International Business Department           Liu Bojia           October 23, 2023

  Cells in our body "age" in response to damage or stress, which is characterised by stagnant growth. These senescent cells no longer divide and do not enter an active death process called apoptosis, but produce a range of inflammatory and growth-promoting molecules (collectively known as SASP molecules) that affect neighbouring cells, leading to a range of physiological processes and even disease. Animal experiments have found that removal of senescent cells attenuates a range of pathological features, and thus senescent cells are considered an important therapeutic target for the prevention of age-related diseases.

  In studies targeting senescent cells, a recent collaboration between researchers at the University of Glasgow (UK) and Mayo Clinic (USA) found that the release of harmful inflammatory SASP molecules from senescent cells is surprisingly caused by the mitochondria in the cells.

  The discovery came as a surprise to scientists. This is because mitochondria are usually considered to play a key role in the process of apoptosis. The mitochondrial outer membrane permeabilisation (MOMP) that occurs on a large scale throughout the apoptotic process is key in mediating the eventual cell death. And now researchers have found that mitochondrial outer membrane permeabilisation also occurs in cellular senescence - a very different fate to apoptosis. What's going on here?

  According to the researchers' paper, published in the journal Nature, they found in senescent cells that outer membrane permeabilisation occurs in a small part of the mitochondrion, rather than on a large scale. Hence, they call it minority MOMP (miMOMP for short).

  This level of leakage does not induce apoptosis, but it does release the DNA it contains into the cytoplasm, enough to activate the cGAS-STING pathway, the intracellular "alarm" that monitors for aberrant DNA, which in turn elicits an inflammatory response that allows senescent cells to release SASP molecules such as IL-6 and IL-8.

  The good news is that the researchers went on to discover that this partial leakage in the mitochondria can be "remedied" to stop inflammation and achieve anti-aging effects.

  BAX and BAK are two proteins that are critical for MOMP, and the researchers also observed BAX activation during miMOMP events in senescent cells.

  The researchers found that in senescent cells, most mitochondria are in a state of hyperfusion, while only a small number of mitochondria rupture, giving rise to the miMOMP phenomenon. miMOMP is sufficient to induce higher mitochondrial DNA secretion in the cytoplasm through BAX/BAK activation, which activates cGAS-STING, a major regulatory pathway of SASP, and ultimately drives the onset of SASP.

  Therefore, the researchers tried to use a small molecule BAX inhibitor to treat senescent cells in order to inhibit miMOMP.

  This new approach yielded promising results, not only effectively avoiding mitochondrial leakage and SASP molecule release in in vitro cellular experiments, but also making aged mice younger in animal experiments. Compared to older mice of the same age, older mice treated with BAX inhibitors showed better neuromuscular coordination, stronger balance and muscle grip strength, and also reduced the inflammatory state of the brain. Although there was no significant change in lifespan, overall, health could be maintained longer in old age.

  "This work of ours reveals an unexpected association between the inflammatory properties of senescent cells and mitochondria." Professor Stephen Tait of the School of Cancer Sciences at the University of Glasgow, UK, co-corresponding author of the research paper, concluded, "We found that mitochondrial outer membrane permeabilisation, which is closely linked to cell death, also promotes inflammatory responses in senescent cells. These findings open up new areas of research with exciting prospects for the development of anti-ageing therapies."