2021PoblockaMPhD.pdf (35.99 MB)

New approaches to target cellular senescence for the amelioration of age-related pathologies.

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thesis
posted on 10.09.2021, 14:32 by Marta A. Pobłocka
Aging has been broadly defined as a functional decline that progresses with time and leads to impaired function and increased vulnerability to death. Cellular senescence is one of the main factors involved in this age-related functional decline and it has been shown that the percentage of senescent cells in tissues increases with age in different organs and in age-related disorders. Therefore, cellular senescence has been characterized as one of the hallmarks of aging. Consistent with this, elimination of senescent cells could ameliorate the negative effects of ageing, as it has already been shown in mouse models. However, the currently available methods of targeting and eliminating senescent cells lack specificity and have off-target effects. The first barrier that slows the development of anti-senescent drugs is lack of specific markers for senescence. To overcome this issue, we validated VPS26A, EBP50 and PLD3, which were recently identified in a screen of proteins specifically upregulated in senescent cells. Moreover, we propose novel approaches to target and eliminate senescent cells. Our first approach is an Antibody Drug Conjugates that specifically identifies and directly eliminates senescent cells through a marker expressed in their plasma membrane. Second, we used senoblocking, a strategy that aims to block cellular senescence before it occurs. For that purpose, we treated a progeroid mouse model with Ibrutinib, a clinically available BTK inhibitor. It has been previously hown that BTK inhibition interrupts cellular senescence. The treatment resulted in an improvement of healthspan and protection of a decline in brain and skeletal muscle performance. The third approach tested relied on the combinations of BCL-XL inhibitors, A1331852 and 9-hydroxyellipiticine, that synergistically kill senescent cells. The results from our research introduce novel promising therapeutic interventions for the elimination of senescent cells which could find a translational application in the future.

History

Supervisor(s)

Salvador Macip

Date of award

17/05/2021

Author affiliation

Department of Molecular and Cell Biology

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en