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Tomatidine is a senotherapeutic compound that improves cognitive function and reduces cellular senescence in aged mice

ABSTRACT: Cellular senescence contributes to aging and age-related dysfunction across multiple tissues, including the brain. Here, we identify tomatidine, an aglycone of tomatine naturally found in tomatoes, as a senotherapeutic agent. In vitro, tomatidine selectively suppressed SASP expression without affecting p16Ink4a or p21Cip1 levels in senescent human brain microvascular endothelial cells. In aged mice, dietary tomatidine reduced frailty and improved motor coordination and cognitive performance. These functional benefits were accompanied by a reduction in senescence markers (e.g., p16, p21, and telomere-associated DNA damage foci) in liver, skin, and hippocampal neurons, as well as decreased neuroinflammation and microglial activation. Tomatidine also reduced senescence in brain endothelial cells and increased the expression of tight junction–associated proteins. Together, these findings suggest that tomatidine is as a promising senotherapeutic with the potential to preserve cognitive and vascular function during aging. As a naturally occurring compound with oral bioavailability and a favorable safety profile, tomatidine holds strong translational promise for future therapeutic development.

ORGANISM(S): Mus musculus

PROVIDER: GSE312732 | GEO | 2026/04/03

REPOSITORIES: GEO

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Tomatidine is a senotherapeutic compound that improves cognitive function and reduces cellular senescence in aged mice

Project description:Tomatidine is a senotherapeutic compound that improves cognitive function and reduces cellular senescence in aged mice

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Project description:Aging is a major international concern and brings with it formidable socioeconomical and healthcare challenges. An attainable approach to improve general health in humans is using small molecules. Tomatidine, a natural compound abundant in unripe tomatoes, inhibits aging-related skeletal muscle atrophy in mice. Here we show that tomatidine extends lifespan and healthspan in the aging animal model C. elegans, which shares many major longevity pathways with those of mammals. Tomatidine improves behaviors related to healthspan, including increased pharyngeal pumping and swimming movement, and also reduces deterioration of muscle cells in worms. Microarray, imaging, and behavioral analysis reveal that tomatidine maintains mitochondrial homeostasis through mitochondrial biogenesis and PINK-1/DCT-1-dependent mitophagy. Mechanistically, tomatidine induces mitochondrial hormesis by mildly inducing ROS production, which in turn activates the cellular antioxidant response SKN-1/Nrf2 pathway, followed by increased mitophagy in worms, primary rat neurons, and human cells. Our data suggest that tomatidine may delay some physiological aspects of aging, and points to new approaches for pharmacological interventions towards diseases of aging.

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Response of yeast to tomatidine treatment

Project description:Genome-wide expression profiling was used to identify genes that showed altered expression in response to treatment with the fungistatic saponin tomatidine. Overnight batch cultures of strain S288C were diluted to an optical density at 600nm of 0.1. After 1 hour of growth at 30°C, the compounds were added and the cultures were incubated for an additional 5 hours prior to harvesting. Control cultures were treated with the solvent dimethylformamide (DMF). Tomatidine treated cultures were grown in the presence of tomatidine (dissolved in DMF) at concentations of 7.5 uM and 15 uM. Growth inhibition by the compounds was monitored by measuring the OD600nm. Cells were pelleted and frozen in liquid nitrogen. Acid-washed glass beads (0.5 mm diameter; Sigma) were added and the cells disrupted using two 20 s cycles at speed setting 6 in the Savant Bio 101 Fast Prep FP120. Total RNA was isolated using the Qiagen RNeasy kit (Qiagen, Inc., Valencia, CA, USA). Microarray hybridisation was performed using the Affymetrix GeneChip® Yeast genome S98 array using protocols described by Affymetrix, Inc. (Santa Clara, CA, USA) (as previously described (Zhu et al., 2001). Data were analyzed using Affymetrix® Microarray Suite version 5.0 software Keywords: dose response

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