RSS-Feed abonnieren
DOI: 10.1055/s-0039-3402033
Aging and the Biological Response to Liver Injury
![](https://www.thieme-connect.de/media/sld/202003/lookinside/thumbnails/10-1055-s-0039-3402033_1900058-1.jpg)
Abstract
Interest in understanding the aging process has recently risen in the scientific community. Aging, commonly defined as the functional decline in the function of organs and tissues, is indeed the major risk factor for the development of many chronic diseases, such as cardiovascular diseases, pathologies of nervous system, or cancer. To date, the influence of aging in the pathophysiology of liver and biliary diseases is not fully understood. Although liver cells have a high regenerative capacity, hepatocytes and cholangiocytes undergo extensive molecular changes in response to aging. Following time-dependent damage induced by aging, liver cells initially activate compensatory mechanisms that, if hyperstimulated, may lead to the decline of regenerative capacity and the development of pathologies. A deeper understanding of molecular aging has undoubtedly the potential to improve the clinical management of patients, possibly unveiling new pathways for selective drug treatment.
* Co-senior authors.
Publikationsverlauf
Artikel online veröffentlicht:
30. Dezember 2019
© 2020. Thieme. All rights reserved.
Thieme Medical Publishers
333 Seventh Avenue, New York, NY 10001, USA.
-
References
- 1 Moskalev AA, Shaposhnikov MV, Plyusnina EN. , et al. The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res Rev 2013; 12 (02) 661-684
- 2 McHugh D, Gil J. Senescence and aging: causes, consequences, and therapeutic avenues. J Cell Biol 2018; 217 (01) 65-77
- 3 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013; 153 (06) 1194-1217
- 4 North BJ, Sinclair DA. The intersection between aging and cardiovascular disease. Circ Res 2012; 110 (08) 1097-1108
- 5 Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med 2010; 362 (04) 329-344
- 6 de Magalhães JP. How ageing processes influence cancer. Nat Rev Cancer 2013; 13 (05) 357-365
- 7 Landis JN, Murphy CT. Integration of diverse inputs in the regulation of Caenorhabditis elegans DAF-16/FOXO. Dev Dyn 2010; 239 (05) 1405-1412
- 8 Wolff S, Dillin A. The trifecta of aging in Caenorhabditis elegans. Exp Gerontol 2006; 41 (10) 894-903
- 9 Ruzanov P, Riddle DL, Marra MA, McKay SJ, Jones SM. Genes that may modulate longevity in C. elegans in both dauer larvae and long-lived daf-2 adults. Exp Gerontol 2007; 42 (08) 825-839
- 10 Mair W, Dillin A. Aging and survival: the genetics of life span extension by dietary restriction. Annu Rev Biochem 2008; 77: 727-754
- 11 Narasimhan SD, Yen K, Tissenbaum HA. Converging pathways in lifespan regulation. Curr Biol 2009; 19 (15) R657-R666
- 12 Flachsbart F, Caliebe A, Kleindorp R. , et al. Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci U S A 2009; 106 (08) 2700-2705
- 13 Li Y, Wang WJ, Cao H. , et al. Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet 2009; 18 (24) 4897-4904
- 14 Rudolph KL, Chang S, Millard M, Schreiber-Agus N, DePinho RA. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science 2000; 287 (5456): 1253-1258
- 15 Baker DJ, Wijshake T, Tchkonia T. , et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011; 479 (7372): 232-236
- 16 Baker DJ, Childs BG, Durik M. , et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 2016; 530 (7589): 184-189
- 17 Zhu Y, Tchkonia T, Pirtskhalava T. , et al. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 2015; 14 (04) 644-658
- 18 Schmucker DL. Age-related changes in liver structure and function: Implications for disease?. Exp Gerontol 2005; 40 (8-9): 650-659
- 19 Noureddin M, Yates KP, Vaughn IA. , et al; NASH CRN. Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients. Hepatology 2013; 58 (05) 1644-1654
- 20 Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999; 30 (06) 1356-1362
- 21 Kim IH, Kisseleva T, Brenner DA. Aging and liver disease. Curr Opin Gastroenterol 2015; 31 (03) 184-191
- 22 Meier P, Seitz HK. Age, alcohol metabolism and liver disease. Curr Opin Clin Nutr Metab Care 2008; 11 (01) 21-26
- 23 Poynard T, Ratziu V, Charlotte F, Goodman Z, McHutchison J, Albrecht J. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c. J Hepatol 2001; 34 (05) 730-739
- 24 Rodríguez-Osorio I, Mena A, Meijide H. , et al. Liver-related events and mortality among elderly patients with advanced chronic hepatitis C treated with direct-acting antivirals. PLoS One 2019; 14 (06) e0217052
- 25 Sajja KC, Mohan DP, Rockey DC. Age and ethnicity in cirrhosis. J Investig Med 2014; 62 (07) 920-926
- 26 Cheung AC, Lammers WJ, Murillo Perez CF. , et al; Global PBC Study Group. Effects of age and sex of response to ursodeoxycholic acid and transplant-free survival in patients with primary biliary cholangitis. Clin Gastroenterol Hepatol 2019; 17 (10) 2076-2084.e2
- 27 Weismüller TJ, Trivedi PJ, Bergquist A. , et al; International PSC Study Group. Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis. Gastroenterology 2017; 152 (08) 1975-1984.e8
- 28 Randall HB, Cao S, deVera ME. Transplantation in elderly patients. Arch Surg 2003; 138 (10) 1089-1092
- 29 Adani GL, Baccarani U, Lorenzin D. , et al. Elderly versus young liver transplant recipients: patient and graft survival. Transplant Proc 2009; 41 (04) 1293-1294
- 30 Shankar N, AlBasheer M, Marotta P, Wall W, McAlister V, Chandok N. Do older patients utilize excess health care resources after liver transplantation?. Ann Hepatol 2011; 10 (04) 477-481
- 31 Mousa OY, Nguyen JH, Ma Y. , et al. Evolving role of liver transplantation in elderly recipients. Liver Transpl 2019; 25 (09) 1363-1374
- 32 Welling TH, Heidt DG, Englesbe MJ. , et al. Biliary complications following liver transplantation in the model for end-stage liver disease era: effect of donor, recipient, and technical factors. Liver Transpl 2008; 14 (01) 73-80
- 33 Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW. DNA repair, genome stability, and aging. Cell 2005; 120 (04) 497-512
- 34 Aunan JR, Watson MM, Hagland HR, Søreide K. Molecular and biological hallmarks of ageing. Br J Surg 2016; 103 (02) e29-e46
- 35 Hoeijmakers JH. DNA damage, aging, and cancer. N Engl J Med 2009; 361 (15) 1475-1485
- 36 Honig LS, Kang MS, Cheng R. , et al. Heritability of telomere length in a study of long-lived families. Neurobiol Aging 2015; 36 (10) 2785-2790
- 37 Armanios M, Alder JK, Parry EM, Karim B, Strong MA, Greider CW. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am J Hum Genet 2009; 85 (06) 823-832
- 38 Kuszel L, Trzeciak T, Richter M, Czarny-Ratajczak M. Osteoarthritis and telomere shortening. J Appl Genet 2015; 56 (02) 169-176
- 39 Carlquist JF, Knight S, Cawthon RM. , et al. Shortened telomere length is associated with paroxysmal atrial fibrillation among cardiovascular patients enrolled in the Intermountain Heart Collaborative Study. Heart Rhythm 2016; 13 (01) 21-27
- 40 Hunt SC, Kimura M, Hopkins PN. , et al. Leukocyte telomere length and coronary artery calcium. Am J Cardiol 2015; 116 (02) 214-218
- 41 Bocklandt S, Lin W, Sehl ME. , et al. Epigenetic predictor of age. PLoS One 2011; 6 (06) e14821
- 42 Koch CM, Wagner W. Epigenetic-aging-signature to determine age in different tissues. Aging (Albany NY) 2011; 3 (10) 1018-1027
- 43 Hannum G, Guinney J, Zhao L. , et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 2013; 49 (02) 359-367
- 44 Mostoslavsky R, Chua KF, Lombard DB. , et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 2006; 124 (02) 315-329
- 45 Kanfi Y, Naiman S, Amir G. , et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 2012; 483 (7388): 218-221
- 46 Freije JM, López-Otín C. Reprogramming aging and progeria. Curr Opin Cell Biol 2012; 24 (06) 757-764
- 47 Rando TA, Chang HY. Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell 2012; 148 (1-2): 46-57
- 48 Koga H, Kaushik S, Cuervo AM. Protein homeostasis and aging: the importance of exquisite quality control. Ageing Res Rev 2011; 10 (02) 205-215
- 49 Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE. Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 2009; 78: 959-991
- 50 Labbadia J, Morimoto RI. The biology of proteostasis in aging and disease. Annu Rev Biochem 2015; 84: 435-464
- 51 Zhang C, Cuervo AM. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 2008; 14 (09) 959-965
- 52 Hoenicke L, Zender L. Immune surveillance of senescent cells--biological significance in cancer- and non-cancer pathologies. Carcinogenesis 2012; 33 (06) 1123-1126
- 53 Kang TW, Yevsa T, Woller N. , et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 2011; 479 (7374): 547-551
- 54 Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol 2013; 75: 685-705
- 55 Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007; 8 (09) 729-740
- 56 Collins CJ, Sedivy JM. Involvement of the INK4a/Arf gene locus in senescence. Aging Cell 2003; 2 (03) 145-150
- 57 Doles J, Storer M, Cozzuto L, Roma G, Keyes WM. Age-associated inflammation inhibits epidermal stem cell function. Genes Dev 2012; 26 (19) 2144-2153
- 58 Nakamura AJ, Chiang YJ, Hathcock KS. , et al. Both telomeric and non-telomeric DNA damage are determinants of mammalian cellular senescence. Epigenetics Chromatin 2008; 1 (01) 6
- 59 Sedelnikova OA, Horikawa I, Zimonjic DB, Popescu NC, Bonner WM, Barrett JC. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol 2004; 6 (02) 168-170
- 60 Wang C, Jurk D, Maddick M, Nelson G, Martin-Ruiz C, von Zglinicki T. DNA damage response and cellular senescence in tissues of aging mice. Aging Cell 2009; 8 (03) 311-323
- 61 Chen QM, Prowse KR, Tu VC, Purdom S, Linskens MH. Uncoupling the senescent phenotype from telomere shortening in hydrogen peroxide-treated fibroblasts. Exp Cell Res 2001; 265 (02) 294-303
- 62 Nogueira V, Park Y, Chen CC. , et al. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 2008; 14 (06) 458-470
- 63 el Sayed F, Bazex J, Cathala J, Viraben R, Bouissou X, Gorguet B. Fixed pigmented erythema caused by chlormezanone [in French]. Ann Dermatol Venereol 1992; 119 (09) 671-672
- 64 van Deursen JM. The role of senescent cells in ageing. Nature 2014; 509 (7501): 439-446
- 65 Blagosklonny MV. Cell senescence and hypermitogenic arrest. EMBO Rep 2003; 4 (04) 358-362
- 66 Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997; 88 (05) 593-602
- 67 Trost TM, Lausch EU, Fees SA. , et al. Premature senescence is a primary fail-safe mechanism of ERBB2-driven tumorigenesis in breast carcinoma cells. Cancer Res 2005; 65 (03) 840-849
- 68 Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G. DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation. Mol Biol Cell 2006; 17 (04) 1583-1592
- 69 Alimonti A, Nardella C, Chen Z. , et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J Clin Invest 2010; 120 (03) 681-693
- 70 Deng Q, Liao R, Wu BL, Sun P. High intensity ras signaling induces premature senescence by activating p38 pathway in primary human fibroblasts. J Biol Chem 2004; 279 (02) 1050-1059
- 71 Takahashi A, Ohtani N, Yamakoshi K. , et al. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat Cell Biol 2006; 8 (11) 1291-1297
- 72 Meng L, Quezada M, Levine P. , et al. Functional role of cellular senescence in biliary injury. Am J Pathol 2015; 185 (03) 602-609
- 73 Sato K, Glaser S, Kennedy L. , et al. Preclinical insights into cholangiopathies: disease modeling and emerging therapeutic targets. Expert Opin Ther Targets 2019; 23 (06) 461-472
- 74 Verma S, Tachtatzis P, Penrhyn-Lowe S. , et al. Sustained telomere length in hepatocytes and cholangiocytes with increasing age in normal liver. Hepatology 2012; 56 (04) 1510-1520
- 75 Sasaki M, Ikeda H, Yamaguchi J, Nakada S, Nakanuma Y. Telomere shortening in the damaged small bile ducts in primary biliary cirrhosis reflects ongoing cellular senescence. Hepatology 2008; 48 (01) 186-195
- 76 Tabibian JH, O'Hara SP, Splinter PL, Trussoni CE, LaRusso NF. Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis. Hepatology 2014; 59 (06) 2263-2275
- 77 Fontana L, Partridge L, Longo VD. Extending healthy life span--from yeast to humans. Science 2010; 328 (5976): 321-326
- 78 Kenyon CJ. The genetics of ageing. Nature 2010; 464 (7288): 504-512
- 79 Barzilai N, Huffman DM, Muzumdar RH, Bartke A. The critical role of metabolic pathways in aging. Diabetes 2012; 61 (06) 1315-1322
- 80 Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun 2014; 5: 3557
- 81 Mattison JA, Roth GS, Beasley TM. , et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 2012; 489 (7415): 318-321
- 82 Houtkooper RH, Williams RW, Auwerx J. Metabolic networks of longevity. Cell 2010; 142 (01) 9-14
- 83 Sahin E, DePinho RA. Axis of ageing: telomeres, p53 and mitochondria. Nat Rev Mol Cell Biol 2012; 13 (06) 397-404
- 84 Wang K, Klionsky DJ. Mitochondria removal by autophagy. Autophagy 2011; 7 (03) 297-300
- 85 Szarc vel Szic K, Declerck K, Vidaković M, Vanden Berghe W. From inflammaging to healthy aging by dietary lifestyle choices: is epigenetics the key to personalized nutrition?. Clin Epigenetics 2015; 7: 33
- 86 Giunta S. Exploring the complex relations between inflammation and aging (inflamm-aging): anti-inflamm-aging remodelling of inflammaging, from robustness to frailty. Inflamm Res 2008; 57 (12) 558-563
- 87 Bonomini F, Rodella LF, Rezzani R. Metabolic syndrome, aging and involvement of oxidative stress. Aging Dis 2015; 6 (02) 109-120
- 88 Cogger VC, Svistounov D, Warren A. , et al. Liver aging and pseudocapillarization in a Werner syndrome mouse model. J Gerontol A Biol Sci Med Sci 2014; 69 (09) 1076-1086
- 89 Cogger VC, Warren A, Fraser R, Ngu M, McLean AJ, Le Couteur DG. Hepatic sinusoidal pseudocapillarization with aging in the non-human primate. Exp Gerontol 2003; 38 (10) 1101-1107
- 90 Mohamad M, Mitchell SJ, Wu LE. , et al. Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age-related insulin resistance. Aging Cell 2016; 15 (04) 706-715
- 91 Basso A, Piantanelli L, Rossolini G, Roth GS. Reduced DNA synthesis in primary cultures of hepatocytes from old mice is restored by thymus grafts. J Gerontol A Biol Sci Med Sci 1998; 53 (02) B111-B116
- 92 Blokker BA, Maijo M, Echeandia M. , et al. Fine-tuning of sirtuin 1 expression is essential to protect the liver from cholestatic liver disease. Hepatology 2019; 69 (02) 699-716
- 93 Ramirez T, Li YM, Yin S. , et al. Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression. J Hepatol 2017; 66 (03) 601-609
- 94 Lazzerini Denchi E, Celli G, de Lange T. Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication. Genes Dev 2006; 20 (19) 2648-2653
- 95 Lin S, Nascimento EM, Gajera CR. , et al. Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury. Nature 2018; 556 (7700): 244-248
- 96 Daum B, Walter A, Horst A, Osiewacz HD, Kühlbrandt W. Age-dependent dissociation of ATP synthase dimers and loss of inner-membrane cristae in mitochondria. Proc Natl Acad Sci U S A 2013; 110 (38) 15301-15306
- 97 Hagen TM, Yowe DL, Bartholomew JC. , et al. Mitochondrial decay in hepatocytes from old rats: membrane potential declines, heterogeneity and oxidants increase. Proc Natl Acad Sci U S A 1997; 94 (07) 3064-3069
- 98 Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 2017; 14 (07) 397-411
- 99 Maeso-Díaz R, Ortega-Ribera M, Fernández-Iglesias A. , et al. Effects of aging on liver microcirculatory function and sinusoidal phenotype. Aging Cell 2018; 17 (06) e12829
- 100 Marcos R, Lopes C, Malhão F. , et al. Stereological assessment of sexual dimorphism in the rat liver reveals differences in hepatocytes and Kupffer cells but not hepatic stellate cells. J Anat 2016; 228 (06) 996-1005
- 101 Warren A, Cogger VC, Fraser R, Deleve LD, McCuskey RS, Le Couteur DG. The effects of old age on hepatic stellate cells. Curr Gerontol Geriatr Res 2011; 2011: 439835
- 102 Hunt NJ, Kang SWS, Lockwood GP, Le Couteur DG, Cogger VC. Hallmarks of aging in the liver. Comput Struct Biotechnol J 2019; 17: 1151-1161
- 103 McDaniel K, Meng F, Wu N. , et al. Forkhead box A2 regulates biliary heterogeneity and senescence during cholestatic liver injury in mice. Hepatology 2017; 65 (02) 544-559
- 104 Tabibian JH, Macura SI, O'Hara SP. , et al. Micro-computed tomography and nuclear magnetic resonance imaging for noninvasive, live-mouse cholangiography. Lab Invest 2013; 93 (06) 733-743
- 105 Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Modulation of the microenvironment by senescent biliary epithelial cells may be involved in the pathogenesis of primary biliary cirrhosis. J Hepatol 2010; 53 (02) 318-325
- 106 Aravinthan AD, Alexander GJM. Senescence in chronic liver disease: Is the future in aging?. J Hepatol 2016; 65 (04) 825-834
- 107 Zhou T, Wu N, Meng F. , et al. Knockout of secretin receptor reduces biliary damage and liver fibrosis in Mdr2−/− mice by diminishing senescence of cholangiocytes. Lab Invest 2018; 98 (11) 1449-1464
- 108 Wu N, Meng F, Zhou T. , et al. The secretin/secretin receptor axis modulates ductular reaction and liver fibrosis through changes in transforming growth factor-β1-mediated biliary senescence. Am J Pathol 2018; 188 (10) 2264-2280
- 109 Wan Y, Meng F, Wu N. , et al. Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells. Hepatology 2017; 66 (02) 528-541
- 110 Pasciu D, Montisci S, Greco M. , et al. Aging is associated with increased clonogenic potential in rat liver in vivo. Aging Cell 2006; 5 (05) 373-377
- 111 Marongiu F, Serra MP, Doratiotto S. , et al. Aging promotes neoplastic disease through effects on the tissue microenvironment. Aging (Albany NY) 2016; 8 (12) 3390-3399
- 112 Marongiu F, Serra MP, Fanti M, Cadoni E, Serra M, Laconi E. Regenerative medicine: shedding light on the link between aging and cancer. Cell Transplant 2017; 26 (09) 1530-1537
- 113 Serra M, Marongiu F, Pisu MG, Serra M, Laconi E. Time-restricted feeding delays the emergence of the age-associated, neoplastic-prone tissue landscape. Aging (Albany NY) 2019; 11 (11) 3851-3863
- 114 Gokarn R, Solon-Biet SM, Cogger VC. , et al. Long-term dietary macronutrients and hepatic gene expression in aging mice. J Gerontol A Biol Sci Med Sci 2018; 73 (12) 1618-1625
- 115 Derous D, Mitchell SE, Wang L. , et al. The effects of graded levels of calorie restriction: XI. Evaluation of the main hypotheses underpinning the life extension effects of CR using the hepatic transcriptome. Aging (Albany NY) 2017; 9 (07) 1770-1824
- 116 Timchenko NA. Aging and liver regeneration. Trends Endocrinol Metab 2009; 20 (04) 171-176
- 117 Wang GL, Salisbury E, Shi X, Timchenko L, Medrano EE, Timchenko NA. HDAC1 cooperates with C/EBPalpha in the inhibition of liver proliferation in old mice. J Biol Chem 2008; 283 (38) 26169-26178
- 118 Jin J, Iakova P, Jiang Y, Medrano EE, Timchenko NA. The reduction of SIRT1 in livers of old mice leads to impaired body homeostasis and to inhibition of liver proliferation. Hepatology 2011; 54 (03) 989-998
- 119 Wieland A, Frank DN, Harnke B, Bambha K. Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2015; 42 (09) 1051-1063
- 120 Mariat D, Firmesse O, Levenez F. , et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol 2009; 9: 123
- 121 Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Nageshwar Reddy D. Role of the normal gut microbiota. World J Gastroenterol 2015; 21 (29) 8787-8803
- 122 Maroni L, Pinto C, Giordano DM. , et al. Aging-related expression of Twinfilin-1 regulates cholangiocyte biological response to injury. Hepatology 2019; 70 (03) 883-898