New Gene Therapy Strategy With the Potential to Delay Ageing

Ageing is a mysterious, albeit inevitable, part of life for which the science is hardly understood. Only in the 1980’s was it determined that the factors affecting ageing were encoded within our genomes (Rose & Charlesworth, 1980). Since then, the genetics of ageing have been studied extensively in simple organisms, such as yeast or the nematode worm C. elegans. But what determines how humans age?

Researchers in Beijing set out to answer this question in a recent study by exploiting genome editing to screen potential human genes that play a role in cellular senescence (Wang et al., 2021). Senescence is at the heart of ageing; it is the process by which cell growth stops and cells succumb to deterioration. The accumulation of senescent cells in organs is associated with many age-related disorders such as Parkinson’s, Alzheimer’s and osteoporosis in mice models (Bussian et al., 2018; Chinta et al., 2018; Farr et al., 2017).

The research team employed CRISPR/Cas9 gene editing to conduct ‘loss-of-function’ screens of target genes using genome-wide single guide RNA (sgRNA) libraries. sgRNA is a guide molecule that recognises a target gene of interest in the DNA and tells Cas9 exactly where to edit it. Screenings like this enable scientists to introduce mutations into the target gene in order to reduce or eliminate its function and suppress expression of the protein encoded by it. By knocking out genes and seeing how cells are affected, scientists can get a sense of their function. 

The screenings revealed over 100 potential candidate genes involved in promoting senescence, and conducted further investigations the effect of inactivating the top 50 of these genes. One particular gene of interest, termed KAT7, is a gene encoding a histone acetyltransferase. It is an enzyme involved in controlling gene expression over time by modifying DNA (Yan et al., 2018). The researchers found that targeting KAT7 for knockdown by sgRNA and Cas9 reduced senescence, ultimately increasing the longevity of human mesenchymal precursor cells (hMPCs) with Werner Syndrome, an accelerated ageing disease. Even more exciting, injection of the same KAT7-targeting sgRNA/Cas9 complex into the liver cells of mice were shown to reduce senescence in those liver cells, as well as altogether extending the lifespan of the mice.

Although much more research is needed, the results of this study are promising and the implications are extensive: its has set forth a potential new gene therapy strategy for aging and provided insight into novel functions of KAT7 as well as a list of new candidate genes for further research. In reality, identifying the full scope of genes involved in senescence is necessary for developing gene therapy for these diseases as more than one longevity-associated gene may need to be targeted for efficacious treatment (Davidsohn et al., 2019). But even though immortality may still be beyond our grasp, the capacity to enhance human life span no longer seems impossible.