Developing tau tangles doesn’t mean a person has Alzheimer’s disease – in fact, it happens to nearly everyone to varying degrees. But because these changes start in the locus coeruleus, some brain researchers – myself included – see this area as a canary in the coal mine for developing Alzheimer’s disease.

We are exploring whether stopping or slowing down tau tangles in this brain region, or otherwise maintaining its health, may be a way to interrupt how the disease ultimately unfolds and to prevent other aspects of cognitive aging.

Emerging research from my lab and others is investigating the idea that a therapy called vagus nerve stimulation, which is already widely used for other health conditions, could be one way of keeping the locus coeruleus functioning properly.

Cellular senescence drives aging and age-related dysfunction across multiple tissues, including the brain. Through a high-content, senescent cell-based phenotypic screen of a small panel of natural products, we identified tomatidine, an aglycone of tomatine found in tomatoes, as a previously unrecognized senotherapeutic agent. In senescent human brain microvascular endothelial cells and fibroblasts, tomatidine selectively suppressed SASP expression without affecting p16Ink4a or p21Cip1 levels consistent with a senomorphic effect. In aged mice, tomatidine reduced frailty and improved motor coordination and cognitive performance. These functional benefits were accompanied by reduced senescence markers (p16 Ink4a, p21 Cip1, and telomere-associated DNA damage foci) in liver, skin, and hippocampal neurons, along with decreased neuroinflammation and microglial activation. Tomatidine also diminished brain endothelial cell senescence while enhancing tight junction protein expression, suggesting preserved blood–brain barrier integrity. Together, these findings identify tomatidine as a promising senescence-targeting compound with beneficial effects in aged mice and support its further evaluation in mechanistic and translational studies.