br Pharmacological anti aging approaches and

Pharmacological anti-aging approaches and the Hippo pathway Aging and age-related pathologies are the main causes of disabilities and death. As Magalhañes and colleagues suggest, the challenges of developing anti-aging pharmacological therapies may, in part, be due to the complexity of aging molecular mechanisms. There is no clear consensus on theories about aging. Experimental models available for aging research are performed in short-lived organisms. Most age-associated pathways have not been targeted pharmacologically as yet and anti-aging approaches in humans are difficult to address, requiring a long validation time [205]. Despite the importance of effective pharmacological approaches to an increased healthy lifespan and to delay age-related negative conditions, so far few pharmacological compounds including resveratrol, rapamicyn, spermidin and metformin have the ability to promote these desired conditions. This conclusion has been validated in at least three model organisms and confirmed by at least three different laboratories [206]. Here we summarize how the Hippo pathway can be modulated by anti-aging compounds.
Conclusions Although studies have demonstrated association of the Hippo pathway with numerous signaling, the main contribution of the Hippo pathway is the regulation of cell proliferation and growth. In the context of aging process, AMPK pathway is able to regulate activity of the Hippo pathway, as well as the Pentamidine of its target genes, resulting in reduced cell proliferation and growth. Moreover, the Hippo pathway can promote oxidative stress-mediated cell death by inducing apoptosis or inhibiting oxidative stress-mediated cell death by increasing the expression of antioxidant genes. In cancer, low apoptosis promotes uncontrolled cell proliferation leading to cancer initiation and progression, while in aging, low apoptosis contributes to accumulation of the senescent cell. Given that effects of apoptosis in cancer and aging are opposite, future research is needed to elucidate the molecular mechanisms responsible for the Hippo pathway-mediated apoptosis in different cell types and under different environment conditions. Moreover, experiments on various aging animal models are required to confirm/elucidate whether regulation of the Hippo pathway contributes to increasing lifespan and improving the healthspan. Interestingly, the effect of MST1 on autophagy is cell-type specific. For example, while still in embryonic cells, MST1 promotes autophagy, while in neuron, macrophages and cardiac cells and thyroid cancer, MST1 inhibits autophagy. Future studies elucidating the molecular mechanisms responsible of the “dual” effect of the Hippo pathway on autophagy and stress response should be done. In addition, whether direct manipulation of the Hippo pathway components have a positive effect on health and longevity should be clarified before utilizing pharmacological modulators of the Hippo pathway clinically. Similarly, the Hippo pathway also plays a crucial role in cell proliferation in cancer cells making it an attractive target for anticancer therapy. Inactivation of the Hippo pathway and the dysregulation of its downstream effectors, YAP and TAZ, were frequently observed in human cancers. Therefore, anticancer therapies targeting the Hippo pathway could either aim at restoring activity of the Hippo pathway or inhibiting the YAP and TAZ activities. MST1/2 and LATS1/2 are two pairs of core kinases in the Hippo pathway that suppress the function of YAP and TAZ. Reviews from Johnson et al and Guo et al have summarized small molecule agonists that stimulate these two kinase families [221,222]. Notably, the core components of the Hippo pathway are well-conserved and rarely exhibit genetic mutations. Future studies should aim at understanding the underlying mechanisms of the dysregulated activity of the Hippo pathway in cancer and aging. Moreover, in order to develop a tailored therapy to manipulate the Hippo activity in cancer patients, relationship between the dysregulated Hippo pathway and other major oncogenic driver mutations such as KRAS and EGFR should also be examined. Finally, YAP and TAZ do not confer any enzyme activity and their function is mediated by their interacting partners such as TEAD and AMOT. Consequently, pharmacological inhibition of YAP and TAZ mainly focuses on disrupting these protein-protein interactions. The co-crystal structure of YAP and TEAD has recently been determined and, therefore, it would not be surprising if numerous inhibitors were to be developed in the near future.