动物衰老模型的研究进展

doi:10.12300/j.issn.1674-5817.2022.094

摘要/Abstract

摘要：

随着全球老龄化日益严重，衰老相关问题成了健康领域的一个研究热点。近年来，动物衰老模型得到广泛开发与应用，在衰老机制研究中具有重要意义。其中，线虫和果蝇等寿命较短的动物在衰老研究中具有天然优势；各类大鼠、小鼠衰老模型被用于多种衰老研究；同时，非洲青鳉鱼等新型动物衰老模型也相继得以开发应用。本文回顾了目前在衰老研究中使用的主要动物模型，并对各模型的建立方法、模型成功与否的评价指标、优缺点进行分析，以期为相关研究提供参考。

关键词: 衰老, 动物模型, 评价

Abstract:

With the increasing severity of global aging, aging-related issues have become the hotspot in the field of health. In recent years, animal aging models have been widely developed and applied, which is of great significance in the study of aging mechanism. Animals with short life span, such as Caenorhabditis Elegans and Drosophila Melanogaster, have natural advantages in the study of aging. Various rat and mouse aging models have been used in aging studies. In recent years, new animal aging models have been developed, such as the African turquoise killifish. The authors reviewed main animal models used in the study of aging, and analyzed the establishment methods, evaluation indexes, advantages and disadvantages of each model in order to provide reference for related research.

Key words: Aging, Animal model, Evaluation

中图分类号:

R-332

尹丹阳, 胡怡, 史仍飞. 动物衰老模型的研究进展[J]. 实验动物与比较医学, 2023, 43(2): 156-162.

Danyang YIN, Yi HU, Rengfei SHI. Advances in Animal Aging Models[J]. Laboratory Animal and Comparative Medicine, 2023, 43(2): 156-162.

图/表 1

参考文献 60

1	HARPER S, KLIEN E. Forty years of global action on ageing: what has been achieved? [J]. J Popul Ageing, 2022, 15(1):1-5. DOI:10.1007/s12062-022-09362-w .
2	IZQUIERDO M, MERCHANT R A, MORLEY J E, et al. International exercise recommendations in older adults (ICFSR): expert consensus guidelines[J]. J Nutr Health Aging, 2021, 25(7):824-853. DOI:10.1007/s12603-021-1665-8 .
3	BILSKI J, PIERZCHALSKI P, SZCZEPANIK M, et al. Multifactorial mechanism of sarcopenia and sarcopenic obesity. Role of physical exercise, microbiota and myokines[J]. Cells, 2022, 11(1):160. DOI:10.3390/cells11010160 .
4	KRITSILIS M, RIZOU S V, KOUTSOUDAKI P N, et al. Ageing, cellular senescence and neurodegenerative disease[J]. Int J Mol Sci, 2018, 19(10): 2937. DOI:10.3390/ijms19102937 .
5	赵凡凡, 周玉枝, 高丽, 等. D-半乳糖致衰老大鼠模型的研究进展[J]. 药学学报, 2017, 52(3):347-354. DOI:10.16438/j.0513-4870.2016-0696 .
	ZHAO F F, ZHOU Y Z, GAO L, et al. Advances in the study of the rat model of aging induced by D-galactose[J]. Acta Pharmaceutica Sinica, 2017, 52(3):347-354.
6	BRENNER S. The genetics of Caenorhabditis elegans[J]. Genetics, 1974, 77(1):71-94. DOI:10.1093/genetics/77.1.71 .
7	COLLINS J J, HUANG C, HUGHES S, et al. The measurement and analysis of age-related changes in Caenorhabditis elegans[J]. WormBook, 2008:1-21. DOI:10.1895/wormbook. 1.137.1 .
8	PIPER M D W, PARTRIDGE L. Drosophila as a model for ageing[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(9 Pt A):2707-2717. DOI:10.1016/j.bbadis.2017.09.016 .
9	CHINTAPALLI V R, WANG J, DOW J A T. Using FlyAtlas to identify better Drosophila melanogaster models of human disease[J]. Nat Genet, 2007, 39(6):715-720. DOI:10.1038/ng2049 .
10	DEMONTIS F, PERRIMON N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging[J]. Cell, 2010, 143(5):813-825. DOI:10.1016/j.cell.2010.10.007 .
11	OCORR K, PERRIN L, LIM H Y, et al. Genetic control of heart function and aging in Drosophila[J]. Trends Cardiovasc Med, 2007, 17(5):177-182. DOI:10.1016/j.tcm.2007.04.001 .
12	TISSENBAUM H A. Using C. elegans for aging research[J]. Invertebr Reprod Dev, 2015, 59(Sup1):59-63. DOI:10.1080/07924259.2014.940470 .
13	KISHI S, UCHIYAMA J, BAUGHMAN A M, et al. The zebrafish as a vertebrate model of functional aging and very gradual senescence[J]. Exp Gerontol, 2003, 38(7):777-786. DOI:10.1016/s0531-5565(03)00108-6 .
14	GILBERT M J H, ZERULLA T C, TIERNEY K B. Zebrafish (Danio rerio) as a model for the study of aging and exercise: physical ability and trainability decrease with age[J]. Exp Gerontol, 2014, 50:106-113. DOI:10.1016/j.exger.2013.11.013 .
15	KIKUCHI K. Dedifferentiation, transdifferentiation, and proliferation: mechanisms underlying cardiac muscle regeneration in zebrafish[J]. Curr Pathobiol Rep, 2015, 3(1):81-88. DOI:10.1007/s40139-015-0063-5 .
16	ANCHELIN M, ALCARAZ-PÉREZ F, MARTÍNEZ C M, et al. Premature aging in telomerase-deficient zebrafish[J]. Dis Model Mech, 2013, 6(5):1101-1112. DOI:10.1242/dmm.011635 .
17	GENADE T, BENEDETTI M, TERZIBASI E, et al. Annual fishes of the genus Nothobranchius as a model system for aging research[J]. Aging Cell, 2005, 4(5):223-233. DOI:10.1111/j.1474-9726.2005.00165.x .
18	VALENZANO D R, TERZIBASI E, GENADE T, et al. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate[J]. Curr Biol, 2006, 16(3):296-300. DOI:10.1016/j.cub.2005.12.038 .
19	GEYFMAN M, ANDERSEN B. Clock genes, hair growth and aging (Albany NY)[J]. Aging, 2010, 2(3):122-128. DOI:10.18632/aging.100130 .
20	HARTMANN N, REICHWALD K, LECHEL A, et al. Telomeres shorten while Tert expression increases during ageing of the short-lived fish Nothobranchius furzeri[J]. Mech Ageing Dev, 2009, 130(5):290-296. DOI:10.1016/j.mad.2009.01.003 .
21	HAREL I, BENAYOUN B A, MACHADO B, et al. A platform for rapid exploration of aging and diseases in a naturally short-lived vertebrate[J]. Cell, 2015, 160(5):1013-1026. DOI:10.1016/j.cell.2015.01.038 .
22	HU C K, BRUNET A. The African turquoise killifish: a research organism to study vertebrate aging and diapause[J]. Aging Cell, 2018, 17(3): e12757. DOI:10.1111/acel.12757 .
23	DUTTA S, SENGUPTA P. Men and mice: relating their ages[J]. Life Sci, 2016, 152:244-248. DOI:10.1016/j.lfs.2015.10.025 .
24	MITCHELL S J, SCHEIBYE-KNUDSEN M, LONGO D L, et al. Animal models of aging research: implications for human aging and age-related diseases[J]. Annu Rev Animal Biosci, 2015, 3:283-303. DOI:10.1146/annurev-animal-022114-110829 .
25	YUAN R, PETERS L L, PAIGEN B. Mice as a mammalian model for research on the genetics of aging[J]. ILAR J, 2011, 52(1):4-15. DOI:10.1093/ilar.52.1.4 .
26	GUO Y T, NIU K J, OKAZAKI T, et al. Coffee treatment prevents the progression of sarcopenia in aged mice in vivo and in vitro [J]. Exp Gerontol, 2014, 50:1-8. DOI:10.1016/j.exger.2013.11.005 .
27	LEDUC-GAUDET J P, PICARD M, ST-JEAN PELLETIER F, et al. Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice[J]. Oncotarget, 2015, 6(20):17923-17937. DOI:10.18632/oncotarget.4235 .
28	CAMPOREZ J P G, PETERSEN M C, ABUDUKADIER A, et al. Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice[J]. Proc Natl Acad Sci USA, 2016, 113(8):2212-2217. DOI:10.1073/pnas.1525795113 .
29	KOVACHEVA E L, SINHA HIKIM A P, SHEN R Q, et al. Testosterone supplementation reverses sarcopenia in aging through regulation of myostatin, c-Jun NH₂-terminal kinase, Notch, and Akt signaling pathways[J]. Endocrinology, 2010, 151(2):628-638. DOI:10.1210/en.2009-1177 .
30	SELDEEN K L, LASKY G, LEIKER M M, et al. High intensity interval training improves physical performance and frailty in aged mice[J]. J Gerontol A Biol Sci Med Sci, 2018, 73(4):429-437. DOI:10.1093/gerona/glx120 .
31	龚国清, 徐黻本. 小鼠衰老模型研究[J]. 中国药科大学学报, 1991, 22(2):101-103.
	GONG G Q, XU F B. Study of aging model in mice[J]. J China Pharm Univ, 1991, 22(2):101-103.
32	SHEN Y X, XU S Y, WEI W, et al. Melatonin reduces memory changes and neural oxidative damage in mice treated with D-galactose[J]. J Pineal Res, 2002, 32(3):173-178. DOI:10.1034/j.1600-079x.2002.1o850.x .
33	XU X H, ZHAO T Q. Effects of puerarin on D-galactose-induced memory deficits in mice[J]. Acta Pharmacol Sin, 2002, 23(7):587-590.
34	SHANG Y Z, GONG M Y, ZHOU X X, et al. Improving effects of SSF on memory deficits and pathological changes of neural and immunological systems in senescent mice[J]. Acta Pharmacol Sin, 2001, 22(12):1078-1083.
35	SHWE T, PRATCHAYASAKUL W, CHATTIPAKORN N, et al. Role of D-galactose-induced brain aging and its potential used for therapeutic interventions[J]. Exp Gerontol, 2018, 101:13-36. DOI:10.1016/j.exger.2017.10.029 .
36	CEBE T, ATUKEREN P, YANAR K, et al. Oxidation scrutiny in persuaded aging and chronological aging at systemic redox homeostasis level[J]. Exp Gerontol, 2014, 57:132-140. DOI:10.1016/j.exger.2014.05.017 .
37	秦红兵, 杨朝晔, 范忆江, 等. D-半乳糖诱导衰老小鼠模型的建立与评价[J]. 中国组织工程研究与临床康复, 2009, 13(7):1275-1278.
	QIN H B, YANG Z Y, FAN Y J, et al. Establishment and evaluation of aging models induced by D-galactose in mice[J]. Clin J Rehabil Tissue Eng Res, 2009, 13(7):1275-1278.
38	AZMAN K F, ZAKARIA R. D-Galactose-induced accelerated aging model: an overview[J]. Biogerontology, 2019, 20(6):763-782. DOI:10.1007/s10522-019-09837-y .
39	TAKEDA T, HOSOKAWA M, TAKESHITA S, et al. A new murine model of accelerated senescence[J]. Mech Ageing Dev, 1981, 17(2):183-194. DOI:10.1016/0047-6374(81)90084-1 .
40	TAKEDA T, HOSOKAWA M, HIGUCHI K. Senescence-accelerated mouse (SAM): a novel murine model of senescence[J]. Exp Gerontol, 1997, 32(1-2):105-109. DOI:10.1016/s0531-5565(96)00036-8 .
41	CHIBA Y, SHIMADA A, KUMAGAI N, et al. The senescence-accelerated mouse (SAM): a higher oxidative stress and age-dependent degenerative diseases model[J]. Neurochem Res, 2009, 34(4):679-687. DOI:10.1007/s11064-008-9812-8 .
42	TAKEDA T, MATSUSHITA T, KUROZUMI M, et al. Pathobiology of the senescence-accelerated mouse (SAM)[J]. Exp Gerontol, 1997, 32(1-2):117-127. DOI:10.1016/S0531-5565(96)00068-X .
43	TAKEDA T. Senescence-accelerated mouse (SAM): with special reference to age-associated pathologies and their modulation[J]. Nihon Eiseigaku Zasshi, 1996, 51(2):569-578. DOI:10.1265/jjh.51.569 .
44	DERAVE W, EIJNDE B O, RAMAEKERS M, et al. Soleus muscles of SAMP8 mice provide an accelerated model of skeletal muscle senescence[J]. Exp Gerontol, 2005, 40(7):562-572. DOI:10.1016/j.exger.2005.05.005 .
45	HERRANZ N, GIL J. Mechanisms and functions of cellular senescence[J]. J Clin Investig, 2018, 128(4):1238-1246. DOI:10.1172/jci95148 .
46	BENSON E K, ZHAO B, SASSOON D A, et al. Effects of p21 deletion in mouse models of premature aging[J]. Cell Cycle, 2009, 8(13):2002-2004. DOI:10.4161/cc.8.13.8997 .
47	VARELA I, CADIÑANOS J, PENDÁS A M, et al. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation[J]. Nature, 2005, 437(7058):564-568. DOI:10.1038/nature04019 .
48	BAKER D J, WIJSHAKE T, TCHKONIA T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders[J]. Nature, 2011, 479(7372):232-236. DOI:10.1038/nature10600 .
49	AKKI A, YANG H L, GUPTA A, et al. Skeletal muscle ATP kinetics are impaired in frail mice[J]. AGE, 2014, 36(1):21-30. DOI:10.1007/s11357-013-9540-0 .
50	XIE W Q, HE M, YU D J, et al. Mouse models of sarcopenia: classification and evaluation[J]. J Cachexia Sarcopenia Muscle, 2021, 12(3):538-554. DOI:10.1002/jcsm.12709 .
51	ACOSTA P B, GROSS K C. Hidden sources of galactose in the environment[J]. Eur J Pediatr, 1995, 154(7 ): S87-S92. DOI:10.1007/BF02143811 .
52	WU D M, LU J, ZHENG Y L, et al. Purple sweet potato color repairs D-galactose-induced spatial learning and memory impairment by regulating the expression of synaptic proteins[J]. Neurobiol Learn Mem, 2008, 90(1):19-27. DOI:10.1016/j.nlm.2008.01.010 .
53	ULLAH F, ALI T, ULLAH N, et al. Caffeine prevents D-galactose-induced cognitive deficits, oxidative stress, neuroinflammation and neurodegeneration in the adult rat brain[J]. Neurochem Int, 2015, 90:114-124. DOI:10.1016/j.neuint.2015.07.001 .
54	TAKIGAWA K, MATSUDA R, UCHITOMI R, et al. Effects of long-term physical exercise on skeletal muscles in senescence-accelerated mice (SAMP8)[J]. Biosci Biotechnol Biochem, 2019, 83(3):518-524. DOI:10.1080/09168451. 2018.1547625 .
55	XIE W Q, HE M, YU D J, et al. Mouse models of sarcopenia: classification and evaluation[J]. J Cachexia Sarcopenia Muscle, 2021, 12(3):538-554. DOI:10.1002/jcsm.12709 .
56	PARTADIREDJA G, KARIMA N, UTAMI K P, et al. The effects of light and moderate intensity exercise on the femoral bone and cerebellum of d-galactose-exposed rats[J]. Rejuvenation Res, 2019, 22(1):20-30. DOI:10.1089/rej.2018.2050 .
57	CHEN W K, TSAI Y L, SHIBU M A, et al. Exercise training augments Sirt1-signaling and attenuates cardiac inflammation in D-galactose induced-aging rats[J]. Aging (Albany NY, 2018, 10(12):4166-4174. DOI:10.18632/aging.101714 .
58	FAN J J, YANG X Q, LI J, et al. Spermidine coupled with exercise rescues skeletal muscle atrophy from D-gal-induced aging rats through enhanced autophagy and reduced apoptosis via AMPK-FOXO3a signal pathway[J]. Oncotarget, 2017, 8(11):17475-17490. DOI:10.18632/oncotarget.15728 .
59	KOU X J, LI J, LIU X R, et al. Swimming attenuates d-galactose-induced brain aging via suppressing miR-34a-mediated autophagy impairment and abnormal mitochondrial dynamics[J]. J Appl Physiol (1985), 2017, 122(6):1462-1469. DOI:10.1152/japplphysiol.00018.2017 .
60	唐慧青, 常书福, 于志锋, 等. SHJH^hr小鼠部分生物学特性及衰老表型的测定与分析[J]. 实验动物与比较医学, 2023, 43(1): 44-52. DOI:10.12300/j.issn.1674-5817.2022.069 .
	TANG H Q, CHANG S F, YU Z F, et al. Investigation on biological characteristics and aging phenotype of SHJH^hr mice[J]. Lab Anim Comp Med, 2023, 43(1): 44-52. DOI:10.12300/j.issn.1674-5817.2022.069 .

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