Abstract
Introduction: Aging is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases such as Alzheimer’s Disease (AD). AD is a progressive degenerative disorder of the brain and is the most common form of dementia.
Methods: To-date no simple, inexpensive and minimally invasive procedure is available to confirm with certainty the early diagnosis of AD prior to the manifestations of symptoms characteristic of the disease. Therefore, if population screening of individuals is to be performed, easily accessible tissues would need to be used for a diagnostic test that would identify those who exhibit altered or aberrant aging profiles that may be indicative of AD risk, so that they can be prioritized for primary prevention. This need for minimally invasive tests could be achieved by targeting saliva, since it is now well recognized that many aging diseases including AD are associated with peripheral biomarkers that are not only restricted to pathology and biomarkers within the brain.
Results: Therefore, the aim of this review is to summarize some of the main findings of salivary biomarkers of aging and AD; including various proteins, metabolites, and alterations to DNA and miRNA. The future of healthy aging resides in innovative platforms, biosensors and point-of-care devices that can extract real time information on the health status of an individual. Those platforms may be achieved through the development and validation of novel biomarkers of health using saliva which, although being the least explored for biomedical purposes, has the distinct advantage that it can be self-collected in a non-invasive manner.
Keywords: Saliva, biomarkers, aging, Alzheimer's disease, proteomics, non-invasive diagnostic.
[1]
Loo JA, Yan W, Ramachandran P, Wong DT. Comparative human salivary and plasma proteomes. J Dent Res 89(10): 1016-23. (2010).
[2]
Hamano Y, Manabe S, Morimoto C, Fujimoto S, Tamaki K. Forensic age prediction for saliva samples using methylation-sensitive high resolution melting: exploratory application for cigarette butts. Sci Rep 7(1): 10444. (2017).
[3]
Kuwayama K, Miyaguchi H, Yamamuro T, Tsujikawa K, Kanamori T, Iwata YT, et al. Effectiveness of saliva and fingerprints as alternative specimens to urine and blood in forensic drug testingDrug Test Anal 2016 8(7): 644-51 (2016).
[4]
Sundberg I, Ramklint M, Stridsberg M, Papadopoulos FC, Ekselius L, Cunningham JL. Salivary melatonin in relation to depressive symptom severity in young adults. PLoS 11(4): e0152814. (2016).
[5]
Smith CH, Boland B, Daureeawoo Y, Donaldson E, Small K, Tuomainen J. Effect of aging on stimulated salivary flow in adults. J Am Geriatr Soc 61(5): 805-8. (2013).
[7]
Carro E, Bartolome F, Bermejo-Pareja F, Villarejo-Galende A, Molina JA, Ortiz P, et al. Early diagnosis of mild cognitive impairment and Alzheimer’s disease based on salivary lactoferrin. Alzheimers Dement (Amst) 8: 131-8. (2017).
[8]
Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 153(6): 1194-217. (2013).
[9]
Quach A, Levine ME, Tanaka T, Lu AT, Chen BH, Ferrucci L, et al. Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging 9(2): 419-46. (2017).
[10]
Blackburn EH, Epel ES, Lin J. Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science 350(6265): 1193-8. (2015).
[11]
Noren Hooten N, Fitzpatrick M, Wood WH 3rd, De S, Ejiogu N, Zhang Y, et al. Age-related changes in microRNA levels in serum. Aging 5(10): 725-40. (2013).
[13]
Lapham K, Kvale MN, Lin J, Connell S, Croen LA, Dispensa BP, et al. Automated assay of telomere length measurement and informatics for 100,000 subjects in the genetic epidemiology research on adult health and aging (GERA) cohort. Genetics 200(4): 1061-72. (2015).
[14]
Brown L, Zhang Y, Mitchel C, Ailshire J. Does telomere length indicate biological, physical and cognitive health among older adults? evidence from the health and retirement study. J Gerontol A Biol Sci Med Sci (2018).
[http://dx.doi.org/10.1093/gerona/gly001]
[http://dx.doi.org/10.1093/gerona/gly001]
[15]
Levine ME, Lu AT, Chen BH, Hernandez DG, Singleton AB, Ferrucci L, et al. Menopause accelerates biological aging. Proc Natl Acad Sci USA 113(33): 9327-32. (2016).
[16]
Jovanovic T, Vance LA, Cross D, Knight AK, Kilaru V, Michopoulos V, et al. Exposure to violence accelerates epigenetic aging in children. Sci Rep 7(1): 8962. (2017).
[17]
Soares Bispo Santos Silva D, Antunes J, Balamurugan K, Duncan G, Sampaio Alho C, McCord B. Evaluation of DNA methylation markers and their potential to predict human aging. Electrophoresis 36(15): 1775-80. (2015).
[18]
Alghanim H, Antunes J, Silva DSBS, Alho CS, Balamurugan K, McCord B. Detection and evaluation of DNA methylation markers found at SCGN and KLF14 loci to estimate human age. Forensic Sci Int Genet 31: 81-8. (2017).
[19]
Park JL, Kwon OH, Kim JH, Yoo HS, Lee HC, Woo KM, et al. Identification of body fluid-specific DNA methylation markers for use in forensic science. Forensic Sci Int Genet 13: 147-53. (2014).
[20]
Bocklandt S, Lin W, Sehl ME, Sanchez FJ, Sinsheimer JS, Horvath S, et al. Epigenetic predictor of age. PLoS One 6(6): e14821. (2011).
[21]
Gopalan S, Carja O, Fagny M, Patin E, Myrick JW, McEwen LM, et al. Trends in DNA methylation with age replicate across diverse human populations. Genetics 206(3): 1659-74. (2017).
[22]
Horvath S, Gurven M, Levine ME, Trumble BC, Kaplan H, Allayee H, et al. An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biol 17(1): 171. (2016).
[23]
Chang WI, Chang JY, Kim YY, Lee G, Kho HS. MUC1 expression in the oral mucosal epithelial cells of the elderly. Arch Oral Biol 56(9): 885-90. (2011).
[24]
Wang Z, Wang Y, Liu H, Che Y, Xu YEL. Age-related variations of protein carbonyls in human saliva and plasma: is saliva protein carbonyls an alternative biomarker of aging? Age (Dordr) 37(3): 9781. (2015).
[25]
Ambatipudi KS, Lu B, Hagen FK, Melvin JE, Yates JR. Quantitative analysis of age specific variation in the abundance of human female parotid salivary proteins. J Proteome Res 8(11): 5093-102. (2009).
[26]
He X, He L, Hannon GJ. The guardian’s little helper: microRNAs in the p53 tumor suppressor network. Cancer Res 67(23): 11099-101. (2007).
[27]
Chen LH, Chiou GY, Chen YW, Li HY, Chiou SH. MicroRNA and aging: a novel modulator in regulating the aging network. Ageing Res Rev 9(1): S59-66. (2010).
[28]
Bahn JH, Zhang Q, Li F, Chan TM, Lin X, Kim Y, et al. The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clin Chem 61(1): 221-30. (2015).
[29]
Machida T, Tomofuji T, Ekuni D, Maruyama T, Yoneda T, Kawabata Y, et al. MicroRNAs in salivary exosome as potential biomarkers of aging. Int J Mol Sci 16(9): 21294-309. (2015).
[30]
Jin XF, Wu N, Wang L, Li J. Circulating microRNAs: a novel class of potential biomarkers for diagnosing and prognosing central nervous system diseases. Cell Mol Neurobiol 33(5): 601-13. (2013).
[31]
Alzheimer's Association. 2016 Alzheimer's disease facts and figures Alzheimers Dement 12(4): 459-509. (2016).
[32]
Francois M, Fenech MF, Thomas P, Hor M, Rembach A, Martins RN, et al. High content, multi-parameter analyses in buccal cells to identify Alzheimer’s disease. Curr Alzheimer Res 13(7): 787-99. (2016).
[33]
Leifert WR, Nguyen T, Rembach A, Martins R, Rainey-Smith S, Masters CL, et al. Buccal cell cytokeratin 14 correlates with multiple blood biomarkers of Alzheimer’s disease risk. J Alzheimers Dis 48(2): 443-52. (2015).
[34]
Leifert WR, Tuli JF, Francois M, Nguyen T, Rembach A, Rumble RL, et al. Buccal cell cytokeratin 14 identifies mild cognitive impairment and Alzheimer’ s disease in the AIBL study of aging. Curr Alzheimer Res 12(3): 233-41. (2015).
[35]
Francois M, Leifert W, Hecker J, Faunt J, Martins R, Thomas P, et al. Altered cytological parameters in buccal cells from individuals with mild cognitive impairment and Alzheimer’s disease. Cytometry A 85A(8): 698-708. (2014).
[36]
Francois M, Leifert W, Martins R, Thomas P, Fenech M. Biomarkers of Alzheimer’s disease risk in peripheral tissues; focus on buccal cells. Curr Alzheimer Res 11: 519-31. (2014).
[37]
Choromanska M, Klimiuk A, Kostecka-Sochon P, Wilczynska K, Kwiatkowski M, Okuniewska N, et al. Antioxidant defence, oxidative stress and oxidative damage in saliva, plasma and erythrocytes of dementia patients. can salivary AGE be a marker of dementia? Int J Mol Sci 18(10): E2205. (2017).
[38]
Tsuruoka M, Hara J, Hirayama A, Sugimoto M, Soga T, Shankle WR, et al. Capillary electrophoresis-mass spectrometry-based metabolome analysis of serum and saliva from neurodegenerative dementia patients. Electrophoresis 34(19): 2865-72. (2013).
[39]
Figueira J, Jonsson P, Nordin Adolfsson A, Adolfsson R, Nyberg L, Ohman A. NMR analysis of the human saliva metabolome distinguishes dementia patients from matched controls. Mol Biosyst 12(8): 2562-71. (2016).
[40]
Kwan RYC, Leung MCP, Lai CKY. A randomized controlled trial examining the effect of acupressure on agitation and salivary cortisol in nursing home residents with dementia. Dement Geriatr Cogn Disord 44(1-2): 92-104. (2017).
[41]
Boston PF, Gopalkaje K, Manning L, Middleton L, Loxley M. Developing a simple laboratory test for Alzheimer’s disease: measuring acetylcholinesterase in saliva - a pilot study. Int J Geriatr Psychiatry 23(4): 439-40. (2008).
[42]
Lau HC, Lee IK, Ko PW, Lee HW, Huh JS, Cho WJ, et al. Non-invasive screening for Alzheimer’s disease by sensing salivary sugar using Drosophila cells expressing gustatory receptor (Gr5a) immobilized on an extended gate ion-sensitive field-effect transistor (EG-ISFET) biosensor. PLoS One 10(2): e0117810. (2015).
[43]
Bermejo-Pareja F, Antequera D, Vargas T, Molina JA, Carro E. Saliva levels of Abeta1-42 as potential biomarker of Alzheimer’s disease: a pilot study. BMC Neurol 10: 108. (2010).
[44]
Farah R, Haraty H, Salame Z, Fares Y, Ojcius DM, Said Sadier N. Salivary biomarkers for the diagnosis and monitoring of neurological diseases. Biomed J 41(2): 63-87. (2018).
[45]
Atik A, Stewart T, Zhang J. Alpha-synuclein as a biomarker for Parkinson’s disease. Brain Pathol 26(3): 410-8. (2016).
[46]
Song W, Kothari V, Velly AM, Cressatti M, Liberman A, Gornitsky M, et al. Evaluation of salivary heme oxygenase-1 as a potential biomarker of early Parkinson’s disease. Mov Disord 33(4): 583-91. (2018).
[47]
Khurshid Z, Zafar MS, Khan RS, Najeeb S, Slowey PD, Rehman IU. Role of salivary biomarkers in oral cancer detection. Adv Clin Chem 86: 23-70. (2018).
[48]
Lira-Junior R, Akerman S, Klinge B, Bostrom EA, Gustafsson A. Salivary microbial profiles in relation to age, periodontal, and systemic diseases. PLoS One 13(3): e0189374. (2018).
[49]
Zhang CZ, Cheng XQ, Li JY, Zhang P, Yi P, Xu X, et al. Saliva in the diagnosis of diseases. Int J Oral Sci 8(3): 133-7. (2016).
[50]
Southwick PC, Yamagata SK, Echols CL Jr, Higson GJ, Neynaber SA, Parson RE, et al. Assessment of amyloid beta protein in cerebrospinal fluid as an aid in the diagnosis of Alzheimer’s disease. J Neurochem 66(1): 259-65. (1996).
[51]
Lee M, Guo JP, Kennedy K, McGeer EG, McGeer PL. A method for diagnosing Alzheimer’s disease based on salivary amyloid-beta protein 42 levels. J Alzheimers Dis 55(3): 1175-82. (2017).
[52]
Lee SL, Thomas P, Hecker J, Faunt J, Fenech M. Chromosomal DNA damage measured using the cytokinesis-block micronucleus cytome assay is significantly associated with cognitive impairment in South Australians. Environ Mol Mutagen 56(1): 32-40. (2015).
[53]
Kim CB, Choi YY, Song WK, Song KB. Antibody-based magnetic nanoparticle immunoassay for quantification of Alzheimer’s disease pathogenic factor. J Biomed Opt 19(5): 051205. (2014).
[54]
Shi M, Sui YT, Peskind ER, Li G, Hwang H, Devic I, et al. Salivary tau species are potential biomarkers of Alzheimer’s disease. J Alzheimers Dis 27(2): 299-305. (2011).
[55]
Olsson B, Lautner R, Andreasson U, Ohrfelt A, Portelius E, Bjerke M, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol 15(7): 673-84. (2016).
[56]
Prvulovic D, Hampel H. Amyloid beta (Abeta) and phospho-tau (p-tau) as diagnostic biomarkers in Alzheimer’s disease. Clin Chem Lab Med 49(3): 367-74. (2011).
[57]
Ashton NJ, Ide M, Scholl M, Blennow K, Lovestone S, Hye A, et al. No association of salivary total tau concentration with Alzheimer’s disease. Neurobiol Aging 70: 125-7. (2018).
[58]
Conrad C, Vianna C, Freeman M, Davies P. A polymorphic gene nested within an intron of the tau gene: implications for Alzheimer’s disease. Proc Natl Acad Sci USA 99(11): 7751-6. (2002).
[59]
Hattori H, Matsumoto M, Iwai K, Tsuchiya H, Miyauchi E, Takasaki M, et al. The tau protein of oral epithelium increases in Alzheimer’s disease. J Gerontol A Biol Sci Med Sci 57(1): M64-70. (2002).
[60]
Kamer AR, Craig RG, Dasanayake AP, Brys M, Glodzik-Sobanska L, de Leon MJ. Inflammation and Alzheimer’s disease: possible role of periodontal diseases. Alzheimers Dement 4(4): 242-50. (2008).
[61]
Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 73(10): 768-74. (2009).
[62]
Sayer R, Law E, Connelly PJ, Breen KC. Association of a salivary acetylcholinesterase with Alzheimer’s disease and response to cholinesterase inhibitors. Clin Biochem 37(2): 98-104. (2004).
[63]
Bakhtiari S, Moghadam NB, Ehsani M, Mortazavi H, Sabour S, Bakhshi M. Can salivary acetylcholinesterase be a diagnostic biomarker for Alzheimer? J Clin Diagn Res 11(1): ZC58-60. (2017).
[64]
Alberini CM. Unwind: chronic stress exacerbates the deficits of Alzheimer’s disease. Biol Psychiatry 65(11): 916-7. (2009).
[65]
Pietrzak RH, Laws SM, Lim YY, Bender SJ, Porter T, Doecke J, et al. Plasma cortisol, brain amyloid-beta, and cognitive decline in preclinical Alzheimer’s disease: a 6-year prospective cohort study. Biol Psychiatry Cogn Neurosci Neuroimaging 2(1): 45-52. (2017).
[66]
Hatfield CF, Herbert J, van Someren EJ, Hodges JR, Hastings MH. Disrupted daily activity/rest cycles in relation to daily cortisol rhythms of home-dwelling patients with early Alzheimer’s dementia. Brain 127(Pt 5): 1061-74. (2004).
[67]
Giubilei F, Patacchioli FR, Antonini G, Sepe Monti M, Tisei P, Bastianello S, et al. Altered circadian cortisol secretion in Alzheimer’s disease: clinical and neuroradiological aspects. J Neurosci Res 66(2): 262-5. (2001).
[68]
Venturelli M, Sollima A, Ce E, Limonta E, Bisconti AV, Brasioli A, et al. Effectiveness of exercise- and cognitive-based treatments on salivary cortisol levels and sundowning syndrome symptoms in patients with alzheimer’s disease. J Alzheimers Dis 53(4): 1631-40. (2016).
[69]
Norton MC, Smith KR, Ostbye T, Tschanz JT, Corcoran C, Schwartz S, et al. Greater risk of dementia when spouse has dementia? The Cache County study. J Am Geriatr Soc 58(5): 895-900. (2010).
[70]
de la Rubia Orti JE, Sancho Castillo S, Benlloch M, Julian Rochina M, Corchon Arreche S, Garcia-Pardo MP. Impact of the relationship of stress and the immune system in the appearance of alzheimer’s Disease. J Alzheimers Dis 55(3): 899-903. (2017).
[71]
Wolf OT, Convit A, Thorn E, de Leon MJ. Salivary cortisol day profiles in elderly with mild cognitive impairment. Psychoneuroendocrinology 27(7): 777-89. (2002).
[72]
Cox SR, Valdes Hernandez MDC, Kim J, Royle NA, MacPherson SE, Ferguson KJ, et al. Associations between hippocampal morphology, diffusion characteristics, and salivary cortisol in older men. Psychoneuroendocrinology 78: 151-8. (2017).
[73]
Kovach CR, Woods DL, Logan BR, Raff H. Diurnal variation of cortisol in people with dementia: relationship to cognition and illness burden. Am J Alzheimers Dis Other Demen 26(2): 145-50. (2011).
[74]
Ouanes S, Castelao E, Gebreab S, von Gunten A, Preisig M, Popp J. Life events, salivary cortisol, and cognitive performance in nondemented subjects: a population-based study. Neurobiol Aging 51: 1-8. (2017).
[75]
Kwan RY, Leung MC, Lai CK. The effect of acupressure on agitation and salivary cortisol in people with dementia: a pilot study. J Altern Complement Med 22(11): 903-10. (2016).
[76]
Kwan RYC, Leung MCP, Lai CKY. Acupressure for managing agitation in people with dementia: design of a protocol using the delphi technique. Complement Med Res 24(2): 104-9. (2017).
[77]
Yilmaz A, Geddes T, Han B, Bahado-Singh RO, Wilson GD, Imam K, et al. Diagnostic biomarkers of alzheimer’s disease as identified in saliva using 1h nmr-based metabolomics. J Alzheimers Dis 58(2): 355-9. (2017).
[78]
Wang J, Schipper HM, Velly AM, Mohit S, Gornitsky M. Salivary biomarkers of oxidative stress: acritical review. Free Radic Biol Med 85: 95-104. (2015).
[79]
Banasova L, Kamodyova N, Jansakova K, Tothova L, Stanko P, Turna J, et al. Salivary DNA and markers of oxidative stress in patients with chronic periodontitis. Clin Oral Investig 19(2): 201-7. (2015).
[80]
Villa-Correa YA, Isaza-Guzman DM, Tobon-Arroyave SI. Prognostic value of 8-hydroxy-2′-deoxyguanosine and human neutrophil elastase/alpha1-proteinase inhibitor complex as salivary biomarkers of oxidative stress in chronic periodontitis. J Periodontol 86(11): 1260-7. (2015).
Related Books
Frontiers in Clinical Drug Research - CNS and Neurological Disorders
Frontiers in Clinical Drug Research - CNS and Neurological Disorders
Frontiers in Clinical Drug Research - CNS and Neurological Disorders
Frontiers in Clinical Drug Research-Dementia
Frontiers in Clinical Drug Research - CNS and Neurological Disorders
Article Metrics
97
15
1