Stem cells application in frailty
Abstract
Frailty can be defined as a systematic physiological decline that typically occurs in the nervous, muscular, metabolic, and immune systems of the older people. A multitude of risk factors have been identified to contribute to cause or exacerbate frailty, these risk factors lead to a heightened complexity and difficulty in preventing and treating frailty, which seriously threatens the health and well-being of the elderly people. Because of the unique characteristic of stem cells, including being a convenient source, low immunogenicity, and multi-directional differentiation potential, considerable advancements have been made in the field of frailty research. In this review, we summarized the impacts of the main risk factors, including genetic factors, ageing, sex differences, polypharmacy, malnutrition and unhealthy lifestyles in the onset and progression of frailty, provided an overview of the recent research progress in preclinical and clinical applications of stem cells in frailty, and discussed application limitations of stem cells in frailty and proposed the possible solutions. It was concluded that stem cells represent an ideal potential treatment method for frailty, offering significant advantages in terms of convenience, immunogenicity, and pluripotency.
References
1. Fried LP, Tangen CM, Walston J, et al. Frailty in Older Adults: Evidence for a Phenotype. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2001; 56(3): M146–M157. doi: 10.1093/gerona/56.3.m146
2. Walston J, Robinson TN, Zieman S, et al. Integrating Frailty Research into the Medical Specialties—Report from a U13 Conference. Journal of the American Geriatrics Society. 2017; 65(10): 2134–2139. doi: 10.1111/jgs.14902
3. Dent E, Martin FC, Bergman H, et al. Management of frailty: opportunities, challenges, and future directions. Lancet. 2019; 394: 1376–1386. doi:10.1016/S0140-6736(19)31785-4
4. Ye Y, Noche RB, Szejko N, et al. A genome-wide association study of frailty identifies significant genetic correlation with neuropsychiatric, cardiovascular, and inflammation pathways. GeroScience. 2023; 45(4): 2511–2523. doi: 10.1007/s11357-023-00771-z
5. Salvioli S, Basile MS, Bencivenga L, et al. Biomarkers of aging in frailty and age-associated disorders: State of the art and future perspective. Ageing Research Reviews. 2023; 91: 102044. doi: 10.1016/j.arr.2023.102044
6. Dallaire M, Houde-Thibeault A, Bouchard-Tremblay J, et al. Impact of frailty and sex-related differences on postural control and gait in older adults with Parkinson’s Disease. Experimental Gerontology. 2024; 186: 112360. doi: 10.1016/j.exger.2024.112360
7. Zhang L, Zeng X, He F, et al. Inflammatory biomarkers of frailty: A review. Experimental Gerontology. 2023; 179: 112253. doi: 10.1016/j.exger.2023.112253
8. The World at Six Billion. Population Division. Department of Economic and Social Affairs. United Nations Secretariat. 1999; p. 12.
9. Kurnat-Thoma EL, Murray MT, Juneau P. Frailty and Determinants of Health Among Older Adults in the United States 2011–2016. Journal of Aging and Health. 2021; 34(2): 233–244. doi: 10.1177/08982643211040706
10. Collard RM, Boter H, Schoevers RA, et al. Prevalence of Frailty in Community—Dwelling Older Persons: A Systematic Review. Journal of the American Geriatrics Society. 2012; 60(8): 1487–1492. doi: 10.1111/j.1532-5415.2012.04054.x
11. O’Halloran AM, Hartley P, Moloney D, et al. Informing patterns of health and social care utilisation in Irish older people according to the Clinical Frailty Scale. HRB Open Research. 2021; 4: 54. doi: 10.12688/hrbopenres.13301.1
12. Takele MD, Sany K, Getie K, et al. Prevalence and associated factors of frailty among community dweller older adults living in Gondar town, northwest, Ethiopia: a community based cross-sectional study. BMC Public Health. 2023; 23(1). doi: 10.1186/s12889-023-16201-w
13. Yunmei Yang, Xiping Tuo, Pulin Yu. Geriatrics Branch of Chinese Medical Association, Editorial Committee of Chinese Journal of Geriatrics Consensus of Chinese Experts on the Prevention of Senile Weakness (2022) (Chinese). Chinese Journal of Geriatrics. 2022; 41 (5): 503–511.
14. Giacomelli E, Vahsen BF, Calder EL, et al. Human stem cell models of neurodegeneration: From basic science of amyotrophic lateral sclerosis to clinical translation. Cell Stem Cell. 2022; 29(1): 11–35. doi: 10.1016/j.stem.2021.12.008
15. James EC, Tomaskovic-Crook E, Crook JM. Bioengineering Clinically Relevant Cardiomyocytes and Cardiac Tissues from Pluripotent Stem Cells. International Journal of Molecular Sciences. 2021; 22(6): 3005. doi: 10.3390/ijms22063005
16. Tang J, Wang H, Huang X, et al. Arterial Sca1 + Vascular Stem Cells Generate De Novo Smooth Muscle for Artery Repair and Regeneration. Cell Stem Cell. 2020; 26(1): 81–96. doi: 10.1016/j.stem.2019.11.010
17. Morizane R, Lam AQ, Freedman BS, et al. Nephron organoids derived from human pluripotent stem cells model kidney development and injury. Nature Biotechnology. 2015; 33(11): 1193–1200. doi: 10.1038/nbt.3392
18. Soysal P, Stubbs B, Lucato P, et al. Inflammation and frailty in the elderly: A systematic review and meta-analysis. Ageing Research Reviews. 2016; 31: 1–8. doi: 10.1016/j.arr.2016.08.006
19. Qu T, Yang H, Walston JD, et al. Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL-10) and its relationship with serum interleukin-6 levels in the syndrome of frailty. Cytokine. 2009; 46(3): 319–324. doi: 10.1016/j.cyto.2009.02.015
20. Angioni D, Lu WH, Sourdet S, et al. Biomarkers of Age-Related Frailty and Frailty Related to Diseases: An Exploratory, Cross-Sectional Analysis from the MAPT Study. The Journal of nutrition, health and aging. 2022; 26(6): 545–551. doi: 10.1007/s12603-022-1793-9
21. Teng H, Hong Y, Cao J, et al. Senescence marker protein30 protects lens epithelial cells against oxidative damage by restoring mitochondrial function. Bioengineered. 2022; 13(5): 12955–12971. doi: 10.1080/21655979.2022.2079270
22. Cardoso AL, Fernandes A, Aguilar-Pimentel JA, et al. Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases. Ageing Research Reviews. 2018; 47: 214–277. doi: 10.1016/j.arr.2018.07.004
23. Roh E, Hwang SY, Song E, et al. Association of plasma brain-derived neurotrophic factor levels and frailty in community-dwelling older adults. Scientific Reports. 2022; 12(1). doi: 10.1038/s41598-022-19706-3
24. Mone P, de Donato A, Varzideh F, et al. Functional role of miR-34a in diabetes and frailty. Frontiers in Aging. 2022; 3. doi: 10.3389/fragi.2022.949924
25. Pansarasa O, Mimmi MC, Davin A, et al. Inflammation and cell-to-cell communication, two related aspects in frailty. Immunity & Ageing. 2022; 19(1). doi: 10.1186/s12979-022-00306-8
26. Sanz-Ros J, Romero-García N, Mas-Bargues C, et al. Small extracellular vesicles from young adipose-derived stem cells prevent frailty, improve health span, and decrease epigenetic age in old mice. Science Advances. 2022; 8(42). doi: 10.1126/sciadv.abq2226
27. Ramos S, Pereira AG, Ferrari FS, et al. Circulating miRNAs are associated with frailty and ST-elevation myocardial infarction pathways. Archives of Gerontology and Geriatrics. 2023; 106: 104870. doi: 10.1016/j.archger.2022.104870
28. Ahlström G, Wallén EF, Tideman M, et al. Ageing people with intellectual disabilities and the association between frailty factors and social care: A Swedish national register study. Journal of Intellectual Disabilities. 2021; 26(4): 900–918. doi: 10.1177/17446295211037170
29. Sanford AM. Anorexia of aging and its role for frailty. Current Opinion in Clinical Nutrition & Metabolic Care. 2017; 20(1): 54–60. doi: 10.1097/mco.0000000000000336
30. Gale CR, Cooper C. Attitudes to Ageing and Change in Frailty Status: The English Longitudinal Study of Ageing. Gerontology. 2017; 64(1): 58–66. doi: 10.1159/000477169
31. Lin H, Wang D, Ma S, et al. Frailty’s Prevalence and the Association with Aging-Related Health Conditions in Chinese Community Dwelling Elderly. Khan R, ed. Computational Intelligence and Neuroscience. 2022; 2022: 1–8. doi: 10.1155/2022/1748162
32. Kulminski A, Yashin A, Arbeev K, et al. Cumulative index of health disorders as an indicator of aging-associated processes in the elderly: Results from analyses of the National Long Term Care Survey. Mechanisms of Ageing and Development. 2007; 128(3): 250–258. doi: 10.1016/j.mad.2006.12.004
33. Kulminski A, Ukraintseva SV, Akushevich I, et al. Accelerated accumulation of health deficits as a characteristic of aging. Experimental Gerontology. 2007; 42(10): 963–970. doi: 10.1016/j.exger.2007.05.009
34. Fernandez-Bolaños M, Otero Á, Zunzunegui MV, et al. Sex Differences In The Prevalence Of Frailty In A Population Aged 75 And Older In Spain. Journal of the American Geriatrics Society. 2008; 56(12): 2370–2371. doi: 10.1111/j.1532-5415.2008.02032.x
35. Song X, Mitnitski A, Rockwood K. Prevalence and 10-Year Outcomes of Frailty in Older Adults in Relation to Deficit Accumulation. Journal of the American Geriatrics Society. 2010; 58(4): 681–687. doi: 10.1111/j.1532-5415.2010.02764.x
36. Romero-Ortuno R, Fouweather T, Jagger C. Cross-national disparities in sex differences in life expectancy with and without frailty. Age and Ageing. 2014; 43(2): 222–228. doi: 10.1093/ageing/aft115
37. Hanlon P, Nicholl BI, Jani BD, et al. Frailty and pre-frailty in middle-aged and older adults and its association with multimorbidity and mortality: a prospective analysis of 493 737 UK Biobank participants. Lancet Public Health. 2018; 3: e323–e332. doi:10.1016/S2468-2667(18)30091-4
38. Samson LD, Boots AMH, Ferreira JA, et al. In-depth immune cellular profiling reveals sex-specific associations with frailty. Immunity & Ageing. 2020; 17(1). doi: 10.1186/s12979-020-00191-z
39. Pacheco NL, Noren Hooten N, Zhang Y, et al. Sex-specific transcriptome differences in a middle-aged frailty cohort. BMC Geriatrics. 2022; 22(1). doi: 10.1186/s12877-022-03326-7
40. Gutiérrez-Valencia M, Izquierdo M, Cesari M, et al. The relationship between frailty and polypharmacy in older people: A systematic review. British Journal of Clinical Pharmacology. 2018; 84(7): 1432–1444. doi: 10.1111/bcp.13590
41. Kimura H, Kalantar-Zadeh K, Rhee CM, et al. Polypharmacy and Frailty among Hemodialysis Patients. Nephron. 2021; 145(6): 624–632. doi: 10.1159/000516532
42. Karim AM, Li J, Panhwar MS, et al. Impact of malnutrition and frailty on mortality and major amputation in patients with CLTI. Catheterization and Cardiovascular Interventions. 2022; 99(4): 1300–1309. doi: 10.1002/ccd.30113
43. Sharma Y, Avina P, Ross E, et al. The overlap of frailty and malnutrition in older hospitalised patients: An observational study. Asia Pac J Clin Nutr. 2021; 30: 457–463. doi:10.6133/apjcn.202109_30(3).0012
44. Liu W, Chen S, Jiang F, et al. Malnutrition and Physical Frailty among Nursing Home Residents: A Cross-Sectional Study in China. The Journal of nutrition, health and aging. 2020; 24(5): 500–506. doi: 10.1007/s12603-020-1348-x
45. Lv J, Wu L, Sun S, et al. Smoking, alcohol consumption, and frailty: A Mendelian randomization study. Frontiers in Genetics. 2023; 14. doi: 10.3389/fgene.2023.1092410
46. Crane HM, Ruderman SA, Whitney BM, et al. Associations between drug and alcohol use, smoking, and frailty among people with HIV across the United States in the current era of antiretroviral treatment. Drug Alcohol Depend 2022: 240: 109649. doi: 10.1016/j.drugalcdep. 2022.109649
47. Fu Z, Zhou T, Dong F, et al. Secondhand smoke is positively associated with pre-frailty and frailty in non-smoking older adults. Frontiers in Psychiatry. 2022; 13. doi: 10.3389/fpsyt.2022.1095254
48. Mulasso A, Roppolo M, Rainoldi A, et al. Effects of a Multicomponent Exercise Program on Prevalence and Severity of the Frailty Syndrome in a Sample of Italian Community-Dwelling Older Adults. Healthcare. 2022; 10(5): 911. doi: 10.3390/healthcare10050911
49. Gimeno-Mallench L, Sanchez-Morate E, Parejo-Pedrajas S, et al. The Relationship between Diet and Frailty in Aging. Endocrine, Metabolic & Immune Disorders—Drug Targets. 2020; 20(9): 1373–1382. doi: 10.2174/1871530320666200513083212
50. Haran JP, McCormick BA. Aging, Frailty, and the Microbiome—How Dysbiosis Influences Human Aging and Disease. Gastroenterology. 2021; 160: 507–523. doi:10.1053/j.gastro. 2020.09.060.
51. Gordon EH, Hubbard RE. Frailty: understanding the difference between age and ageing. Age and Ageing. 2022; 51(8). doi: 10.1093/ageing/afac185
52. Heris RM, Shirvaliloo M, Abbaspour-Aghdam S, et al. The potential use of mesenchymal stem cells and their exosomes in Parkinson’s disease treatment. Stem Cell Research & Therapy. 2022; 13(1). doi: 10.1186/s13287-022-03050-4
53. Das M, Mayilsamy K, Mohapatra SS, et al. Mesenchymal stem cell therapy for the treatment of traumatic brain injury: progress and prospects. Reviews in the Neurosciences. 2019; 30(8): 839–855. doi: 10.1515/revneuro-2019-0002
54. Cofano F, Boido M, Monticelli M, et al. Mesenchymal Stem Cells for Spinal Cord Injury: Current Options, Limitations, and Future of Cell Therapy. International Journal of Molecular Sciences. 2019; 20(11): 2698. doi: 10.3390/ijms20112698
55. Bagno L, Hatzistergos KE, Balkan W, et al. Mesenchymal Stem Cell-Based Therapy for Cardiovascular Disease: Progress and Challenges. Molecular Therapy. 2018; 26(7): 1610–1623. doi: 10.1016/j.ymthe.2018.05.009
56. Chung JW, Chang WH, Bang OY, et al. Efficacy and Safety of Intravenous Mesenchymal Stem Cells for Ischemic Stroke. Neurology. 2021; 96: e1012–e1023. doi:10.1212/WNL. 0000000000011440
57. Yang W, Yin R, Zhu X, et al. Mesenchymal stem-cell-derived exosomal miR-145 inhibits atherosclerosis by targeting JAM-A. Molecular Therapy—Nucleic Acids. 2021; 23: 119–131. doi: 10.1016/j.omtn.2020.10.037
58. Li H, Wei J, Zhang Z, et al. Menstrual blood-derived endometrial stem cells alleviate neuroinflammation by modulating M1/M2 polarization in cell and rat Parkinson’s disease models. Stem Cell Research & Therapy. 2023; 14(1). doi: 10.1186/s13287-023-03330-7
59. Ning Y, Huang P, Chen G, et al. Atorvastatin-pretreated mesenchymal stem cell-derived extracellular vesicles promote cardiac repair after myocardial infarction via shifting macrophage polarization by targeting microRNA-139-3p/Stat1 pathway. BMC Medicine. 2023; 21(1): 96. doi: 10.1186/s12916-023-02778-x
60. Egea V, Megens RTA, Santovito D, et al. Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques. Cardiovasc Res. 2023;119(1):155-166. doi: 10.1093/cvr/cvac022.
61. Chen HX, Liang FC, Gu P, et al. Exosomes derived from mesenchymal stem cells repair a Parkinson’s disease model by inducing autophagy. Cell Death & Disease. 2020; 11(4). doi: 10.1038/s41419-020-2473-5
62. Li F, Zhang A, Li M, et al. Induced neural stem cells from Macaca fascicularis show potential of dopaminergic neuron specification and efficacy in a mouse Parkinson’s disease model. Acta Histochemica. 2022; 124(6): 151927. doi: 10.1016/j.acthis.2022.151927
63. Sun S, Zhang Q, Li M, et al. GDNF Promotes Survival and Therapeutic Efficacy of Human Adipose-Derived Mesenchymal Stem Cells in a Mouse Model of Parkinson’s Disease. Cell Transplantation. 2020; 29: 096368972090851. doi: 10.1177/0963689720908512
64. Khan MI, Jeong ES, Khan MZ, et al. Stem cells-derived exosomes alleviate neurodegeneration and Alzheimer’s pathogenesis by ameliorating neuroinflamation, and regulating the associated molecular pathways. Scientific Reports. 2023; 13(1). doi: 10.1038/s41598-023-42485-4
65. Zhao Y, Zhu XY, Song T, et al. Mesenchymal stem cells protect renal tubular cells via TSG-6 regulating macrophage function and phenotype switching. American Journal of Physiology-Renal Physiology. 2021; 320(3): F454–F463. doi: 10.1152/ajprenal.00426.2020
66. Chang YM, Shibu MA, Chen CS, et al. Adipose derived mesenchymal stem cells along with Alpinia oxyphylla extract alleviate mitochondria-mediated cardiac apoptosis in aging models and cardiac function in aging rats. J Ethnopharmacol. 2021; 264: 113297. doi:10.1016/ j.jep.2020.113297.
67. Sekenova A, Li Y, Issabekova A, et al. TNF-α Preconditioning Improves the Therapeutic Efficacy of Mesenchymal Stem Cells in an Experimental Model of Atherosclerosis. Cells. 2023; 12(18): 2262. doi: 10.3390/cells12182262
68. Li Y, Shi G, Liang W, et al. Allogeneic Adipose-Derived Mesenchymal Stem Cell Transplantation Alleviates Atherosclerotic Plaque by Inhibiting Ox-LDL Uptake, Inflammatory Reaction and Endothelial Damage in Rabbits. Cells. 2023; 12(15): 1936. doi: 10.3390/cells12151936
69. Horitani K, Iwasaki M, Kishimoto H, et al. Repetitive spikes of glucose and lipid induce senescence-like phenotypes of bone marrow stem cells through H3K27me3 demethylase-mediated epigenetic regulation. American Journal of Physiology-Heart and Circulatory Physiology. 2021; 321(5): H920–H932. doi: 10.1152/ajpheart.00261.2021
70. Dong J, Zhang Z, Huang H, et al. miR-10a rejuvenates aged human mesenchymal stem cells and improves heart function after myocardial infarction through KLF4. Stem Cell Research & Therapy. 2018; 9(1). doi: 10.1186/s13287-018-0895-0
71. Go V, Sarikaya D, Zhou Y, et al. Extracellular vesicles derived from bone marrow mesenchymal stem cells enhance myelin maintenance after cortical injury in aged rhesus monkeys. Experimental Neurology. 2021; 337: 113540. doi: 10.1016/j.expneurol.2020.113540
72. Zhi F, Ding Y, Wang R, et al. Exosomal hsa_circ_0006859 is a potential biomarker for postmenopausal osteoporosis and enhances adipogenic versus osteogenic differentiation in human bone marrow mesenchymal stem cells by sponging miR-431-5p. Stem Cell Research & Therapy. 2021; 12(1). doi: 10.1186/s13287-021-02214-y
73. Song J, Liu J, Cui C, et al. Mesenchymal stromal cells ameliorate diabetes-induced muscle atrophy through exosomes by enhancing AMPK/ULK1-mediated autophagy. Journal of Cachexia, Sarcopenia and Muscle. 2023; 14(2): 915–929. doi: 10.1002/jcsm.13177
74. Wang C, Zhao B, Zhai J, et al. Clinical-grade human umbilical cord-derived mesenchymal stem cells improved skeletal muscle dysfunction in age-associated sarcopenia mice. Cell Death & Disease. 2023; 14(5). doi: 10.1038/s41419-023-05843-8
75. Kono Y, Takegaki J, Ohba T, et al. Magnetization of mesenchymal stem cells using magnetic liposomes enhances their retention and immunomodulatory efficacy in mouse inflamed skeletal muscle. International Journal of Pharmaceutics. 2021; 596: 120298. doi: 10.1016/j.ijpharm.2021.120298
76. Liu B, Ding F, Liu Y, et al. Human umbilical cord—derived mesenchymal stem cells conditioned medium attenuate interstitial fibrosis and stimulate the repair of tubular epithelial cells in an irreversible model of unilateral ureteral obstruction. Nephrology. 2018; 23(8): 728–736. doi: 10.1111/nep.13099
77. Golpanian S, DiFede DL, Khan A, et al. Allogeneic Human Mesenchymal Stem Cell Infusions for Aging Frailty. The Journals of Gerontology: Series A. 2017; 72(11): 1505–1512. doi: 10.1093/gerona/glx056
78. Golpanian S, DiFede DL, Pujol MV, et al. Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty. Oncotarget. 2016; 7(11): 11899–11912. doi: 10.18632/oncotarget.7727
79. Tompkins BA, DiFede DL, Khan A, et al. Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial. The Journals of Gerontology: Series A. 2017; 72(11): 1513–1522. doi: 10.1093/gerona/glx137
80. Wang Z, Chai C, Wang R, et al. Single‐cell transcriptome atlas of human mesenchymal stem cells exploring cellular heterogeneity. Clinical and Translational Medicine. 2021; 11(12). doi: 10.1002/ctm2.650
81. Wang Z, Li X, Yang J, et al. Single-cell RNA sequencing deconvolutes the in vivo heterogeneity of human bone marrow-derived mesenchymal stem cells. International Journal of Biological Sciences. 2021; 17(15): 4192–4206. doi: 10.7150/ijbs.61950
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