Lipid (per) oxidation in mitochondria:an emerging target in the ageing process?

Lipids are essential for physiological processes such as maintaining membrane integrity, providing a source of energy and acting as signalling molecules to control processes including cell proliferation, metabolism, inflammation and apoptosis. Disruption of lipid homeostasis can promote pathological changes that contribute towards biological ageing and age-related diseases. Several age-related diseases have been associated with altered lipid metabolism and an elevation in highly damaging lipid peroxidation products; the latter has been ascribed, at least in part, to mitochondrial dysfunction and elevated ROS formation. In addition, senescent cells, which are known to contribute significantly to age-related pathologies, are also associated with impaired mitochondrial function and changes in lipid metabolism. Therapeutic targeting of dysfunctional mitochondrial and pathological lipid metabolism is an emerging strategy for alleviating their negative impact during ageing and the progression to age-related diseases. Such therapies could include the use of drugs that prevent mitochondrial uncoupling, inhibit inflammatory lipid synthesis, modulate lipid transport or storage, reduce mitochondrial oxidative stress and eliminate senescent cells from tissues. In this review, we provide an overview of lipid structure and function, with emphasis on mitochondrial lipids and their potential for therapeutic targeting during ageing and age-related disease

Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD

Tissue hypoxia occurs when local oxygen demand exceeds oxygen supply. In chronic inflammatory conditions such as IBD, the increased oxygen demand by resident and gut-infiltrating immune cells coupled with vascular dysfunction brings about a marked reduction in mucosal oxygen concentrations. To counter the hypoxic challenge and ensure their survival, mucosal cells induce adaptive responses, including the activation of hypoxia-inducible factors (HIFs) and modulation of nuclear factor-kappa B (NF-kappa B). Both pathways are tightly regulated by oxygen-sensitive prolyl hydroxylases (PHDs), which therefore represent promising therapeutic targets for IBD. In this Review, we discuss the involvement of mucosal hypoxia and hypoxia-induced signalling in the pathogenesis of IBD and elaborate in detail on the role of HIFs, NF-kappa B and PHDs in different cell types during intestinal inflammation. We also provide an update on the development of PHD inhibitors and discuss their therapeutic potential in IBD