Unraveling Heterogeneity in Cellular Senescence to Target Signs of Aging and Cancer
Marjolein P. Baar 1 , Diana A. Putavet 1 Johannes Lehmann 1 , Peter L.J. de Keizer 1,2*
1 University Medical Center Utrecht, Utrecht University, the Netherlands
2 Cleara Biotech B.V., Utrecht, the Netherlands
* Correspondence: [email protected]
Senescent cells are causal for aging, and the associated loss in healthspan. They do so through long-term systemic signaling to their environment, potentially enhancing a state of stemness and interfering with tissue renewal. Previously, we identified the interaction between the damage-associated proteins FOXO4 and p53 as a pivot in the viability of high secreting, damaged senescent cells. Inhibition of FOXO4, or interference with its interaction with p53 using cell penetrating peptides could selectively eliminate senescent cells and target signs of aging in vivo. Altogether, it may thus be possible to restore healthspan once it has already declined.
Today, I will argue how individual subtypes of senescence may contribute to specific diseases. Furthermore, I will show how cancer cells that have survived damaging therapy may develop senescence-like features and become targetable by specific anti-senescence therapy. It will be crucial to dissect senescence heterogeneity and identify molecular mechanisms that dictate sensitivity or resistance. Our current research is focused on these mechanisms and optimizing our FOXO4-p53 drugs for clinical translation.
1 University Medical Center Utrecht, Utrecht University, the Netherlands
2 Cleara Biotech B.V., Utrecht, the Netherlands
* Correspondence: [email protected]
Senescent cells are causal for aging, and the associated loss in healthspan. They do so through long-term systemic signaling to their environment, potentially enhancing a state of stemness and interfering with tissue renewal. Previously, we identified the interaction between the damage-associated proteins FOXO4 and p53 as a pivot in the viability of high secreting, damaged senescent cells. Inhibition of FOXO4, or interference with its interaction with p53 using cell penetrating peptides could selectively eliminate senescent cells and target signs of aging in vivo. Altogether, it may thus be possible to restore healthspan once it has already declined.
Today, I will argue how individual subtypes of senescence may contribute to specific diseases. Furthermore, I will show how cancer cells that have survived damaging therapy may develop senescence-like features and become targetable by specific anti-senescence therapy. It will be crucial to dissect senescence heterogeneity and identify molecular mechanisms that dictate sensitivity or resistance. Our current research is focused on these mechanisms and optimizing our FOXO4-p53 drugs for clinical translation.
