Nutritional Hormesis and Aging

Hayes, D. P.

doi:10.2203/dose-response.09-012.hayes

Cited by 8 publications

(1 citation statement)

References 29 publications

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“…13 ), and individual effects of particular substances can vary qualitatively depending on concentrations, as in hormesis (e.g. Calabrese 2008a , b , c ; Calabrese and Baldwin 1997 , 2001 , 2003 ; Calabrese and Blain 2005 , 2009 ; Cook and Calabrese 2006 ; Cox 2009 ; Gems and Partridge 2008 ; Gómez-Pinilla 2008 ; Hadacek et al 2010 ; Hayes 2009 ; Hoffmann 2009 ; Mattson 2008a , b ; Radak et al 2008 ; Rattan 2004 , 2008 ; Rattan and Demirovic 2009 ; Ristow and Zarse 2010 ; Sørensen et al 2009 ), so any analysis should be a systems analysis. The simple fact that, for instance, iron chelators improve prospects in Alzheimer’s implies that there is a background level of natural repair (otherwise chelators would only slow the neurodegeneration and not reverse it) and that is not necessarily apparent from measuring only net effects.…”

Section: Discussion: Toxicology As Systems Biologymentioning

confidence: 99%

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples

2010

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Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-κB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions.

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