Fisetin Clears Senescent Cells Through the Pi3k-Akt-Bcl-2/Bcl-xl Pathway to Alleviate Diabetic Aortic Aging
Xiao-Man Ji1, Xin-Xin Dong1, Jia-Peng Li1
1Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Abstract:
Vascular aging is a major contributor to age-related cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) induced early arterial aging and excessive senescent cells (SCs) burden in vessels. Inhibiting cellular senescence or eliminating SCs could effectively improve aging-related CVDs. Fisetin, a flavonoid extracted from cotinus coggygria scop, has shown potential in alleviating aging by clearing SCs. This study investigated the unexplored mechanisms and efficacy of fisetin in alleviating T2DM-related aortic aging. The T2DM mouse model was induced using a high-fat diet and low-dose streptozotocin injection. Chronic fisetin treatment's protective effects against aortic aging were assessed via senescence-associated beta-galactosidase (SA-β-Gal) staining, histopathology, and vasomotor function. RNA-sequencing and western blotting identified relevant signaling pathways and protein expression. Fisetin's effects on SCs and senescence-associated secretory phenotype (SASP) factors were evaluated through cell viability, apoptosis, and co-culture assays. Docking simulations suggested fisetin as a potential Phosphoinositide 3-kinase (Pi3k) inhibitor. In vivo, chronic fisetin treatment reduced aortic SCs burden, alleviating T2DM-related and natural aortic aging. In vitro, fisetin selectively induced apoptosis of senescent endothelial cells via regulating the Pi3k-Protein Kinase B (Akt)-B-cell lymphoma (Bcl)-2/Bcl-xl pathway and suppressed SASP and its detrimental effects. Furthermore, fisetin combined with metformin therapy showed superior anti-aging effects on T2DM-related aortic aging compared to metformin monotherapy. In conclusion, chronic fisetin treatment alleviates T2DM-related aortic aging via clearing the SCs burden and abrogating the SASP factors. Fisetin combined with metformin therapy might be a potential therapeutic strategy for T2DM-related CVDs.
Insights
Fisetin, a natural compound, combats vascular aging in type 2 diabetes by clearing senescent cells and reducing harmful secretions. Combined with metformin, it offers a promising strategy for treating diabetes-related cardiovascular diseases.
Area of Science:
- Gerontology
- Cardiovascular Biology
- Endocrinology
Background:
- Vascular aging is a key factor in age-related cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM).
- Cellular senescence, characterized by an accumulation of senescent cells (SCs), significantly contributes to vascular aging and associated diseases.
- Fisetin, a flavonoid, has demonstrated potential in mitigating aging processes by clearing SCs.
Purpose of the Study:
- To investigate the mechanisms and efficacy of fisetin in alleviating T2DM-induced aortic aging.
- To evaluate fisetin's impact on SCs burden, senescence-associated secretory phenotype (SASP), and vascular function in a T2DM mouse model.
- To explore the synergistic effects of fisetin and metformin in treating T2DM-related aortic aging.
Main Methods:
- A T2DM mouse model was established using a high-fat diet and streptozotocin.
- Chronic fisetin treatment effects were assessed using SA-β-Gal staining, histopathology, and vasomotor function tests.
- RNA-sequencing, western blotting, cell viability, apoptosis, co-culture assays, and docking simulations were employed to elucidate mechanisms.
Main Results:
- Fisetin treatment reduced aortic SCs burden and alleviated both T2DM-related and natural aortic aging.
- In vitro, fisetin induced apoptosis in senescent endothelial cells by regulating the Pi3k-Akt-Bcl-2/Bcl-xl pathway and suppressed SASP.
- Combination therapy with fisetin and metformin demonstrated superior anti-aging effects on T2DM-related aortic aging compared to metformin alone.
Conclusions:
- Chronic fisetin treatment effectively alleviates T2DM-related aortic aging by clearing SCs and abrogating SASP factors.
- Fisetin selectively targets senescent endothelial cells, offering a mechanism for its protective effects.
- Fisetin combined with metformin presents a potential therapeutic strategy for T2DM-related cardiovascular diseases.
