‘Cellular senescence’ is a cell-cycle state where cells that used to proliferate stop responding to growth stimuli. This state primarily causes age-related changes in the body, and diseases like Alzheimer’s, arthritis, atherosclerosis, Parkinson’s, and some cancers.
While senolytic drugs (i.e. those that kill old cells) exist and have had some success in vivo, their non-specific nature means that scientists have not been able to effectively use them in humans without unsolicited side effects before.
However, preclinical studies in mice models suggest that the drugs “have been shown to increase healthspan and lifespan”, reducing the effect of age-related diseases like osteoporosis.
This information served as a “rationale” for a global team of scientists from Spain, Nigeria, and Saudi Arabia. They delved into creating a more targeted therapy that can safely remove senescent cells from the body.
To kill an aging cell
“Copying an idea already in use in cancer therapies, we tweaked an antibody so it could recognize these cells and deliver a toxic cargo specifically into them,” explained Associate Professor Dr. Salvador Macip, corresponding author of the study and the head of the Mechanisms of Aging and Cancer laboratory at the University of Leicester.
He categorizes these antibodies as ‘second generation senolytics’.
They used an antibody design called antibody-drug conjugates (ADCs) so that they can carry the senolytic drug duocarmycin with them. These ADCs target a newly discovered cell-membrane marker B2M, present only in senescent cells, and unload their drug into them.
Testing the ADC’s efficacy in their proof-of-concept stage, the scientists confirmed that they only affected cells expressing the B2M marker. Furthermore, the non-senescent proliferating cells remained safe, showing that the ADC’s were, indeed, specific to their target.
The researchers now want to understand the exact mechanism through which the ADC’s act when they meet their target. They also recommend preclinical in vivo studies to determine if the therapy is safe enough for a human clinical trial.
The possibilities for these ADCs are promising, according to the manuscript, published in Scientific Reports. The authors say that the treatment would be particularly useful in reducing chances for tumor relapse after chemotherapy, as the remaining senescent cells primarily cause that condition.
Source: University of Leicester