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Cancer Drug Delays Cellular Senescence

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Researchers have discovered that the powerhouses of our cells, the mitochondria, also play a role in triggering cells to enter senescence, a dormant state in which cells cease to divide and begin to shut down, ready to die.

Mitochondria trigger cytoplasmic chromatin and inflammation

The new study shows that the mitochondria in each cell communicate with its nucleus, causing it to shut down and enter a senescent state [1]. Dr. Peter Adams, one of the study’s researchers, has spent over a decade investigating how chromatin clusters, a mixture of DNA and proteins typically encountered in the cell nucleus, actually leak out of the nucleus and into the cytoplasm in senescent cells. This leaking then triggers a cascade of inflammatory signals, which are linked to the onset of various age-related diseases.

This in itself is fascinating, but the researchers wanted to know why chromatin clusters form in the first place and leak into the cytoplasm. With the help of a human lung cell model of senescence, they set out to find the answer. They discovered that mitochondria were the drivers of the chromatin leakage via communication with the cellular nucleus.

This finding builds on the increasing appreciation that the mitochondria are not simply present in the cell to generate energy; they also serve as important signaling, sensing, and regulatory mediators. As they are a critical part of energy metabolism, they have evolved to adjust to a cells changing metabolic status and requirements.

The researchers also discovered that a histone deacetylase inhibitor (HDAC inhibitor), a drug already approved by the FDA for cancer treatment, was able to shift these senescent cells from an enlarged and flat shape back to a healthier, more youthful shape.

The lung cells treated using the HDAC inhibitor were also found to have improved mitochondrial function compared to their untreated counterparts. The treated cells also secreted a lower level of proinflammatory signals and had less cytoplasmic chromatin leakage.

A similar situation was also observed in the livers of mice whose livers were subject to induced senescence via radiation exposure or high-dose acetaminophen, a painkiller.

Don’t rush out to buy HDAC inhibitors



Unfortunately, there is a catch with HDAC inhibitors: they have some pretty nasty side effects, including nausea, fatigue, dehydration, diarrhea, thrombocytopenia, lymphopenia, and neutropenia. Therefore, it isn’t a suitable therapy for healthy people to take, and it causes a reduction of immune cells in the bloodstream, which is a particularly serious concern. In short, do not try this at home, folks!

The researchers are now preparing to search for less harsh drugs and compounds that can delay senescence by screening drug libraries. If they can find compounds that interrupt this communication between mitochondria and the nucleus without the harsh side effects of HDAC inhibitors, this could form the basis of a therapy to support better health as we age.



Cellular senescence is a potent tumor suppressor mechanism but also contributes to aging and aging-related diseases. Senescence is characterized by a stable cell cycle arrest and a complex proinflammatory secretome, termed the senescence-associated secretory phenotype (SASP). We recently discovered that cytoplasmic chromatin fragments (CCFs), extruded from the nucleus of senescent cells, trigger the SASP through activation of the innate immunity cytosolic DNA sensing cGAS–STING pathway. However, the upstream signaling events that instigate CCF formation remain unknown. Here, we show that dysfunctional mitochondria, linked to down-regulation of nuclear-encoded mitochondrial oxidative phosphorylation genes, trigger a ROS–JNK retrograde signaling pathway that drives CCF formation and hence the SASP. JNK links to 53BP1, a nuclear protein that negatively regulates DNA double-strand break (DSB) end resection and CCF formation. Importantly, we show that low-dose HDAC inhibitors restore expression of most nuclear-encoded mitochondrial oxidative phosphorylation genes, improve mitochondrial function, and suppress CCFs and the SASP in senescent cells. In mouse models, HDAC inhibitors also suppress oxidative stress, CCF, inflammation, and tissue damage caused by senescence-inducing irradiation and/or acetaminophen-induced mitochondria dysfunction. Overall, our findings outline an extended mitochondria-to-nucleus retrograde signaling pathway that initiates formation of CCF during senescence and is a potential target for drug-based interventions to inhibit the proaging SASP.

Targeting this communication pathway has the potential to prevent or reduce the production of inflammatory signals produced by senescent cells, so blocking it could thus reduce the health impact of aging.

While this does not directly remove senescent cells and can be considered more of a stopgap, it is still a viable approach while potentially better solutions are developed and refined, such as using senolytics to totally remove these dangerous cells so that they cannot secrete inflammatory signals at all. Given the researchers may quite quickly identify more suitable drugs to achieve their goal, this might be considered a low-hanging fruit, with senolytics being a potentially better longer-term option.

Literature

[1] Vizioli, M. G., Liu, T., Miller, K. N., Robertson, N. A., Gilroy, K., Lagnado, A. B., … & Kruger, P. J. (2020). Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes & Development.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
  1. davidjc_af
    February 22, 2020

    So well, ok fine. But it seems the mitochondria are somewhat dysfunctional and the signaling causing CCF are a way of putting the cell into a senescent state so you don’t have bad mitochondria proliferating.

    Or perhaps if you rescue a cell like this it has a messed up metabolism. In aggregate this could be a problem especially if the cell begins to divide and spread bad mitochondria around.

    It’s interesting but this makes me a bit wary until they can determine if the mitochondria are actually functional and healthy.

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