In the body of every adult human there live cells that have stopped dividing but have not died. They are like old workers who no longer show up for their shift but still take up space on the factory floor and sometimes get in the way of the young. Such cells release substances that cause inflammation and accelerate the aging of tissues. Scientists have long been searching for a way to remove them without touching their healthy neighbors.
It turns out that a familiar antioxidant, N-acetylcysteine, can become just such a tool if given at a high dose. In the lab, human muscle cells were grown and aged with the chemotherapy drug doxorubicin. Then the antioxidant was added for three days at a concentration of 20 millimoles. The senescent cells began to die off: the share of dead cells nearly doubled. Ordinary cells were barely affected.
This two-phase response resembles the behavior of fisetin, a natural compound already known as a senolytic. Low doses of the antioxidant slightly protected both senescent and ordinary cells. High doses killed only the senescent ones. This suggests that the mechanism is not the suppression of the PI3K/Akt/mTORC1 signaling pathway, as was previously thought, but rather an excess of reductants that the cell cannot process.
It was previously unclear why some antioxidants kill senescent cells even though they usually protect them. Now it is clear that everything depends on the dose and on how far the cell has already been pushed out of balance. This discovery does not promise a quick drug, but it does point to where to look: not only at removing oxidants, but also at not overloading the cell with reductants.
The practical benefit is not yet clear. N-acetylcysteine is sold as a supplement for liver support, but the concentrations that kill senescent cells are tens of times higher than those reached in the blood after taking it. New delivery methods or other substances with the same effect are needed.
So a senescent cell turns out to be vulnerable precisely when someone tries too hard to save it. The pan of the scale, overflowing with reductants, tips over, and the cell dies. Perhaps this is the key to clearing the body of old cells without harming the young ones.
N-acetylcysteine is often sold as a dietary supplement to support the liver and lungs. In this work, it was used at concentrations tens of times higher than those reached in the blood after taking the supplement.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.