The crucial physiological process of heme breakdown yields biliverdin (BV) and bilirubin (BR) as byproducts. BV, BR, and the enzymes involved in their production (the "yellow players-YP") are increasingly documented as endogenous modulators of human health. Mildly elevated serum bilirubin concentration has been correlated with a reduced risk of multiple chronic pro-oxidant and pro-inflammatory diseases, especially in the elderly. BR and BV per se have been demonstrated to protect against neurodegenerative diseases, in which heme oxygenase (HMOX), the main enzyme in the production of pigments, is almost always altered. HMOX upregulation has been interpreted as a tentative defense against the ongoing pathologic mechanisms. With the demonstration that multiple cells possess YP, their propensity to be modulated, and their broad spectrum of activity on multiple signaling pathways, the YP have assumed the role of an adjustable system that can promote health in adults. Based on that, there is an ongoing effort to induce their activity as a therapeutic option, and natural compounds are an attractive alternative to the goal, possibly requiring only minimal changes in the life style. We review the most recent evidence of the potential of natural compounds in targeting the YP in the context of the most common pathologic condition of adult and elderly life.

Department of Life Sciences University of Trieste 34139 Trieste Italy

Department of Science and Technology Philippine Council for Health Research and Development Bicutan Taguig City 1631 Philippines

Eijkman Research Centre for Molecular Biology Research Organization for Health National Research and Innovation Agency Cibinong 16915 Indonesia

Institute of Medical Biochemistry and Laboratory Diagnostics and 4th Department of Internal Medicine General University Hospital and 1st Faculty of Medicine Charles University 12000 Prague Czech Republic

Liver brain Unit Rita Moretti Fondazione Italiana Fegato Onlus Bldg Q AREA Science Park ss14 Km 163 5 Basovizza 34149 Trieste Italy

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