Manipulating the exposome to enable better ageing

Abstract

The sum total of life course exposures creates an exposome that has a significant impact on age-related health. Understanding the interplay between exposome factors and the (epi) genome, offers pertinent insights into the ageing process and its relationship with the accumulation of allostatic load. We propose to exploit this to develop a biomimetic approach that will provide insight into how evolution through natural selection in other species has solved many age related human health issues. In particular, we will emphasise the need to reconnect a more mechanistic approach to medical science with a broader natural sciences approach, using biomimetics to mitigate the global burden of age related ill health. In particular, we will discuss how such an approach indicates leverage of the activities of the Nrf 2 gene to enhance health span via reintroduction of the classical 'Food as Medicine' concept, including modulation of the microbiome and the creation of more salutogenic and biophilic environments. Additionally, we will discuss how this approach integrates with novel and developing senotherapies.

Keywords: Nrf2; ageing; allostatic load; biomimetics; exposome; microbiome.

Figure 1.. How changes in the exposome are mediated by the action of Nrf2.

Exposome stress, either external (e.g. environmental and psycho-social), or internal (e.g. redox imbalance, hypoxia, uraemic toxins), results in disassociation of Keap1 from Nrf2. Nrf 2 then translocase to the nucleus, binds to the AREs of cytoprotective genes and inhibits NFkB mediated inflammatory responses, enables maintenance of the Proteosome and enhances mitochondrial activity. Consequently, these actions result in geroprotection through facilitation of adaptive homeostasis in the face of the exposome stress.

Figure 2.. Manipulating the exposome to improve health-span.

A schematic representation of the exposome, defining differing levels of interaction with the (epi)genome. Potential interventions to mitigate the effects of cumulative allostatic and subsequent ill health are indicated beside the respective exposome levels, from the macro-geophysical environmental level to the micro-tissue and cellular physiology level. Potential outcomes are listed on the right hand side of the respective levels.