iron -accelerated aging

11. Iron and UV -UV radiations remove the iron from its protective envelopes (Pourzand et al 1999) -skin iron: three times higher in the skin exposed to UV light (forehead, cheeks) than in non-exposed areas (buttocks, thighs) (Bissett et al 1991)

12. UV Fe2+ storage proteins Fe2+ Fe2+ Fe2+ storage proteins Fe2+ Fe2+ Fe2+ Fe3+ O2.- H2O2 .OH cellular damages UV cellular aging fibroblast Iron and UV UV radiations remove the iron from its protective envelope (Polla BS et al 2013)

13. Protection against free iron: depletion, storage and chelation -ROS-induced lesions are inhibited by a reduction in free iron -depletion has also been shown to be efficient in various animal models such as Duchenne’s myopathy were oxidation at the cellular level plays an important role in the progressive muscle lesions (Clark 1984) as well as in an animal models (Bornman et al, 1998) -iron linked to transport proteins and stored

14. Chele

15. Chelation UV ferritin ferritin Fe2+ Fe2+ A Fe2+ B Fe2+ Fe2+ Fe2+ Fe2+ iron chelator C Figure A: ferritin scavenges iron Figure B: UV damages ferritin which releases iron Figure C: iron chelator scavenges iron with same manner as ferritin (Polla BS et al 2013)

16. Chelation: works by Bissett et al Time of onset of wrinkles in mouse skin treated with 2-furildioxime (FDO), sunscreen and their combination before UV exposure. *ethanol/prop.glycol (Bissett et al 1996) Chelation from the Greek chele, which describes the crab claw

17. Chelation: works by Bissett et al Suppression of UV-induced human skin erythema 24 hours after 3 MED by 2-furildioxime (FDO) (Bissett et al 1994)

18. Chelation: works by Bissett et al Inhibition of sunburn cell formation in human skin 24 hours after 3 MED by 2-furildioxime (FDO) (Bissett et al 1994)

19. Synthetic chelators -desferrioxamine effects on liver ischaemia-reperfusion injury → decrease in oxidative and inflammatory serum markers and in hepatocellular damage (Arkadopoulos et al 2010) -combination with desferrioxamine, deferipone and deferasirox → improve cardiac and hepatic iron load in beta-thallassemia (Berdoukas et al 2009)

20. Synthetic chelators -Parkinson’s disease: abnormal accumulation of iron in affected neurons in the substantia nigra. Desferrioxamine/desferal/ deferiprone: new use in neurodegenerative diseases (Mounsey and Teismann 2012) -Different types of iron chelators have neuroprotective effects, preventing neural apoptosis and activating cellular protective pathways against oxidative stress (Oshiro et al 2011)

21. Natural chelators -quercetine, genisteine, kaempferol,… -”iron-binding motif”: iron chelating agent which may modulate the bioactivity and bioavailability of iron in the body (Guo M et al 2007) quercetin molecule with chelation site chelation site

22. Natural chelators -shuttle for labile iron : effective in loading the metal into the iron-transport protein transferrin (Baccan MM et al 2012) -association between antioxidants and iron chelators in topical approaches

23. Conclusion Modulation of iron levels appears as a very attractive approach in the management of diseases and conditions associated with excess oxidation and in antiaging The skin could provide an excellent model to investigate the preventive effects of iron chelation in inflammation and aging However we are missing clinical research on the effects of iron chelation including in dermatology >> back to work ! And do donate blood ….