Unveiling the Link Between RIPK1, Necroptosis, and Premature Aging

Scientists have discovered that inhibiting necroptosis, a type of programmed cell death, can significantly extend the lifespan of mice with progeria, a rare genetic disorder that causes premature aging. The study, published in Nature Cell Biology, found that blocking the activity of the RIPK1 kinase, a crucial regulator of TNF signalling and cell death, and particularly its kinase function, led to a dramatic extension in survival of mice with progeria.

Progeria, also known as Hutchinson-Gilford progeria syndrome, is a rare genetic disorder that causes children to age rapidly, resulting in a decreased lifespan of only a few years. The condition is caused by a genetic mutation that leads to the accumulation of a toxic protein called prelamin A on the nuclear membrane, which disrupts the nuclear membrane and causes systemic inflammation.

Previous studies have shown that blocking inflammation, genetically or with drugs, can ameliorate many aspects of the progeria phenotype and extend life in mouse models. However, the new study by Wang and Silke is the first to demonstrate that inhibiting necroptosis, and particularly the activity of the RIPK1 kinase, can significantly extend the lifespan of mice with progeria.

The researchers found that Zmpste24−/− mice on a RIPK1 kinase-dead, or, to a slightly lesser extent, necroptosis-deficient background (Ripk3−/− and Mlkl−/−) had a dramatically extended survival. Specifically, the median survival of Zmpste24−/− mice was extended from 17 weeks to 31 weeks when RIPK1 kinase activity was blocked.

Interestingly, the study also found that genetic blocking of RIPK1 kinase inhibition appeared to provide a greater survival advantage than genetic inhibition of necroptosis alone, and that this correlated with an effect on induction of inflammatory cytokines.

The discovery that defects in the processing of lamin A lead to systemic inflammation and progeria syndromes has led to several potential therapeutic targets. However, the new study suggests that genetically blocking RIPK1 kinase activity, but also necroptosis, is a particularly effective approach in delaying symptoms in one mouse model of progeria.

The study also highlights the potential of small molecule inhibitors of RIPK1 kinase activity as a treatment for progeria. The current US Food and Drug Administration (FDA)-approved treatment for progeria is the FTI lonafarnib, which can extend the life of patients by about 2-4 years. However, this treatment is associated with side effects, including nausea and vomiting. In contrast, a multitude of companies are developing specific RIPK1 kinase inhibitors, some of which have already demonstrated an excellent safety profile in clinical trials.

Overall, the study by Wang and Silke sheds new light on the role of necroptosis and RIPK1 kinase activity in progeria and highlights the potential of RIPK1 kinase inhibitors as a promising treatment for this devastating condition.

Source: <https://www.nature.com/articles/s41556-024-01390-2>