What causes cellular ageing — and how can we suppress it?


Thursday, 27 February, 2020


What causes cellular ageing — and how can we suppress it?

US and UK scientists have discovered that mitochondria trigger senescence, the sleep-like state of aged cells, through communication with the cell’s nucleus — and identified an FDA-approved drug that helped suppress the damaging effects of the condition in cells and mice.

Their discovery, published in the journal Genes & Development, could lead to treatments that promote healthy ageing or prevent age-associated diseases such as cancer, Alzheimer’s disease, heart disease and more.

Approximately 80% of older adults have at least two chronic diseases. This is fuelling scientists to dive into the molecular causes of ageing and find medicines that help people live long, healthy lives.

“To cope with the rise of chronic diseases from an ageing population, we must understand the fundamental biological effects of ageing,” said Mark R Collins, President and Director of the Glenn Foundation for Medical Research, which partially funded the new research.

For more than a decade, Professor Peter Adams from the Sanford Burnham Prebys Medical Discovery Institute has studied how clusters of chromatin — the mix of DNA and protein normally found in the cell nucleus — leak out to the cytoplasm in senescent cells, triggering inflammatory signals that can promote a number of undesirable health conditions. He and his team set out to find what prompts the formation of chromatin clusters in the first place, embarking on a series of experiments using a human lung cell model of senescence. They found that mitochondria were the culprits driving the formation of pro-inflammatory cytoplastic chromatin and did so through a retrograde communication path to the nucleus.

“In school we learned that the role of mitochondria is to generate energy — and that DNA controls everything the cell does,” said Prof Adams. “Research is now showing that mitochondria are important sensors for the cell and have a lot of cross-talk with the nucleus, which makes sense given their duty to respond to the cell’s metabolic needs.”

The scientists also found that an HDAC inhibitor, an FDA-approved drug currently used to treat certain cancers, transformed senescent cells from a large and flat form to a healthier and more visually youthful condition. The HDAC inhibitor-treated cells also had better mitochondrial function and less cytoplasmic chromatin, and produced less inflammatory signals. The scientists observed similar beneficial effects when examining the livers of mice in which senescence was induced through radiation or high doses of acetaminophen. However, the side effects of HDAC inhibitors — which include fatigue, nausea and more — make the drugs too toxic for use in preventing disease in healthy individuals.

As a next step, the scientists hope to screen for less toxic senescence-inhibiting drugs. For example, a compound that interrupts the communication between the mitochondria and the nucleus would hold promise as a treatment that promotes healthy ageing.

“This study provides the first concrete link between several known hallmarks of ageing — dysfunctional mitochondria, inflammation and senescent cells — which historically were studied as separate events,” said Prof Adams. “We are hopeful that targeting the molecular drivers of senescence will lead us to safe and effective medicines that help more people stay as healthy as possible, for as long as possible.”

Image credit: ©stock.adobe.com/au/mrmohock

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