Longevity Briefs: A Drug For Killing ‘Zombie Cells’ In Age-Related Disease

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.

Why is this research important: Ageing is thought to be driven in part by senescent cells – damaged cells that are no longer able to divide. Senescent cells are supposed to be removed by the immune system, but during ageing they can accumulate in large numbers, releasing harmful molecules that are thought to contribute to many diseases of ageing. Senescent cells seem to play an important role in cancer, because the senescent cells that form around the tumor provide molecules that help the cancer cells to propagate. Unfortunately, chemotherapy and radiotherapy used to kill cancer cells can also turn nearby healthy cells senescent, which helps the cancer come back and can make it harder to treat.

One approach to making cancer therapies more effective, and perhaps eventually to treat ageing in general, is to use compounds that can selectively destroy senescent cells. These compounds are known as senolytics. One senolytic treatment that has shown promise is a combination of two compounds: dasatinib and quercetin. However, there may be even better senolytics out there, if we can figure out how to make them work safely.

What did the researchers do: In this study, researchers irradiated 5 month-old mice in order to simulate radiotherapy-induced senescence. They then treated them for 10 days with either dasatinib and quercetin, navitoclax, metformin, or left them untreated as a control. Navitoclax is a senolytic drug that works by inhibiting a family of proteins that control apoptosis (‘cell suicide’) – in other words, it makes senescent cells self-destruct. Metformin will be no stranger to anyone who keeps up with anti-ageing research. It’s a drug used to treat diabetes that has been shown to extend lifespan in many model organisms. Among its many effects, metformin appears to suppress the activity of senescent cells, making it a ‘senostatic’.

Some mice received treatment soon after irradiation, while in other cases, researchers waited until the mice began to show signs of frailty from the irradiation before the treatment was given. They then followed the mice for 1 year, which is a significant proportion of the average lifespan of a lab mouse (about 3 years).

Key takeaway(s) from this research: The irradiated mice showed signs of premature ageing such as increased frailty and reduced short-term memory, and increased rates of cancer. However, mice receiving either of the three treatments soon after irradiation did not appear to age any faster than normal. When treatment was delayed, it didn’t reverse signs of frailty in the mice, but it did reduce the rate at which frailty increased over the course of the subsequent year.

The idea of using senolytics to mitigate the negative effects of cancer therapies isn’t new, but a few things make the findings of this study interesting. Firstly, dasatinib + quercetin and metformin were similarly effective treatments, despite the fact that metformin doesn’t actually kill senescent cells. This suggests that suppressing the release of harmful molecules by senescent cells is enough to prevent frailty following radiotherapy. Secondly, Navitoclax was found to be much more effective than the other treatments when it came to preventing certain types of frailty, such as short-term memory decline. The problem with Navitoclax when compared to other senolytics is that it can produce severe side effects, including thrombocytopenia – a deficiency in blood platelets that causes tissue bleeding and slower blood clotting after injury. It might be possible to create a Navitoclax ‘prodrug’ – a drug that only activates in senescent cells, thereby avoiding those side effects.