Research Projects

Rationale: Aging and cellular stress lead to senescence, causing accumulation of dysfunctional cells, particularly in neurons with high energy demands. A major contributing factor includes early mitochondrial dysfunction, which impairs oxidative phosphorylation and calcium balance, eventually leading to neurodegeneration and cognitive decline (1). Conventional therapies overlook mitochondrial health. Emerging evidence suggests that mesenchymal stem cells (MSCs) can transfer functional mitochondria to damaged cells through mechanisms like nanotubes, vesicles, gap junctions, or uptake of free mitochondria, thereby improving bioenergetics and reducing oxidative stress (2,3). Additionally, mitochondria-derived vesicles (mitovesicles) reflect mitochondrial status and may carry stress or recovery signals (4). Therefore, restoring mitochondrial function represents a promising strategy to interrupt the senescence–neurodegeneration axis. Scientific Objectives: The study aims to evaluate whether mitochondria derived from MSCs can reverse neurodegeneration in accelerated-senescence models and improve bioenergetics, reduce oxidative stress, and enhance neurofunction. Additionally, it aims to analyze mitovesicles from aged and treated models to explore their role in senescence propagation and their potential as biomarkers of therapeutic response Hypothesis and Model to Be Tested: It is hypothesized that transfer of MSC-derived mitochondria into accelerated-senescence associated neurodegenerative models will restore mitochondrial function, reduce oxidative stress, and promote functional recovery. It is further proposed that mitovesicles will reflect mitochondrial recovery and serve as non-invasive indicators of treatment efficacy. In vitro model: Induction of accelerated senescence with D-galactose in SH‑SY5Y neuronal cells. In vivo model: C57BL/6J mice will be similarly aged via D galactose administration. Main Experiments: In vitro: D-galactose induced SH‑SY5Y cells will be treated with DMSC-derived mitochondria; uptake will be confirmed using time lapse live imaging. SA-β-gal activity, mitochondrial function assays, and senescence-related markers will be assessed, post mitochondrial treatment. In vivo: D-gal induced mice will be administered with exogenous mitochondria. Behavioral tests (memory, attention), histology, and biochemical analyses will be conducted on brain tissues. Mitovesicles profiling: Vesicles from brain and blood will be isolated and characterized for molecular signatures linked to senescence and therapeutic outcomes to assess biomarker potential. Significance: This project offers a novel, cell-free therapeutic strategy targeting mitochondrial dysfunction—central to neuronal senescence and degeneration. By combining mitochondrial transplantation with mitovesicles profiling, it integrates treatment with biomarker discovery. If successful, it could pave the way for mitochondria-based therapies in age-related neurodegenerative conditions

Mesenchymal stem cells, accelerated senescence, neurodegeneration , Mitochondrial transfer, mitovesicles, Aging