A genetic switch that produces hydrogen sulfide on demand within blood vessel walls reversed age-related wall thickening in old mice
A genetic switch that produces hydrogen sulfide on demand within blood vessel walls reversed age-related wall thickening in old mice
On September 30, 2026, cardiologists at University Hospital Zurich published a preprint describing how they introduced a yeast enzyme into the cells lining blood vessels in old mice. The enzyme remains inactive until it receives a substance the body does not produce, which triggers hydrogen sulfide production at the intended site and time. In humans and mice, blood hydrogen sulfide levels decline with age and atherosclerosis. Restoring hydrogen sulfide in the vessel walls of treated old mice suppressed signs of cellular senescence and reduced arterial wall thickening, a standard ultrasound measure of age-related vascular deterioration in living patients.
Hydrogen sulfide is familiar as a toxic gas that smells of rotten eggs. It is also one of three gases the body produces for internal signaling, alongside nitric oxide (whose role was recognized with the 1998 Nobel Prize in Physiology or Medicine) and carbon monoxide. Hydrogen sulfide production in blood vessels declines with age: healthy people over 65 have one-third the plasma hydrogen sulfide levels of people aged 18–40, and mice with higher levels show better blood vessel dilation. Patients over 80 with atherosclerosis have even lower levels than healthy people, a finding confirmed in a cohort of 110 patients and a separate group awaiting bypass surgery.
David Sinclair’s laboratory at Harvard identified a link between hydrogen sulfide and vascular aging in 2018: the age-related decline in the coenzyme NAD+ suppresses the regulatory protein SIRT1 in vascular cells, which in turn reduces the activity of the enzyme that produces hydrogen sulfide. Restoring NAD+ in old mice partially restored youthful blood flow. A more specific question remained unresolved: whether restoring hydrogen sulfide itself would be sufficient, bypassing the NAD+/SIRT1 pathway.
The available tools could not test this directly: hydrogen sulfide donors (salts such as sodium hydrosulfide or molecules that release the gas slowly) raise its levels throughout the body and cannot activate the signal in selected cells at a chosen time. The Zurich group addressed this with a remotely controlled switch. They used a yeast enzyme absent from mammals that remains inactive until supplied with a specific “key”: D-cysteine, the mirror-image form of a common amino acid that the body does not use. Without the key, the switch remains inactive; with it, the switch produces hydrogen sulfide in the intended cell at the intended time. The same switch had already been tested in vascular aging in 2024, but it was placed in the fat surrounding the vessel. The vessel wall was rejuvenated indirectly, through a reduction in inflammatory signaling from the fat. This time, the switch was introduced directly into the cells of the vessel wall for the first time.
In senescent human vascular cells, the switch suppressed molecular signs of senescence and restored cell shape, viability, and the ability to grow new capillaries. A different enzyme switch produced the same effects, indicating that hydrogen sulfide itself was responsible. In living old mice, the gene encoding the switch was delivered so that it functioned only in cells of the vessel wall. Four weeks of treatment with the key increased hydrogen sulfide in the aorta, suppressed genes associated with inflammation and senescence, and reduced vessel wall thickening and signs of fibrotic remodeling, with no noticeable side effects.
In February 2026, an independent Spanish group working with Cleveland Clinic researchers showed in ordinary male mice that boosting production of the same gas with garlic-derived compounds extends their lifespan and improves metabolism, movement, and brain function, without any genetic switch.