Park So-Hyun, Choi Pyeong Geun, Kim Hee-Soo, Lee Eunyoung, Lee Da-Hye, Kim Min Jung, Kim Daedong, Seo Hyo-Deok, Hahm Jeong-Hoon, Jeon Tae-Il, Huh Yang-Hoon, Ahn Jiyun, Ha Tae-Youl, Jung Chang Hwa
Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, Jeollabuk-do, Republic of Korea.
Department of Food Biotechnology, University of Science and Technology, Wanju-gun, Jeollabuk-do, Republic of Korea.
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1):e13710. doi: 10.1002/jcsm.13710.
Sarcopenia, characterized by a gradual decline in skeletal muscle mass and function with age, significantly impacts both quality of life and mortality. Autophagy plays a crucial role in maintaining muscle health. There is growing interest in leveraging autophagy to mitigate muscle ageing effects. The impact of natural autophagy activators on skeletal muscle ageing remains elusive. This study aims to identify natural autophagy activators and assess their effects on skeletal muscle ageing.
To discover novel autophagy activators, we screened 493 natural products and identified Castanea crenata flower extract (CCFE) as a promising candidate. We investigated the effect of CCFE on cellular senescence in C2C12 cells induced by etoposide. In animal experiments, aged mice (18 months old) were fed a diet supplemented with 0.1% and 0.2% CCFE for 3 months. We assessed exercise capacity, mitochondrial function and autophagic flux to determine the impact of CCFE on skeletal muscle ageing. The components present in CCFE were analysed using LC-MS/MS, and their functional properties were examined.
CCFE enhanced autophagic flux (LC3II 80% increase, p < 0.05) and reduced senescence-associated β-galactosidase activity (32.78% decrease, p < 0.001). In aged mice, a 3-month supplementation with CCFE improved muscle weight (18% increase, p < 0.05) and function (treadmill performance increased by 60%, p < 0.5; grip strength increased by 25%, p < 0.05). It alleviated mitochondrial dysfunction (basal oxygen consumption rate increased by 59%, p < 0.05) and restored autophagy. CCFE enhanced autophagy by activating AMPK (80% increase, p < 0.01) and inhibiting Atg5 protein acetylation (65% decrease, p < 0.001), with contributions from ellagic acid and polyamines. CCFE supplementation restored polyamine levels (serum spermidine increased from 0.98 ± 0.08 to 2.22 ± 0.05 μg/mL, p < 0.001) and increased urolithin levels (serum urolithin A increased from 0 to 18.79 ± 0.062 ng/mL, p < 0.001), metabolites produced by the gut microbiome from ellagic acid in aged mice.
CCFE effectively suppressed skeletal muscle ageing by preventing mitochondrial dysfunction and restoring autophagic flux in aged mice. It achieved this by modulating AMPK and EP300 acetyltransferase activity, with contributions from its constituents, ellagic acid and polyamines. These findings highlight the potential of CCFE as a therapeutic agent for extending healthspan and mitigating sarcopenia, providing a basis for future clinical trials.
肌肉减少症的特征是骨骼肌质量和功能随年龄逐渐下降，对生活质量和死亡率均有显著影响。自噬在维持肌肉健康方面起着关键作用。利用自噬来减轻肌肉衰老效应的兴趣日益浓厚。天然自噬激活剂对骨骼肌衰老的影响仍不明确。本研究旨在鉴定天然自噬激活剂并评估其对骨骼肌衰老的影响。
为发现新型自噬激活剂，我们筛选了493种天然产物，并确定日本栗花提取物（CCFE）为有潜力的候选物。我们研究了CCFE对依托泊苷诱导的C2C12细胞衰老的影响。在动物实验中，给18个月大的老年小鼠喂食添加0.1%和0.2%CCFE的饮食，持续3个月。我们评估运动能力、线粒体功能和自噬通量，以确定CCFE对骨骼肌衰老的影响。使用液相色谱-串联质谱法（LC-MS/MS）分析CCFE中的成分，并检测其功能特性。
CCFE增强了自噬通量（LC3II增加80%，p<0.05），并降低了衰老相关β-半乳糖苷酶活性（降低32.78%，p<0.001）。在老年小鼠中，补充CCFE 3个月可改善肌肉重量（增加18%，p<0.05）和功能（跑步机运动能力提高60%，p<0.5；握力提高25%，p<0.05）。它减轻了线粒体功能障碍（基础氧消耗率增加59%，p<0.05）并恢复了自噬。CCFE通过激活AMPK（增加80%，p<0.01）和抑制Atg5蛋白乙酰化（降低65%，p<0.001）增强自噬，鞣花酸和多胺起了作用。补充CCFE可恢复多胺水平（血清亚精胺从0.98±0.08增加到2.22±0.05μg/mL，p<0.001）并增加尿石素水平（血清尿石素A从0增加到18.79±0.062ng/mL，p<0.001），尿石素是老年小鼠肠道微生物群对鞣花酸产生的代谢产物。
CCFE通过预防老年小鼠的线粒体功能障碍和恢复自噬通量，有效抑制了骨骼肌衰老。它通过调节AMPK和EP300乙酰转移酶活性实现这一点，其成分鞣花酸和多胺起了作用。这些发现突出了CCFE作为一种延长健康寿命和减轻肌肉减少症的治疗剂的潜力，为未来的临床试验提供了依据。
