LSD1 prevents cells from switching off the DNA damage alarm in time and locks them into senescence: a clinical-stage LSD1 inhibitor reduced aging markers in mice

LSD1 prevents cells from switching off the DNA damage alarm in time and locks them into senescence: a clinical-stage LSD1 inhibitor reduced aging markers in mice

On September 15, the Journal of Clinical Investigation published a paper by a team from the Mayo Clinic and Tongji University: in aged mice and senescent cells, the enzyme LSD1 accumulates not because the cell produces more of it, but because the cell fails to recycle it fast enough. LSD1 removes a chemical mark from the protein ATM, the cell's principal DNA damage sensor, preventing ATM from shutting down on schedule after repair is complete. An LSD1 inhibitor already in human clinical trials reduced senescence markers in the kidneys, heart, and liver of mice and protected them from fur graying after irradiation.

When a DNA strand breaks inside a cell, the protein ATM rapidly binds the break site and triggers a signal that halts division while repair proceeds. If ATM does not deactivate in time after the damage is fixed, the cell becomes trapped in senescence, a stable arrest of division during which it secretes substances that harm surrounding tissues.

It was previously known that in the first hours after damage, ATM activation is initiated by a chemical modification at position 3016 on ATM itself. What remained unclear was whether removal of a different mark, a methyl group, from the same position (demethylation) also influences ATM activity.

The answer turned out to involve LSD1, the first enzyme discovered to be capable of removing such marks from proteins. LSD1 had already been linked to senescence of individual cells, but not to aging of whole organs. LSD1 accumulates in the kidneys, heart, liver, and other organs of aged mice, as well as in artificially senescent cells, because the cell cannot clear it quickly enough.

The reason lies in autophagy, the process by which a cell recycles worn-out proteins. Normally, LSD1 binds two proteins of this clearance system, LC3 and Beclin1, and is sent off for degradation. During aging, autophagy weakens, the binding is disrupted, and LSD1 accumulates in the nucleus, the same compartment where ATM resides. Suppressing autophagy raised LSD1 levels even in young organs, while boosting it with rapamycin lowered LSD1 in old ones.

Once LSD1 reaches ATM, it strips the methyl mark from the same position 3016 where the activating mark was previously found. This creates a temporal separation: the activating mark switches ATM on in the first hours after damage, while removal of the methyl mark roughly 12 hours later prevents ATM from switching off on time. The mechanism involves WIP1, an enzyme that normally silences ATM after repair is complete. As long as position 3016 lacks its methyl mark, WIP1 binds it less effectively, and the alarm persists longer than necessary.

This loop can be broken from two sides. Senolytics, drugs that target senescent cells, reduced LSD1 and senescence markers in the kidneys, heart, and liver of aged mice, revealing a self-reinforcing cycle in which senescent cells and LSD1 sustain each other. In the kidney specifically, the same senolytic pair had already been tested on its own: an eight-month course of dasatinib plus quercetin in aged mice restored the kidney-protective protein Klotho and reduced tissue scarring. Meanwhile, the LSD1 inhibitor ORY-1001 reduced DNA damage and senescence in those same three organs in both irradiated and aged mice.

ORY-1001 is iadademstat, a compound already being evaluated in human clinical trials for acute myeloid leukemia, myelodysplastic syndrome, and small-cell lung cancer, but not for aging: the effect on senescence has been demonstrated only in mice and cell cultures.

This work links two separately studied hallmarks of aging, a persistent DNA damage signal and declining cellular clearance, into a single switch at one amino acid of ATM. LSD1 does not determine whether the alarm turns on; it determines how long the alarm lasts. That duration decides whether a cell returns to division or becomes locked in senescence.