ADAPT: Efficacy of a Dietary Supplement to Increase Resilience and Inhibit the Oxidative Stress Response During and After Exercise

The Nrf-2 pathway is the major cellular defence against oxidative and electrophilic stresses. Briefly, following dissociation from Keap1 (a scaffolding protein which binds Nrf2 and Cul3 ubiquitin ligase for proteasome degradation), Nrf-2 accumulates in the nucleus where it activates the antioxidant response element (ARE) in the promoter region of many antioxidant genes, including catalase, glutathione peroxidases (GPX), and superoxide dismutase (SOD). As such, it is an attractive target for both dietary and pharmacological interventions aiming to increase resilience to oxidative stress. Most diet-derived bioactive Nrf-2 inducers contain Michael acceptor groups (an α, β-unsaturated carbonyl moiety). Curcumin, for example, contains two Michael acceptor groups and is a known activator of Nrf-2. An additional bioactive with a Michael accepter group is trans-cinnamaldehyde (CA) (a component found in the stem bark of Cinnamomum cassia), which, like curcumin, is an Nrf-2 activator in a dose-dependent manner.

Therefore, the purpose of this study will be to assess the effect of bioactive Nrf-2 inducers, based on the presence of an α, β-unsaturated carbonyl moiety, on resilience markers such as antioxidant enzyme activities and markers of oxidative stress, such as TBARS, to an exercise challenge. The hypothesis is that specific plant bioactive increase the production of antioxidant enzyme activities at baseline, and thereby decrease levels of TBARS upon an exercise challenge. Ultimately, the use of novel resilience markers and signatures could significantly improve the ability to prove the efficacy by which pro-oxidant dietary bioactive improve lifelong health, as well as targeting those with lowest resilience as a way to make best use of limited healthcare resources.

The intervention supplement will consist of a mix of dietary bioactive with an α, β-unsaturated carbonyl moiety (provided in individual capsules), of which the efficacy to beneficially affect platelet activity, with and without a H2O2 (Hydrogen Peroxide) challenge, was recently established: sulforaphane (SUL), green tea extract (epigallocatechin gallate) (EGCG) and cinnamaldehyde (Cin).

It is intended to use a mix of dietary bioactive for the proposed human intervention study, as different compounds could affect multiple pathways and therefore, have a broader efficacy. In addition, bioavailability of compounds may be influenced by presence of other compounds, as has been suggested in the literature (effect of piperine on EGCG bioavailability).

Bioavailability data for each of these compounds were extracted from the literature and these have been used, alongside practical considerations, to decide on the dosing strategy. The desired composition of the supplement mix has been set as follows: