能量限制对不同年龄小鼠海马自噬活性及新异环境适应能力的影响

油惠娟; 赵玉晴; 刘莹莹; 张鹏翼; 傅力; 杨风英

营养学报 ›› 2024, Vol. 46 ›› Issue (5) : 462-468.

论著

油惠娟¹, 赵玉晴¹, 刘莹莹², 张鹏翼¹, 傅力³, 杨风英¹

作者信息 +

EFFECTS OF CALORIC RESTRICTION ON HIPPOCAMPAL AUTOPHAGY ACTIVITY AND ADAPTABILITY TO UNFAMILIAR ENVIRONMENT IN MICE OF DIFFERENT AGES

YOU Hui-juan¹, ZHAO Yu-qing¹, LIU Ying-ying², ZHANG Peng-yi¹, FU Li³, YANG Feng-ying¹

Author information +

文章历史 +

摘要

目的研究能量限制对不同年龄小鼠新异环境适应能力的影响并探讨其与海马自噬活性的关系。方法将120只刚断乳C57BL/6小鼠随机平均分为自由摄食组（AL）和能量限制组（CR）,CR组摄食量是同龄AL组的70%;喂养至1.5、3、12、20月龄时,每组随机抽取15只,行旷场实验后处死取材;采用Western blot和免疫组织化学染色法检测海马自噬及泛素化蛋白水平。结果 CR延缓成年小鼠新异环境适应能力的增龄性下降,体现在旷场活动距离、中央区活动时间、直立次数（CR^12m>AL^12m,P<0.05; CR^20m>AL^20m,P<0.01）,但对幼年小鼠新异环境适应能力产生不利影响,体现在旷场活动距离（CR^3m<AL^3m,P<0.05）、中央区活动时间（CR^1.5m<AL^1.5m,P<0.01;CR^3m<AL^3m,P<0.05）;CR显著激活成年后小鼠海马自噬（LC3II/LC3I、beclin1：CR^12m>AL^12m, CR^20m>AL^20m;p62：CR^20m<AL^20m. P<0.05）并加速泛素化蛋白的清除（Ub、Ub-IOD:CR^12m<AL^12m,CR^20m<AL^20m. P<0.05),但对幼年小鼠,CR显著升高3月龄LC3II/LC3I的同时亦升高p62表达水平(p62:CR^1.5m>AL^1.5m,CR^3m>AL^3m. P<0.05)。结论海马发育成熟后通过能聊限制激活自噬进而维持神经元内环境稳定,对脑健康有利;幼年期能量限制虽然激活海马自噬体的形成但抑制自噬降解效率,对认知功能发展不利。

Abstract

Objective To investigate the effects of caloric restriction on the adaptive ability of mice of different ages to novel environments and to explore its relationship with hippocampal autophagic activity. Methods A total of 120 newly weaned C57BL/6 mice were randomly divided into an ad libitum feeding group (AL) and a caloric restriction group (CR). The food intake of the CR group was 70% of that of the AL group of the same age. Fifteen mice were randomly selected from each group at the ages of 1.5, 3, 12, and 20 months and were sacrificed and sampled after the open-field experiments. The levels of autophagy and ubiquitinated proteins in the hippocampus were examined by Western blot and immunohistochemical staining. Results CR delayed the age related decline in the ability to adapt to novel environments in adult mice, as reflected in the distance travelled in the open field, the duration of activity in the central zone, and the number of uprights (CR^12m>AL^12m,P<0.05; CR^20m>AL^20m, P<0.01）. However, there were adverse effects on the ability to adapt to novel environments in juvenile mice, as evidenced by the distance travelled in the open field (CR^3m<AL^3m,P<0.05）, central district activity hours (CR^1.5m<AL^1.5m, P<0.01; CR^3m<AL^3m, P<0.05）. CR significantly activated hippocampal autophagy in adult mice（LC3II/LC3I,beclin1：CR^12m>AL^12m, CR^20m>AL^20m;p62：CR^20m<AL^20m. P<0.05）and accelerated the clearance of ubiquitinated proteins（Ub, Ub-IOD:CR^12m<AL^12m,CR^20m<AL^20m. P<0.05). However, in young mice, CR significantly increased LC3II/LC3I and p62 expression at 3 months of age(p62:CR^1.5m>AL^1.5m,CR^3m>AL^3m. P<0.05). Conclusion After hippocampal maturation, autophagy is activated by caloric restriction to maintain the stability of the neuronal environment, which is beneficial to brain health. Although caloric restriction in infancy activates the formation of hippocampal autophagosomes, it inhibits the degradation efficiency of autophagy, which is detrimental to the development of cognitive function.

导出引用

油惠娟, 赵玉晴, 刘莹莹, 张鹏翼, 傅力, 杨风英. 能量限制对不同年龄小鼠海马自噬活性及新异环境适应能力的影响[J]. 营养学报. 2024, 46(5): 462-468

YOU Hui-juan, ZHAO Yu-qing, LIU Ying-ying, ZHANG Peng-yi, FU Li, YANG Feng-ying. EFFECTS OF CALORIC RESTRICTION ON HIPPOCAMPAL AUTOPHAGY ACTIVITY AND ADAPTABILITY TO UNFAMILIAR ENVIRONMENT IN MICE OF DIFFERENT AGES[J]. Acta Nutrimenta Sinica. 2024, 46(5): 462-468

中图分类号： R153.2

参考文献

[1] Madeo F, Carmona-Gutierrezd D, Hofer SJ, et al. Caloric restriction mimetics against age-associated disease: targets, mechanisms, and therapeutic potential[J]. Cell Metab, 2019, 29: 592–610.
[2] Yang C, Xia S, Zhang W, et al. Modulation of Atg genes expression in aged rat liver, brain, and kidney by caloric restriction analyzed via single-nucleus/cell RNA sequencing[J]. Autophagy, 2023, 19: 706–715.
[3] Escobar KA, Cole NH, Mermier CM, et al. Autophagy and aging: maintaining the proteome through exercise and caloric restriction[J]. Aging Cell, 2019, 18: e12876.
[4] 杨风英,谭思洁,宋祺鹏,等. 能量限制对不同年龄小鼠海马mTOR通路活性及空间学习能力的影响[J]. 营养学报, 2021, 43: 538–543.
[5] Cameron KM, Speakman JR.Reduction of dietary energy density reduces body mass regain following energy restriction in female mice[J]. J Nutr, 2011, 141: 182–188.
[6] Zhuang H, Yao X, Li H, et al. Long-term high-fat diet consumption by mice throughout adulthood induces neurobehavioral alterations and hippocampal neuronal remodeling accompanied by augmented microglial lipid accumulation[J]. Brain Behav Immun, 2022, 100: 155–171.
[7] Yang F, Chu X, Yin M, et al. mTOR and autophagy in normal brain aging and caloric restriction ameliorating age-related cognition deficits[J]. Behav Brain Res, 2014, 264: 82–90.
[8] Li Q, Liu Y, Sun M.Autophagy and Alzheimer's disease[J]. Cell Mol Neurobiol, 2017, 37: 377–388.
[9] Chaudhry N, Sica M, Surabhi S, et al. Lamp1 mediates lipid transport, but is dispensable for autophagy in Drosophila[J]. Autophagy, 2022, 18: 2443–2458.
[10] Bagherniya M, Butler AE, Barreto GE, et al. The effect of fasting or calorie restriction on autophagy induction: A review of the literature[J]. Ageing Res Rev, 2018, 47: 183–197.
[11] Wong SQ, Kumar AV, Mills J, et al. Autophagy in aging and longevity[J]. Hum Genet, 2020, 139: 277–290.
[12] Aman Y, Schmauck-Medina T, Hansen M, et al. Autophagy in healthy aging and disease[J]. Nat Aging, 2021, 1: 634–650.
[13] Liu S, Yao S, Yang H, et al. Autophagy: regulator of cell death[J]. Cell Death Dis, 2023, 14: 648.
[14] Watanabe Y, Taguchi K, Tanaka M.Ubiquitin, autophagy and neurodegenerative diseases[J]. Cells, 2020, 9: 2022.
[15] Liu WJ, Ye L, Huang WF, et al. p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation[J]. Cell Mol Biol Lett, 2016, 21: 29.
[16] Zhan J, He J, Zhou Y, et al. Crosstalk between the autophagy-lysosome pathway and the ubiquitin-proteasome pathway in retinal pigment epithelial cells[J]. Curr Mol Med, 2016, 16: 487–495.
[17] Pickford F, Masliah E, Britschgi M, et al. The autophagy-related protein Beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice[J]. J Clin Invest, 2008, 118: 2190–2199.
[18] Wu JC, Qi L, Wang Y, et al. The regulation of N-terminal Huntingtin (Htt552) accumulation by Beclin1[J]. Acta Pharmacol Sin, 2012, 33: 743–751.
[19] Hill SM, Wrobel L, Ashkenazi A, et al. VCP/p97 regulates Beclin-1-dependent autophagy initiation[J]. Nat Chem Biol, 2021, 17: 448–455.
[20] Chandrasekaran V, Hediyal TA, Anand N, et al. Polyphenols, autophagy and neurodegenerative diseases: a review[J]. Biomolecules, 2023, 13: 1196.
[21] Jung CH, Jun CB, Ro SH, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery[J]. Mol Biol Cell, 2009, 20: 1992–2003.
[22] Zhu Z, Yang C, Iyaswamy A, et al. Balancing mTOR signaling and autophagy in the treatment of Parkinson's disease[J]. Int J Mol Sci, 2019, 20: 728.
[23] SÓos L, Garabuczi É, Saghy T, et al. Palmitate inhibits mouse macrophage efferocytosis by activating an mTORC1-regulated rho kinase 1 pathway: therapeutic implications for the treatment of obesity[J]. Cells, 2022, 11: 3502.