Longevity Briefs: Clearing Senescent ‘Zombie Cells’ With Ultrasound?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

As we age, our bodies accumulate senescent cells – cells that are no longer able to divide but also refuse to die. These ‘zombie cells’ contribute to both age-related diseases and general age-related decline, largely by releasing a cocktail of inflammatory molecules known as the senescence-associated secretory phenotype (SASP). We might be able to treat many age-related diseases and improve general health in old age by removing these cells, or at least by blocking the release of these harmful molecules. Traditional methods to remove senescent cells have focused on drugs, but in this study researchers explore an interesting alternative – a physical stimulus in the form of ultrasound. Since previous research had suggested that low-intensity pulsed ultrasound (LIPUS) could promote wound healing by regulating the release of inflammatory molecules, researchers wanted to see if it would have an effect on senescent cells.

The discovery:

The researchers started by letting human fibroblasts divide until they became senescent, then exposing them to LIPUS in cell culture. They found that this led to an increase in the release of certain SASP signalling molecules. This might sound like a bad thing, however, they found that the specific molecules released were primarily immune cell attractants. These are molecules that serve as signals for the immune system to seek out and destroy senescent cells. Sure enough, the medium from these cultured senescent cells was found to activate immune cells and promote their migration.

Looking into the mechanism, researchers found that LIPUS stimulation physically perturbed the cellular membrane structure in senescent cells by opening small pores. This activated an enzyme within the membrane called NOX4, triggering the production of a type of pro-inflammatory molecule that in turn activated pathways that regulate the SASP.

Finally, researchers tested this approach in a mouse model in which skin ageing is accelerated via exposure to ultraviolet light. They found that LIPUS treatment over the course of 5 days significantly enhanced immune cell migration and reduced markers of senescence within the skin, suggesting a reduction in senescent cell number.

The implications:

Ultrasound is a non-invasive technique that can easily be applied in the clinic, so the idea that it could be applied to remove senescent cells or complement other senescence-targeting treatments is exciting. You may be wondering if LIPUS might put non-senescent cells at risk of being attacked by the immune system too, and the answer appears to be no. The researchers also tested LIPUS on cells that had not divided enough times to reach senescence and found that it did not have the same effect, which may be partly due to the fact that ‘younger’ cells have a different membrane structure. 

Of course, this all needs to be carefully validated in humans, and the attributes of the ultrasound need to be fine-tuned to ensure that they do have the intended effects on the right cell types. Unlike many pharmaceutical approaches, this technique is also likely to depend on the health of the recipient’s immune system, which is usually capable of removing senescent cells without any help, but becomes increasingly compromised in old age.