Targeting Senescent Cells Essay Example

senescent cells, a lentiviral shRNA was used to inhibit its expression in cells prior to senescent induction. Through inhibition, Baar et al. and colleagues saw that the cells did not become senescent and had undergone apoptosis instead. Furthermore, in cells already senescent, they saw that the inhibition of FOXO4 had decreased the cell viability and density. These results suggested that FOXO4 plays a key role in the generation of senescent cells.

To better understand the role of FOXO4 in senescent cells, the authors first focused on FOXO4’s pattern during senescence. During senescence development, FOXO4 was found to reside in promyelocytic leukemia (PML) bodies that were adjacent to 53BP1-containing DNA-SCARS. Localized to DNA-SCARS in senescent cells was also. As both FOXO4 and co-localized to these structures and FOXOs have been known to bind, it was proposed that FOXO4 interacts with.

Thus, the authors focused on interfering with this binding to possibly induce apoptosis. In order to interfere with this binding, Baar et al. created a D-retro inverso (DRI)-isoform that corresponded to the reverse sequence of the FOXO4 domain involved with binding to this DRI isoform was utilized as previous DRI-modified peptides produced new chemical properties that improved potency in vitro and in vivo. Furthermore, previous DRI-modified peptides were discovered to be therapeutically effective in clinical trials.

After creating FOXO4-DRI, the peptide was then fused with a HIV-TAT peptide to facilitate cellular uptake. What Baar et al. and colleagues noticed was that FOXO4-DRI outcompeted FOXO4 in binding to as it had a higher affinity. This binding of FOXO4-DRI to presented similar results to FOXO4 shRNAs. Nuclear exclusion of occurred, which allowed for it to interact with mitochondria to cause the

release of cytochrome and induce apoptosis. In addition to observing FOXO4-DRI in senescent cells, the authors also observed the effects of FOXO4-DRI in normal cells. They also discovered that in the normal cells, FOXO4-DRI did not produce any damaging effects.

Based on the results that FOXO4-DRI could induce apoptosis in vitro, Baar et al and colleagues wanted to also look at its effects on senescent cells in vivo. Additionally, they wanted to see if FOXO4-DRI could restore tissue homeostasis in damaged tissues. To do so, they used a fast-aging XpdTTD/TTD mouse model, a naturally aged mouse model for a control, and chemotherapy-treated animals. Each of these models all consisted of a high number of senescent cells. When treated with FOXO4-DRI, several parameters were observed to determine whether tissue homeostasis was restored. These parameters were exploratory behavior, voluntary running wheel activity, standard tissue function tests specifically for the liver and kidney, and fur density. From observing these parameters across all three treated models, significant functional improvements were seen.

This paper by Barr et al. offers new insight into understanding senescent cells. The observations made by the authors on FOXO4’s involvement in inhibition of apoptosis allowed for the discovery of a new possible therapeutic agent, FOXO4-DRI. Although further studies still need to be conducted to better understand its pharmacokinetic properties, Barr et al. and colleagues have opened a new door for restoring tissue homeostasis in patients undergoing chemotherapy treatment or suffering from age-related disease.