Identification of HSP90 inhibitors as a novel class of senolytics

By Heike Fuhrmann-Stroissnigg, Y. Ling, J. Zhao, S. McGowan, Yi Zhu, R. W. Brooks, D. Grassi, Siobhán Q. Gregg, Jennifer L. Stripay, A. Dorronsoro and 10 more. Nature Communications, 2017

620 citations recorded by the source corpus.

Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging. To identify novel and more optimal senotherapeutic drugs and combinations, we established a senescence associated β-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells. We used primary Ercc1−/− murine embryonic fibroblasts with reduced DNA repair capacity, which senesce rapidly if grown at atmospheric oxygen. This platform was used to screen a small library of compounds that regulate autophagy, identifying two inhibitors of the HSP90 chaperone family as having significant senolytic activity in mouse and human cells. Treatment of Ercc1−/∆ mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16INK4a expression. These results demonstrate the utility of our screening platform to identify senotherapeutic agents as well as identified HSP90 inhibitors as a promising new class of senolytic drugs. The accumulation of senescent cells is thought to contribute to the age-associated decline in tissue function. Here, the authors identify HSP90 inhibitors as a new class of senolytic compounds in an in vitro screening and show that administration of a HSP90 inhibitor reduces age-related symptoms in progeroid mice.

Subfields: Aging, Endocrine and Autonomic Systems, Physiology

View Paper: https://www.semanticscholar.org/paper/75a2484a24067d78ca91ed40dc971ce24f8eafc4

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Aging

1. J. Kirkland
2. T. Tchkonia
3. J. Campisi
4. M. Demaria
5. Manuel Serrano
6. V. Krizhanovsky
7. M. Collado
8. J. Passos

In Endocrine and Autonomic Systems

1. J. Campisi

In Physiology

1. J. Campisi
2. J. Kirkland
3. T. Tchkonia
4. M. Demaria
5. Manuel Serrano
6. Alejandra Hernandez-Segura
7. J. Nehme
8. M. Collado

Citations in the corpus

• Cellular Senescence: Defining a Path Forward. (2019, background): “/ D mice with senolytic drugs reduces senescence markers and extends health span (Fuhrmann-Stroissnigg et al., 2017; Yousefzadeh et al., 2018; Zhu et al., 2015).”
• Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “Finally, HSP90 inhibitors have recently be shown to be effective in delaying the onset of aging related symptoms in a mouse model of progeria (129).”
• Hallmarks of Cellular Senescence. (2018, positive): “Finally, HSP90 was shown to be a key protein for the survival of senescent cells via stabilization of P-AKT [88].”
• Fisetin is a senotherapeutic that extends health and lifespan (2018, methodology): “To determine if other flavonoidsmight havemore potent senotherapeutic activity than quercetin, a panel of flavonoids was screened for effects on senescence induced by oxidative stress [49].”