ShcA proteins: new targets for age-related diseases?

Evidence suggests that ShcA proteins may accelerate aging – targeting them could reduce age-related diseases.

Src homology and collagen A (ShcA) proteins are a family of adapter proteins regulating various physiological processes, including cell growth, cell migration metabolism. However, their role in aging has remained largely unknown – until now. Recent evidence suggests that ShcA proteins may play a critical role in aging and regulate the onset of age-related diseases [1].

Longevity.Technology: The ShcA protein family consists of three protein variants: p46Shc, p52Shc and p66Shc. In response to external stimuli, ShcA proteins activate various signalling cascades, enabling cells to respond to different signals. Although all three ShcA proteins contain domains mediating their interaction with lipids and other proteins, the cellular responses initiated by the different ShcA variants are extremely diverse [2].

In contrast to p46Shc and p52Shc, p66Shc contains a CH2 domain, making p66Shc’s structure unique. Intriguingly, p66Shc has multifaceted roles in cell growth, inducing both cell proliferation and cell death. This dual functionality of p66Shc in cell growth is largely attributed to the additional CH2 domain and its unique structure [2].

In a recent review article published in the journal Ageing Research Reviews, Hilal Ahmad Mir et al. highlight that p66Shc may represent a reliable diagnostic and prognostic biomarker for chronic age-related disorders. The authors note that in addition to regulating cell growth and cell migration, p66Shc also regulates the production of reactive oxygen species (ROS), thereby orchestrating cellular responses to oxidative stress. [2].

Under oxidative stress conditions, p66Shc promotes mitochondrial dysfunction and enhances ROS production, exacerbating oxidative stress and increasing the risk for neurodegenerative and metabolic age-related diseases [2, 3]. In mice, p66Shc depletion extended lifespan by 30% and protected animals from acute ischemia and brain aging.

Additionally, low p66Shc expression levels have been associated with a decreased risk of diabetes and other metabolic disorders [2, 4].

Moreover, alterations in p66Shc expression promote tumour progression by enhancing cancer cell metastasis and inducing STAT3-driven immune suppression. Therefore, the authors highlight that the p66Shc/ROS pathway may represent a promising target for the treatment of cancer, neurodegeneration, metabolic disorders and other chronic age-related diseases [2].

Despite increasing evidence implicating the p66Shc/ROS pathway in many age-related pathologies, p66shc inhibition may cause undesirable effects owing to the paradoxical roles of p66Shc in cell growth and apoptosis. Hence, further in-depth structural and functional studies are required to fully uncover the role of the p66Shc/ROS pathway in health and disease and develop interventions that specifically inhibit certain functions of p66Shc while maintaining others.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624076/
[2] https://www.sciencedirect.com/science/article/pii/S1568163720302749
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3454471/
[4] https://bit.ly/2SSmxAC
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