In the orchestra of the cell, there is a tuner that muffles one important note far too aggressively. That note is a chemical mark on the protein that packages DNA, and once it disappears, the cell starts to play out of tune: it repairs its genes less accurately and ages faster. In Hutchinson-Gilford progeria syndrome, a rare disease of accelerated aging, blood vessel cells lose exactly this mark. Scientists set out to find who in the orchestra was to blame.

The culprit turned out to be an enzyme named HDAC2. It removes the acetyl mark from histone H4 at position 16, and without that mark, the DNA packaging becomes too tight. The cell can then no longer accurately repair double-strand breaks in the genome, and instead falls back on a rough method that accumulates errors. In cells from progeria patients, this enzyme is overactive.

Researchers tested various compounds that interfere with HDAC2. One of them, isolated from a marine bacterium, raised the level of the needed mark in patients' blood vessel cells by 101 percent. The cells kept dividing longer: by passage 20, the share of dividing cells had risen from 12 to 75 percent. The aging marker beta-galactosidase accumulated three times more slowly, and DNA damage declined.

The strongest effect came from combining an HDAC2 inhibitor with lonafarnib, a drug already approved for treating progeria. Together, they preserved the cells' ability to divide in 84 percent of cells even after long-term culturing. That means combination therapy could become a real way to slow vascular aging in patients.

Now the challenge for scientists is to create more precise HDAC2 inhibitors that leave other proteins untouched, and to test them in animal models of progeria. If all goes well, the cell's orchestra will sound clean again, and patients' blood vessels will stay young for longer.

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