VitaSeno

Rhys Anderson· Jun 9, 2026

senescent cell genome molecular landscape, CRISPR-Cas9 knockout screening, microscopic cellular texture, intricate chromatin detail, soft scientific palette

TL;DR

This project aims to utilise a genome-wide CRISPR-Cas9 knockout screen to identify novel senolytic drug targets whilst providing new mechanistic insights into how senescent cells function and survive.

Background information

Cellular senescence is a phenomenon in which damaged or stressed cells irreversibly exit the cell cycle and adopt a pro-inflammatory phenotype, disrupting tissue homeostasis and causing cytotoxic effects on neighbouring cells.

Senescent cells accumulate with age in humans and are associated with numerous diseases, including osteoarthritis, cardiovascular disease, cancer, and neurodegeneration. In animal models, the targeted removal of senescent cells has been shown to improve health and extend lifespan. Consequently, there is substantial therapeutic interest in developing senolytics - drugs that selectively eliminate senescent cells1.

As global populations continue to age and the incidence of age-related diseases rises, the need for effective interventions grows accordingly. As the removal of senescent cells has the potential to address a broad spectrum of age-associated conditions, the global market for senolytics is positioned to be a multibillion-dollar opportunity across multiple therapeutic areas.

Approach

Synthetic lethality is the biological phenomenon whereby inactivation of either gene A or B is tolerable, yet the loss of both is lethal2. Using this approach for target discovery has seen great success in the cancer field, for example the development of PARP inhibitors for treating BRCA-deficient cancers3. Whilst early attempts relied on RNA interference methods, the advent of CRISPR-based gene editing has made full genome screening more tangible/scalable to the point where numerous big pharma companies have synthetic lethality cancer drug discovery programmes.

Senescence research has established that numerous proteins show differential abundance in proliferating versus senescent cells. For example SIRT1, HMGB24, MCM5 proteins, Lamin B16 and several others are present at extremely low levels / absent in senescent cells. These proteins therefore represent attractive “bait” genes for synthetic lethality experiments.

I now propose that synthetic lethality should be applied to longevity research to discover new drug targets to selectively kill senescent cells.

Experimental Plan

Months 1-2: Create a stable knock-out cell line for the “bait” gene of interest.

Months 3-4: Perform a genome-wide CRISPR-Cas9 knockout screen in wild type vs knock-out cells.

Months 5-6: Next Generation Sequencing and MAGeCK analysis to determine which genes are essential for the survival of knock-out cells.

Months: 7-8: Senolytic validation - determine which hits are essential for senescent cell survival by knocking-out the genes of the top screen hits in proliferating vs senescent cells and perform cell viability assays.

Project Outputs and Future directions

Upon completing these experiments, we hope to identify a number of genes that are essential for the survival of senescent cells, with the most compelling hits serving as novel senolytic targets for future drug-discovery campaigns.

In addition to their translational potential, these genes will provide a foundation for further basic research aimed at elucidating the mechanisms that render them critical for senescent-cell viability.

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