Myocardiocyte senescence in ischemic heart disease and breathome changes

Table 1 Myocardiocytes aging in the pathophysiology of ischemic heart disease: Cellular mechanisms, molecular pathways, and clinical implications

Aging-related cellular change	Key molecular pathways	Clinical implications	Therapeutic targets/strategies	Ref.
Cellular senescence and senescence-associated secretory phenotype	NF-κB, CaMKII, cGAS-STING, TGF-β/transforming growth factor beta-activated kinase 1, p38, phosphatidyl-inositol-3-kinase/Akt/mTOR	Promotes inflammation, impairs repair, worsens outcomes	Senolytics, NF-κB/cGAS-STING inhibitors	Li et al[22], Glück et al[23], Dasgupta et al[24], Li et al[25], Sweeney et al[26], Yan et al[27]
Mitochondrial dysfunction and mPTP	Akt, glycogen synthase kinase-3beta, PKC isoforms, mPTP regulators (cyclophilin D, FoF1 adenosine triphosphate synthase), reactive oxygen species	Increased ischemic injury, reduced tolerance, cell death	Mitochondria-targeted antioxidants, mPTP inhibitors (e.g., cyclosporine A, melatonin)	Mendoza and Karch[28], Liu et al[29], Petrosillo et al[30], Zhu et al[31], Li et al[32]
Impaired autophagy and proteostasis	The mTOR, AMPK, autophagy-lysosome pathway	Accumulation of damaged proteins/organelles, worsened ischemic outcomes	Autophagy inducers (e.g., AMPK activators, H2S)	Leon and Gustafsson[33], Sithara and Drosatos[34], Chen et al[35]
Telomere shortening and apoptosis	The p16INK4a, p53, GDF11, IGF-1, telomerase	Reduced regenerative capacity, increased apoptosis, heart failure	Telomerase activators, IGF-1, GDF11	Torella et al[36], Chen et al[37], Adili et al[38]
Metabolic shifts and energy imbalance	Pyruvate dehydrogenase, protein acetylation, SIRT1, AMPK	Disrupted energy metabolism, increased ischemic susceptibility	SIRT1 activators, metabolic modulators	Sithara and Drosatos[34], Rajakumar et al[39]
Extracellular matrix remodeling and fibrosis	TGF-β, collagen synthesis, matrix metalloproteinases	Increased stiffness, impaired function, adverse remodeling	Anti-fibrotic agents, TGF-β inhibitors	Yan et al[27], Carbonin et al[40], Horn[41], Shih et al[42]
Stem cell senescence and regenerative decline	The p16INK4a, p53, Mybl2, vascular endothelial growth factor	Reduced efficacy of cell therapy, impaired repair	Stem cell rejuvenation (platelet-rich plasma, Mybl2 overexpression)	Torella et al[36], Cianflone et al[43], Khatiwala and Cai[44], Fan et al[45], Wang et al[46], Guo et al[47]
Chronic inflammation and immune infiltration	NF-κB, cGAS-STING, cytokines (IL-1α, IL-8)	Exacerbated injury, adverse remodeling	Anti-inflammatory agents, cGAS-STING inhibitors	Yan et al[27], Guo et al[47], Zhao et al[48], Fang et al[49], Xu et al[50], Wang et al[51]
Impaired cardioprotective signaling	Akt, PKCε, G protein-coupled receptor, circadian genes (Bmal1, Per2)	Loss of ischemic preconditioning, increased injury	PKC/Akt activators, circadian modulators	Honma et al[52], Przyklenk et al[53], Bartling et al[54], Bonney et al[55]
ER stress and mitochondrial crosstalk	ATF6, GRP-78, calpain 1, mitochondria-associated membranes, YAP/SERCA2a	Mitochondrial dysfunction, increased apoptosis	ER stress inhibitors (4-PBA, metformin), calpain inhibitors	Qin et al[56], Yuan et al[57], Chen et al[58], Chen et al[59]
Circadian rhythm disruption	Bmal1, Per2, RCAN1, HDAC3, Rev-erbα	Increased susceptibility, impaired repair	Chronotherapy, melatonin, and REV-ERB agonists	Bonney et al[55], Chen et al[60], Mia et al[61], Nuszkiewicz et al[62]

Akt: Protein kinase B; AMPK: AMP-activated protein kinase; ER: Endoplasmic reticulum; IGF-1: Insulin-like growth factor-1; IL: Interleukin; mTOR: Mammalian target of rapamycin; mPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NF-κB: Nuclear factor kappa B; PKC: Protein kinase C; TGF-β: Transforming growth factor-beta.