TY - JOUR
T1 - Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits
AU - Sengun, Elif
AU - Zhou, Lily
AU - Kelsey, Maxfield
AU - Turan, Nilufer N.
AU - Lu, Yichun
AU - Kabakov, Anatoli Y.
AU - Bronk, Peter
AU - Mi, Eric
AU - Kim, Tae Yun
AU - Vijayakumar, Shilpa
AU - Price, Dana
AU - Nussbaum, Sade Solola
AU - Song, Christopher
AU - Feng, Jun
AU - Sellke, Frank W.
AU - Dubielecka-Szczerba, Patrycja
AU - Del Monte, Federica
AU - Nerbonne, Jeanne
AU - Uydes-Dogan, B. Sonmez
AU - Roder, Karim
AU - Choi, Bum Rak
AU - Van Wagoner, David R.
AU - Sedivy, John M.
AU - Koren, Gideon
N1 - Publisher Copyright:
© 2026 Heart Rhythm Society.
PY - 2026/4/1
Y1 - 2026/4/1
N2 - Background Atrial fibrillation (AF) is the most common arrhythmia among the elderly and a major contributor to morbidity and mortality. Inflammation plays a central role in AF pathogenesis, and aging is a key independent risk factor. Cellular senescence is a hallmark of aging and contributes to age-related disease through the senescence-associated secretory phenotype (SASP), characterized by proinflammatory and profibrotic factors. Objective This study aimed to determine whether senescent atrial cells contribute to age-related AF risk and whether senolytic therapy can mitigate this phenotype. Methods Young (≤1 year) and aged (≥4 years) New Zealand White rabbits were evaluated using optical mapping, patch-clamp electrophysiology, and histologic and molecular analyses. Senescence markers were assessed using senescence-associated β-galactosidase staining, immunofluorescence, and RNA sequencing. Human atrial specimens from patients with and without AF were examined to assess translational relevance. Aged rabbits received the senolytic compound fisetin to evaluate its effects on atrial senescence and arrhythmia susceptibility. Results Aged rabbits displayed electrophysiological heterogeneity, prolonged action potentials, and increased AF inducibility, recapitulating clinical features of elderly human atria. Atrial tissue from aged rabbits and patients with AF showed an increase in senescent myocytes and myofibroblasts with upregulation of inflammatory SASP genes. SASP factor expression correlated with left atrial diameter in human samples, an AF risk factor. Short-term fisetin treatment eliminated most senescent atrial cells, reduced inducible AF, and decreased reentry activity without impairing atrial function. Conclusion Senescent atrial cells promote a proinflammatory, proarrhythmic substrate predisposing to AF. Senolytic therapy with fisetin alleviates this phenotype, suggesting a potential strategy to prevent age-related AF.
AB - Background Atrial fibrillation (AF) is the most common arrhythmia among the elderly and a major contributor to morbidity and mortality. Inflammation plays a central role in AF pathogenesis, and aging is a key independent risk factor. Cellular senescence is a hallmark of aging and contributes to age-related disease through the senescence-associated secretory phenotype (SASP), characterized by proinflammatory and profibrotic factors. Objective This study aimed to determine whether senescent atrial cells contribute to age-related AF risk and whether senolytic therapy can mitigate this phenotype. Methods Young (≤1 year) and aged (≥4 years) New Zealand White rabbits were evaluated using optical mapping, patch-clamp electrophysiology, and histologic and molecular analyses. Senescence markers were assessed using senescence-associated β-galactosidase staining, immunofluorescence, and RNA sequencing. Human atrial specimens from patients with and without AF were examined to assess translational relevance. Aged rabbits received the senolytic compound fisetin to evaluate its effects on atrial senescence and arrhythmia susceptibility. Results Aged rabbits displayed electrophysiological heterogeneity, prolonged action potentials, and increased AF inducibility, recapitulating clinical features of elderly human atria. Atrial tissue from aged rabbits and patients with AF showed an increase in senescent myocytes and myofibroblasts with upregulation of inflammatory SASP genes. SASP factor expression correlated with left atrial diameter in human samples, an AF risk factor. Short-term fisetin treatment eliminated most senescent atrial cells, reduced inducible AF, and decreased reentry activity without impairing atrial function. Conclusion Senescent atrial cells promote a proinflammatory, proarrhythmic substrate predisposing to AF. Senolytic therapy with fisetin alleviates this phenotype, suggesting a potential strategy to prevent age-related AF.
KW - Aging
KW - Atrial fibrillation
KW - Atrial remodeling
KW - Cellular senescence
KW - Inflammation
KW - Senescence-associated secretory phenotype (SASP)
KW - Senolytic therapy
UR - https://www.scopus.com/pages/publications/105028765004
U2 - 10.1016/j.hrthm.2026.01.007
DO - 10.1016/j.hrthm.2026.01.007
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C2 - 41513056
AN - SCOPUS:105028765004
SN - 1547-5271
VL - 23
SP - e675-e691
JO - Heart Rhythm
JF - Heart Rhythm
IS - 4
ER -