Presbyacusis: Pathophysiology, Immunosenescence and Inflammaging: Comparison
Please note this is a comparison between Version 1 by Srdjan M. Vlajkovic and Version 3 by Camila Xu.

Age-related hearing loss (ARHL), or presbyacusis, is a type of sensorineural hearing loss that primarily affects the elderly. However, the age of onset, rate of decline, and severity of hearing loss vary widely. This article is a narrative review of the association between As a rRHL, immune system ageing (immunosenescence), and chronic inflammation (inflammaging). As a result of ageing, the immune system can become defective, leading to the accumulation of unresolved inflammatory processes in the body. Various stimuli can sustain inflammaging, including pathogens, cell debris, nutrients, and gut microbiota. We postulate that inflammaging accelerates age-related cochlear degeneration, thus contributing to the development of ARHL.

  • age-related hearing loss
  • presbyacusis
  • immunosenescence
  • inflammaging
  • chronic inflammation

1. Introduction

Age-related hearing loss (ARHL), or presbyacusis, is a type of sensorineural hearing loss that primarily affects the elderly [1]. However, the age of onset, rate of decline, and severity of hearing loss vary widely.
ARHL is the most common sensory disorder, with a high economic impact [2][3]. The World Health Organization (WHO) estimates that by 2050, 2.5 billion people, predominantly over 60, will be living with some degree of hearing loss [4][5]. Despite the high prevalence of this sensory disorder, there is a paucity of both preventative and treatment strategies other than prosthetic devices (hearing aids and cochlear implants).
Presbyacusis typically presents as bilateral, progressive, and irreversible [6][7]. The increasing prevalence of presbyacusis may be attributable to environmental factors, notably noise exposure and the rise in metabolic diseases [8][9][10].
This sensory disorder can be characterised by reduced hearing sensitivity and speech understanding in background noise, slowed central processing of acoustic information, and impaired localisation of sound sources [7]. Hearing loss affects high frequencies initially and eventually spreads to lower frequencies involved in speech understanding [7]. Untreated hearing impairment contributes to social isolation, loss of self-esteem, depression, and cognitive decline [11][12][13]. Even mild levels of hearing loss increase the long-term risk of cognitive decline and dementia [14].
ARHL has a complex pathophysiology linked to genetic risk factors that determine the rate and extent of cochlear degeneration. However, the severity of the hearing loss is also influenced by previous otological diseases, chronic illnesses, cumulative noise exposure, use of ototoxic drugs, and lifestyle [15]. Moreover, this condition has been associated with numerous comorbidities, including dementia, frailty, Alzheimer’s disease, and type II diabetes [16][17][18][19][20]. A common trait of these disorders is chronic inflammation in target organs [21]. More recently, changes in gut microbiota have been linked to systemic inflammation affecting multiple organ systems, including the brain and the inner ear [22][23][24].

2. Pathophysiology of Age-Related Hearing Loss

Age-related hearing loss has mixed aetiology [7] and is likely a cumulative result of genetic and epigenetic factors [8][25][26][27] and environmental stressors [28]. Otological diseases, chronic exposure to noise, smoking, or exposure to ototoxic drugs can contribute to the development of ARHL [29][30]. Other factors include diet, gender, comorbidities, and lifestyle [20][31]. Reduced vascularisation in the cochlea, cumulative oxidative stress (OS), low-grade cochlear inflammation, impaired mitochondrial quality control, and mitochondrial DNA damage play a critical role in developing ARHL [8][32]. Age-related degenerative changes in the cochlea can lead to a loss of sensory hair cells and primary auditory neurons, damage to cochlear lateral wall tissues (stria vascularis and spiral ligament), and reduced vascularisation [29][33]. Post-mortem histological studies in the human cochlea have revealed sensory hair cell loss in the organ of Corti (OoC), degenerative changes in the auditory nerve, atrophy of the stria vascularis (SV), and loss of fibrocytes in the spiral ligament (SL) [20][34][35][36]. More recent studies have demonstrated a loss of auditory nerve afferent fibres in the cochlea and synapses between the inner hair cells and type I afferent fibres [37][38]. The ageing process also negatively affects the central auditory pathways [20]. Based on predominant histopathological findings and differences in pure-tone audiometric testing, Schuknetcht et al. proposed classifying ARHL into sensory, neural, strial, and cochlear conductive types [34][35][39]. Many people with ARHL likely have a mixed pathology, but in some cases, the cause of ARHL cannot be determined by histological evaluation of cochlear tissues [40]. At present, ARHL has not been fully reproduced in animal models. However, these models are often used to delineate human pathophysiology, as clinical studies are challenging due to cochlear localisation deep in the temporal bone, precluding histological and high-resolution imaging studies [20]. In animal studies, vascular changes include reduced capillary network and narrowing of the vascular lumen in the SV [41][42][43]. The secretory epithelium of the SV is responsible for maintaining the high potassium (K+) content of the endolymph and generation of the endocochlear potential (EP), which drives sensory transduction in the cochlea [44][45][46]. The SV typically deteriorates in the mid-cochlear to apical regions and is associated with reduced expression levels and activity of sodium-potassium pumps (Na-K-2Cl cotransporter NKCC1 and Na+, K+-ATPase), which leads to reduced EP [47][48][49][50][51][52][53][54]. Reduced activity of sodium-potassium pumps and decreased EP have been demonstrated in ageing gerbils raised in quiet and ageing mice [44][55]. The mouse is a robust and reliable mammalian model for ageing research, and the use of inbred mouse strains was instrumental in investigating the genetics of ARHL. For example, the commonly used C57BL/6 mouse strain develops progressive high-frequency hearing loss caused by a mutation of the cadherin 23 (Cdh23) gene, which encodes a component of the stereocilial tip-link required for gating of the mechanoelectrical transducer (MET) channel in sensory hair cells [56]. Elevated auditory thresholds in ARHL typically result from degeneration and loss of outer hair cells within the OoC. The loss of hair cells progresses from the basal turn of the cochlea (high-frequency region) to the apical turn (low-frequency region) [32]. Degenerative changes also affect synaptic networks between the inner hair cells and afferent auditory nerve fibres, which leads to reduced speech understanding in background noise [57][58][59].

3. Immunosenescence and Inflammaging

Immunosenescence is an age-dependent development of immune dysfunction that involves lymphoid organ remodelling, leading to reduced capacity to control inflammatory cytokines during and after the immune response. Immunosenescence can lead to chronic inflammation in ageing tissues, frequent infections, autoimmune diseases, and cancer due to impaired immune surveillance [21][60][61][62][63][64]. Inflammaging is a relatively new concept described as age-related, low-grade systemic inflammation that may not directly link to microbial infection [32][65]. Various stimuli, including cell debris, nutrients, and gut microbiota, can sustain inflammaging [66]. This sterile or pathogen-driven inflammation increases morbidity and mortality in the elderly [21][67][68]. As a result of ageing, the immune system becomes defective (immunosenescence), leading to the accumulation of unresolved inflammatory processes impacting otherwise healthy organ systems [69]. As a result, inflammaging can contribute to a spectrum of disorders such as Parkinson’s and Alzheimer’s disease, type II diabetes, and cardiovascular disease [70][71][72][73][74][75][76][77][78][79][80][81][82]. However, inflammaging is not a physiological or expected outcome of ageing; instead, a tell-tale of accelerated ageing [66]. Sensorineural hearing loss has also been linked with chronic inflammation [83][84][85]. Despite the historical belief that the cochlea is an immune-privileged organ [86], more recent studies have shown that the cochlea is vulnerable to systemic inflammation [22][87]. Cochlear microcirculation is controlled by tight junctions connecting vascular endothelial cells, forming the blood-labyrinth barrier (BLB) in the lateral wall [88]. The BLB plays a role in preventing pathogen infiltration, maintaining ion homeostasis, and transporting nutrients to the cochlea [89]. Pericytes and perivascular resident macrophage-like melanocytes (PVM/M) represent the second line of support for the BLB. Local inflammation activates PVM/M in the cochlea and thus increases the permeability of the BLB [90]. Furthermore, PVM/M can release proinflammatory cytokines through the tight-junction barrier [90] and increase the permeability of the BLB to the bacterial metabolite lipopolysaccharide (LPS) [88][91]. Similarly, acoustic trauma [88][92][93] and hypoxia [94] can also increase the permeability of the BLB, resulting in cochlear inflammation that predominantly affects the lateral wall tissues (SV and SL) [21][84]. It was shown that vascular cell senescence is a key factor in the breakdown of the blood-brain barrier (BBB) [95], which is physiologically and structurally equivalent to the BLB of the inner ear [22]. This suggests that vascular cell senescence may also affect the integrity and permeability of the BLB. Inflammation has been identified in multiple preclinical and population health studies as a pathophysiological mechanism contributing to ARHL [85]. For example, in the “Hertfordshire Ageing Study”, Verschuur et al. described a progressive increase in the expression of markers associated with systemic inflammation (interleukin-6, C-reactive protein, white blood cell, and neutrophil counts) in subjects with ARHL, which correlated with the elevation in hearing thresholds [63][96]. That study concluded that low-grade inflammation is at the foundation of ARHL. In the English Longitudinal Study of Ageing, Lassale et al. also demonstrated an association between white blood cell counts and age-related hearing impairment [97]. Other studies revealed changes in the number and morphology of macrophages in the ageing cochlea [98][99]. Activated macrophages were present in the lateral wall and auditory nerve and were more abundant in the cochlear basal turn of the older donors [99]. Based on these studies, an ongoing ASPREE-HEARING study was designed to investigate the benefits of low dosages of the anti-inflammatory agent aspirin on the progression of ARHL [100]. The rationale for this researchtudy is that aspirin is an inflammation resolution mediator [101], as it decreases the levels of proinflammatory mediators, including TNF-α, IL-6, and thromboxane B2 (TXB2) [102][103][104]. Preclinical studies have shown that in ageing C57BL/6J mice, the resident macrophages in the basilar membrane of the OoC change morphologically in response to sensory cell degeneration, indicating their activation [105]. This finding is consistent with the up-regulation of genes linked with immune and inflammatory responses in older murine cochleae [106]. Using next-generation sequencing, Su and collaborators [106] revealed multiple immune and inflammatory transcriptomic changes during cochlear ageing. The TNF signalling pathway, toll-like receptor signalling pathway, Jak-STAT signalling pathway, and NF-kB signalling pathway featured prominently among up-regulated genes in aged mice [106]. A senescence-associated secretory phenotype (SASP) is one of the possible factors contributing to inflammaging and associated changes in the central nervous system (CNS). It has been established that cells change their phenotype to senescence as a preventative measure for malignancies; however, these cells accumulate within tissues as the body ages [107]. Even though these cells are growth-arrested, they are still metabolically active and change protein expression primarily due to DNA damage [108]. SASP promotes local inflammation via the secretion of cytokines, chemokines, reactive oxygen and nitrogen species, and growth factors [107]. Proliferative cells of the CNS, such as endothelial and glial cells, can adopt SASP, leading to low-grade chronic inflammation in the ageing brain [109]. It was proposed that the permeability of the BBB might be affected by the build-up of SASP cells [95][110][111]. Despite the similarities between the BBB and the BLB, this aspect of senescence has yet to be established for the BLB and ARHL.

References

  1. Rivas-Chacon, L.D.M.; Martinez-Rodriguez, S.; Madrid-Garcia, R.; Yanes-Diaz, J.; Riestra-Ayora, J.I.; Sanz-Fernandez, R.; Sanchez-Rodriguez, C. Role of oxidative stress in the senescence pattern of auditory cells in age-related hearing loss. Antioxidants 2021, 10, 1497.
  2. Haile, L.M.; Kamenov, K.; Briant, P.S.; Orji, A.U.; Steinmetz, J.D.; Abdoli, A.; Abdollahi, M.; Abu-Gharbieh, E.; Afshin, A.; Ahmed, H.; et al. Hearing loss prevalence and years lived with disability, 1990–2019: Findings from the global burden of disease study 2019. Lancet 2021, 397, 996–1009.
  3. Kiely, K.M.; Mitchell, P.; Gopinath, B.; Luszcz, M.A.; Jagger, C.; Anstey, K.J. Estimating the years lived with and without age-related sensory impairment. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2016, 71, 637–642.
  4. World Health Organization. World Report on Hearing—Executive Summary; World Health Organization: Geneva, Switzerland, 2021.
  5. HCIA. The Social and Economic Cost of Hearing Loss in Australia; Deloitte Access Economics: Canberra, ACT, Australia, 2017.
  6. Kiely, K.M.; Gopinath, B.; Mitchell, P.; Luszcz, M.; Anstey, K.J. Cognitive, health, and sociodemographic predictors of longitudinal decline in hearing acuity among older adults. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2012, 67, 997–1003.
  7. Gates, G.A.; Mills, J.H. Presbycusis. Lancet 2005, 366, 1111–1120.
  8. Wang, J.; Puel, J.L. Presbycusis: An update on cochlear mechanisms and therapies. J. Clin. Med. 2020, 9, 218.
  9. Samocha-Bonet, D.; Wu, B.; Ryugo, D.K. Diabetes mellitus and hearing loss: A review. Ageing Res. Rev. 2021, 71, 101423.
  10. Horikawa, C.; Kodama, S.; Tanaka, S.; Fujihara, K.; Hirasawa, R.; Yachi, Y.; Shimano, H.; Yamada, N.; Saito, K.; Sone, H. Diabetes and risk of hearing impairment in adults: A meta-analysis. J. Clin. Endocrinol. Metab. 2013, 98, 51–58.
  11. Besser, J.; Stropahl, M.; Urry, E.; Launer, S. Comorbidities of hearing loss and the implications of multimorbidity for audiological care. Hear. Res. 2018, 369, 3–14.
  12. Dawes, P.; Emsley, R.; Cruickshanks, K.J.; Moore, D.R.; Fortnum, H.; Edmondson-Jones, M.; McCormack, A.; Munro, K.J. Hearing loss and cognition: The role of hearing AIDS, social isolation and depression. PLoS ONE 2015, 10, e0119616.
  13. Yuan, J.; Sun, Y.; Sang, S.; Pham, J.H.; Kong, W.-J. The risk of cognitive impairment associated with hearing function in older adults: A pooled analysis of data from eleven studies. Sci. Rep. 2018, 8, 2137.
  14. Livingston, G.; Sommerlad, A.; Orgeta, V.; Costafreda, S.G.; Huntley, J.; Ames, D.; Ballard, C.; Banerjee, S.; Burns, A.; Cohen-Mansfield, J.; et al. Dementia prevention, intervention, and care. Lancet 2017, 390, 2673–2734.
  15. Davis, A.; McMahon, C.M.; Pichora-Fuller, K.M.; Russ, S.; Lin, F.; Olusanya, B.O.; Chadha, S.; Tremblay, K.L. Aging and hearing health: The life-course approach. Gerontologist 2016, 56 (Suppl. S2), S256–S267.
  16. Uchida, Y.; Sugiura, S.; Nishita, Y.; Saji, N.; Sone, M.; Ueda, H. Age-related hearing loss and cognitive decline—The potential mechanisms linking the two. Auris Nasus Larynx 2019, 46, 1–9.
  17. Shen, Y.; Ye, B.; Chen, P.; Wang, Q.; Fan, C.; Shu, Y.; Xiang, M. Cognitive decline, dementia, Alzheimer’s disease and presbycusis: Examination of the possible molecular mechanism. Front. Neurosci. 2018, 12, 394.
  18. Fortunato, S.; Forli, F.; Guglielmi, V.; de Corso, E.; Paludetti, G.; Berrettini, S.; Fetoni, A.R. A review of new insights on the association between hearing loss and cognitive decline in ageing. Acta Otorhinolaryngol. Ital. 2016, 36, 155–166.
  19. Mitchell, P.; Gopinath, B.; McMahon, C.M.; Rochtchina, E.; Wang, J.J.; Boyages, S.C.; Leeder, S.R. Relationship of type 2 diabetes to the prevalence, incidence and progression of age-related hearing loss. Diabet. Med. J. Br. Diabet. Assoc. 2009, 26, 483–488.
  20. Bowl, M.R.; Dawson, S.J. Age-related hearing loss. Cold Spring Harb. Perspect. Med. 2019, 9, a033217.
  21. Watson, N.; Ding, B.; Zhu, X.; Frisina, R.D. Chronic inflammation—Inflammaging—In the ageing cochlea: A novel target for future presbycusis therapy. Ageing Res. Rev. 2017, 40, 142–148.
  22. Kociszewska, D.; Chan, J.; Thorne, P.R.; Vlajkovic, S.M. The link between gut dysbiosis caused by a high-fat diet and hearing loss. Int. J. Mol. Sci. 2021, 22, 13177.
  23. Liu, S.; Gao, J.; Zhu, M.; Liu, K.; Zhang, H.L. Gut microbiota and dysbiosis in Alzheimer’s disease: Implications for pathogenesis and treatment. Mol. Neurobiol. 2020, 57, 5026–5043.
  24. Cunningham, A.L.; Stephens, J.W.; Harris, D.A. Gut microbiota influence in type 2 diabetes mellitus (T2DM). Gut Pathog. 2021, 13, 50.
  25. Vaiserman, A.; Lushchak, O. Developmental origins of type 2 diabetes: Focus on epigenetics. Ageing Res. Rev. 2019, 55, 100957.
  26. Pal, S.; Tyler, J.K. Epigenetics and aging. Sci. Adv. 2016, 2, e1600584.
  27. Johnson, K.R.; Zheng, Q.Y. Ahl2, a second locus affecting age-related hearing loss in mice. Genomics 2002, 80, 461–464.
  28. Wang, B.; Jenkins, J.R.; Trayhurn, P. Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: Integrated response to TNF-alpha. Am. J. Physiol. Endocrinol. Metab. 2005, 288, E731–E740.
  29. Yang, C.H.; Schrepfer, T.; Schacht, J. Age-related hearing impairment and the triad of acquired hearing loss. Front. Cell. Neurosci. 2015, 9, 276.
  30. Dawes, P.; Cruickshanks, K.J.; Moore, D.R.; Edmondson-Jones, M.; McCormack, A.; Fortnum, H.; Munro, K.J. Cigarette smoking, passive smoking, alcohol consumption, and hearing loss. J. Assoc. Res. Otolaryngol. 2014, 15, 663–674.
  31. Yamasoba, T.; Lin, F.R.; Someya, S.; Kashio, A.; Sakamoto, T.; Kondo, K. Current concepts in age-related hearing loss: Epidemiology and mechanistic pathways. Hear. Res. 2013, 303, 30–38.
  32. Bazard, P.; Pineros, J.; Frisina, R.D.; Bauer, M.A.; Acosta, A.A.; Paganella, L.R.; Borakiewicz, D.; Thivierge, M.; Mannering, F.L.; Zhu, X.; et al. Cochlear inflammaging in relation to ion channels and mitochondrial functions. Cells 2021, 10, 2761.
  33. Keithley, E.M. Pathology and mechanisms of cochlear aging. J. Neurosci. Res. 2020, 98, 1674–1684.
  34. Schuknecht, H.F. Presbycusis. Laryngoscope 1955, 65, 402–419.
  35. Schuknecht, H.F.; Gacek, M.R. Cochlear pathology in presbycusis. Ann. Otol. Rhinol. Laryngol. 1993, 102, 1–16.
  36. Ohlemiller, K.K. Age-related hearing loss: The status of Schuknecht’s typology. Curr. Opin. Otolaryngol. Head Neck Surg. 2004, 12, 439–443.
  37. Viana, L.M.; O’Malley, J.T.; Burgess, B.J.; Jones, D.D.; Oliveira, C.A.; Santos, F.; Merchant, S.N.; Liberman, L.D.; Liberman, M.C. Cochlear neuropathy in human presbycusis: Confocal analysis of hidden hearing loss in post-mortem tissue. Hear. Res. 2015, 327, 78–88.
  38. Wu, P.Z.; Liberman, L.D.; Bennett, K.; de Gruttola, V.; O’Malley, J.T.; Liberman, M.C. Primary Neural degeneration in the human cochlea: Evidence for hidden hearing loss in the aging ear. Neuroscience 2019, 407, 8–20.
  39. Coppell, K.J.; Galts, C.P.; Huizing, F.Y.; Norton, J.K.; Gray, A.R.; Schultz, K.; Hobbs, C.E.; Aluzaite, K.; Schultz, M. Annual incidence and phenotypic presentation of IBD in southern New Zealand: An 18-year epidemiological analysis. Inflamm. Intest. Dis. 2018, 3, 32–39.
  40. Tu, N.C.; Friedman, R.A. Age-related hearing loss: Unraveling the pieces. Laryngoscope Investig. Otolaryngol. 2018, 3, 68–72.
  41. Carraro, M.; Harrison, R.V. Degeneration of stria vascularis in age-related hearing loss; a corrosion cast study in a mouse model. Acta Oto-Laryngol. 2016, 136, 385–390.
  42. Fetoni, A.R.; Picciotti, P.M.; Paludetti, G.; Troiani, D. Pathogenesis of presbycusis in animal models: A review. Exp. Gerontol. 2011, 46, 413–425.
  43. Gratton, M.A.; Schmiedt, R.A.; Schulte, B.A. Age-related decreases in endocochlear potential are associated with vascular abnormalities in the stria vascularis. Hear. Res. 1996, 102, 181–190.
  44. Bazard, P.; Frisina, R.D.; Acosta, A.A.; Dasgupta, S.; Bauer, M.A.; Zhu, X.; Ding, B. Roles of key ion channels and transport proteins in age-related hearing loss. Int. J. Mol. Sci. 2021, 22, 6158.
  45. Liu, H.; Li, Y.; Chen, L.; Zhang, Q.; Pan, N.; Nichols, D.H.; Zhang, W.J.; Fritzsch, B.; He, D.Z. Organ of corti and stria vascularis: Is there an interdependence for survival? PLoS ONE 2016, 11, e0168953.
  46. Takeuchi, S.; Ando, M.; Kakigi, A. Mechanism generating endocochlear potential: Role played by intermediate cells in stria vascularis. Biophys. J. 2000, 79, 2572–2582.
  47. Dallos, P.; Oertel, D. The Senses a Comprehensive Reference; Elsevier: Amsterdam, The Netherlands, 2008.
  48. Chen, J.; Zhao, H.B. The role of an inwardly rectifying K(+) channel (Kir4.1) in the inner ear and hearing loss. Neuroscience 2014, 265, 137–146.
  49. Mills, J.H.; Schmiedt, R.A.; Schulte, B.A.; Dubno, J.R. Age-related hearing loss: A loss of voltage, not hair cells. In Seminars in Hearing; Thieme Medical Publishers, Inc.: New York, NY, USA, 2006; Volume 27, pp. 228–236.
  50. Ohlemiller, K.; Frisina, R.; Schacht, J.; Popper, A.; Fay, R. Auditory Trauma, Protection, and Repair; Springer: Boston, MA, USA, 2008; pp. 145–194.
  51. Pan, C.C.; Chu, H.Q.; Lai, Y.B.; Sun, Y.B.; Du, Z.H.; Liu, Y.; Chen, J.; Tong, T.; Chen, Q.G.; Zhou, L.Q.; et al. Downregulation of inwardly rectifying potassium channel 5.1 expression in C57BL/6J cochlear lateral wall. J. Huazhong Univ. Sci. Technol. 2016, 36, 406–409.
  52. Pauler, M.; Schuknecht, H.F.; White, J.A. Atrophy of the stria vascularis as a cause of sensorineural hearing loss. Laryngoscope 1988, 98, 754–759.
  53. Schmiedt, R.A.; Lang, H.; Okamura, H.O.; Schulte, B.A. Effects of furosemide applied chronically to the round window: A model of metabolic presbyacusis. J. Neurosci. Off. J. Soc. Neurosci. 2002, 22, 9643–9650.
  54. Schuknecht, H.F.; Montandon, P. Pathology of the ear in pneumococcal meningitis. Arch. Klin. Exp. Ohren Nasen Kehlkopfheilkd. 1970, 195, 207–225.
  55. Ding, B.; Walton, J.P.; Zhu, X.; Frisina, R.D. Age-related changes in Na, K-ATPase expression, subunit isoform selection and assembly in the stria vascularis lateral wall of mouse cochlea. Hear. Res. 2018, 367, 59–73.
  56. Noben-Trauth, K.; Zheng, Q.Y.; Johnson, K.R. Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss. Nat. Genet. 2003, 35, 21–23.
  57. Kujawa, S.G.; Liberman, M.C. Adding insult to injury: Cochlear nerve degeneration after “temporary” noise-induced hearing loss. J. Neurosci. Off. J. Soc. Neurosci. 2009, 29, 14077–14085.
  58. Parthasarathy, A.; Kujawa, S.G. Synaptopathy in the aging cochlea: Characterizing early-neural deficits in auditory temporal envelope processing. J. Neurosci. Off. J. Soc. Neurosci. 2018, 38, 7108–7119.
  59. Sergeyenko, Y.; Lall, K.; Liberman, M.C.; Kujawa, S.G. Age-related cochlear synaptopathy: An early-onset contributor to auditory functional decline. J. Neurosci. Off. J. Soc. Neurosci. 2013, 33, 13686–13694.
  60. Finger, C.E.; Moreno-Gonzalez, I.; Gutierrez, A.; Moruno-Manchon, J.F.; McCullough, L.D. Age-related immune alterations and cerebrovascular inflammation. Mol. Psychiatry 2022, 27, 803–818.
  61. Gruver, A.L.; Hudson, L.L.; Sempowski, G.D. Immunosenescence of ageing. J. Pathol. 2007, 211, 144–156.
  62. Capri, M.; Monti, D.; Salvioli, S.; Lescai, F.; Pierini, M.; Altilia, S.; Sevini, F.; Valensin, S.; Ostan, R.; Bucci, L.; et al. Complexity of anti-immunosenescence strategies in humans. Artif. Organs 2006, 30, 730–742.
  63. Verschuur, C.; Agyemang-Prempeh, A.; Newman, T.A. Inflammation is associated with a worsening of presbycusis: Evidence from the MRC national study of hearing. Int. J. Audiol. 2014, 53, 469–475.
  64. Fulop, T.; Dupuis, G.; Witkowski, J.M.; Larbi, A. The role of immunosenescence in the development of age-related diseases. Rev. Investig. Clin. Organo Hosp. Enferm. Nutr. 2016, 68, 84–91.
  65. Santoro, A.; Bientinesi, E.; Monti, D. Immunosenescence and inflammaging in the aging process: Age-related diseases or longevity? Ageing Res. Rev. 2021, 71, 101422.
  66. Franceschi, C.; Garagnani, P.; Parini, P.; Giuliani, C.; Santoro, A. Inflammaging: A new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 2018, 14, 576–590.
  67. Ferrucci, L.; Fabbri, E. Inflammageing: Chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 2018, 15, 505–522.
  68. Franceschi, C.; Bonafe, M.; Valensin, S.; Olivieri, F.; de Luca, M.; Ottaviani, E.; de Benedictis, G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 2000, 908, 244–254.
  69. Muller, L.; di Benedetto, S.; Pawelec, G. The immune system and its dysregulation with aging. Subcell. Biochem. 2019, 91, 21–43.
  70. Chung, H.Y.; Kim, H.J.; Kim, K.W.; Choi, J.S.; Yu, B.P. Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction. Microsc. Res. Tech. 2002, 59, 264–272.
  71. Murakami, M.; Hirano, T. The molecular mechanisms of chronic inflammation development. Front. Immunol. 2012, 3, 323.
  72. Sanada, F.; Taniyama, Y.; Muratsu, J.; Otsu, R.; Shimizu, H.; Rakugi, H.; Morishita, R. Source of chronic inflammation in aging. Front. Cardiovasc. Med. 2018, 5, 12.
  73. Blake, G.J.; Ridker, P.M. Inflammatory bio-markers and cardiovascular risk prediction. J. Intern. Med. 2002, 252, 283–294.
  74. Dandona, P.; Aljada, A.; Bandyopadhyay, A. Inflammation: The link between insulin resistance, obesity and diabetes. Trends Immunol. 2004, 25, 4–7.
  75. Dorfmuller, P.; Perros, F.; Balabanian, K.; Humbert, M. Inflammation in pulmonary arterial hypertension. Eur. Respir. J. 2003, 22, 358–363.
  76. Harrison, D.G.; Guzik, T.J.; Lob, H.E.; Madhur, M.S.; Marvar, P.J.; Thabet, S.R.; Vinh, A.; Weyand, C.M. Inflammation, immunity, and hypertension. Hypertension 2011, 57, 132–140.
  77. Heppner, F.L.; Ransohoff, R.M.; Becher, B. Immune attack: The role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 2015, 16, 358–372.
  78. Koenig, W.; Sund, M.; Frohlich, M.; Fischer, H.G.; Lowel, H.; Doring, A.; Hutchinson, W.L.; Pepys, M.B. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: Results from the MONICA (monitoring trends and determinants in cardiovascular disease) augsburg cohort study, 1984 to 1992. Circulation 1999, 99, 237–242.
  79. Koziorowski, D.; Tomasiuk, R.; Szlufik, S.; Friedman, A. Inflammatory cytokines and NT-proCNP in Parkinson’s disease patients. Cytokine 2012, 60, 762–766.
  80. Luft, V.C.; Schmidt, M.I.; Pankow, J.S.; Couper, D.; Ballantyne, C.M.; Young, J.H.; Duncan, B.B. Chronic inflammation role in the obesity-diabetes association: A case-cohort study. Diabetol. Metab. Syndr. 2013, 5, 31.
  81. Stenvinkel, P.; Heimburger, O.; Paultre, F.; Diczfalusy, U.; Wang, T.; Berglund, L.; Jogestrand, T. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int. 1999, 55, 1899–1911.
  82. Walker, D.G.; Dalsing-Hernandez, J.E.; Campbell, N.A.; Lue, L.F. Decreased expression of CD200 and CD200 receptor in Alzheimer’s disease: A potential mechanism leading to chronic inflammation. Exp. Neurol. 2009, 215, 5–19.
  83. Fujioka, M.; Kanzaki, S.; Okano, H.J.; Masuda, M.; Ogawa, K.; Okano, H. Proinflammatory cytokines expression in noise-induced damaged cochlea. J. Neurosci. Res. 2006, 83, 575–583.
  84. Fujioka, M.; Okano, H.; Ogawa, K. Inflammatory and immune responses in the cochlea: Potential therapeutic targets for sensorineural hearing loss. Front. Pharmacol. 2014, 5, 287.
  85. Paplou, V.; Schubert, N.M.A.; Pyott, S.J. Age-related changes in the cochlea and vestibule: Shared patterns and processes. Front. Neurosci. 2021, 15, 680856.
  86. Harris, J.P. Immunology of the inner ear: Response of the inner ear to antigen challenge. Otolaryngol.-Head Neck Surg. 1983, 91, 18–32.
  87. Kampfe Nordstrom, C.; Danckwardt-Lilliestrom, N.; Laurell, G.; Liu, W.; Rask-Andersen, H. The human endolymphatic sac and inner ear immunity: Macrophage interaction and molecular expression. Front. Immunol. 2018, 9, 3181.
  88. Shi, X. Pathophysiology of the cochlear intrastrial fluid-blood barrier (review). Hear. Res. 2016, 338, 52–63.
  89. Nyberg, S.; Abbott, N.J.; Shi, X.; Steyger, P.S.; Dabdoub, A. Delivery of therapeutics to the inner ear: The challenge of the blood-labyrinth barrier. Sci. Transl. Med. 2019, 11, eaao0935.
  90. Zhang, F.; Zhang, J.; Neng, L.; Shi, X. Characterization and inflammatory response of perivascular-resident macrophage-like melanocytes in the vestibular system. J. Assoc. Res. Otolaryngol. 2013, 14, 635–643.
  91. Hirose, K.; Hartsock, J.J.; Johnson, S.; Santi, P.; Salt, A.N. Systemic lipopolysaccharide compromises the blood-labyrinth barrier and increases entry of serum fluorescein into the perilymph. J. Assoc. Res. Otolaryngol. 2014, 15, 707–719.
  92. Taylor, R.R.; Nevill, G.; Forge, A. Rapid hair cell loss: A mouse model for cochlear lesions. J. Assoc. Res. Otolaryngol. 2008, 9, 44–64.
  93. Suzuki, M.; Yamasoba, T.; Ishibashi, T.; Miller, J.M.; Kaga, K. Effect of noise exposure on blood-labyrinth barrier in guinea pigs. Hear. Res. 2002, 164, 12–18.
  94. Del Zoppo, G.J.; Hallenbeck, J.M. Advances in the vascular pathophysiology of ischemic stroke. Thromb. Res. 2000, 98, 73–81.
  95. Yamazaki, Y.; Baker, D.J.; Tachibana, M.; Liu, C.C.; van Deursen, J.M.; Brott, T.G.; Bu, G.; Kanekiyo, T. Vascular cell senescence contributes to blood-brain barrier breakdown. Stroke 2016, 47, 1068–1077.
  96. Verschuur, C.A.; Dowell, A.; Syddall, H.E.; Ntani, G.; Simmonds, S.J.; Baylis, D.; Gale, C.R.; Walsh, B.; Cooper, C.; Lord, J.M.; et al. Markers of inflammatory status are associated with hearing threshold in older people: Findings from the hertfordshire ageing study. Age Ageing 2012, 41, 92–97.
  97. Lassale, C.; Vullo, P.; Cadar, D.; Batty, G.D.; Steptoe, A.; Zaninotto, P. Association of inflammatory markers with hearing impairment: The English longitudinal study of ageing. Brain Behav. Immun. 2020, 83, 112–119.
  98. Noble, K.; Brown, L.; Elvis, P.; Lang, H. Cochlear immune response in presbyacusis: A focus on dysregulation of macrophage activity. J. Assoc. Res. Otolaryngol. 2022, 23, 1–16.
  99. Noble, K.V.; Liu, T.; Matthews, L.J.; Schulte, B.A.; Lang, H. Age-related changes in immune cells of the human cochlea. Front. Neurol. 2019, 10, 895.
  100. Lowthian, J.A.; Britt, C.J.; Rance, G.; Lin, F.R.; Woods, R.L.; Wolfe, R.; Nelson, M.R.; Dillon, H.A.; Ward, S.; Reid, C.M.; et al. Slowing the progression of age-related hearing loss: Rationale and study design of the ASPIRIN in HEARING, retinal vessels imaging and neurocognition in older generations (ASPREE-HEARING) trial. Contemp. Clin. Trials 2016, 46, 60–66.
  101. Kalinec, G.M.; Lomberk, G.; Urrutia, R.A.; Kalinec, F. Resolution of cochlear inflammation: Novel target for preventing or ameliorating drug-, noise- and age-related hearing loss. Front. Cell. Neurosci. 2017, 11, 192.
  102. Coleman, J.; Huang, X.; Liu, J.; Kopke, R.; Jackson, R. Dosing study on the effectiveness of salicylate/N-acetylcysteine for prevention of noise-induced hearing loss. Noise Health 2010, 12, 159–165.
  103. Gao, X.R.; Adhikari, C.M.; Peng, L.Y.; Guo, X.G.; Zhai, Y.S.; He, X.Y.; Zhang, L.Y.; Lin, J.; Zuo, Z.Y. Efficacy of different doses of aspirin in decreasing blood levels of inflammatory markers in patients with cardiovascular metabolic syndrome. J. Pharm. Pharmacol. 2009, 61, 1505–1510.
  104. Yamashita, D.; Jiang, H.Y.; le Prell, C.G.; Schacht, J.; Miller, J.M. Post-exposure treatment attenuates noise-induced hearing loss. Neuroscience 2005, 134, 633–642.
  105. Frye, M.D.; Yang, W.; Zhang, C.; Xiong, B.; Hu, B.H. Dynamic activation of basilar membrane macrophages in response to chronic sensory cell degeneration in aging mouse cochleae. Hear. Res. 2017, 344, 125–134.
  106. Su, Z.; Xiong, H.; Liu, Y.; Pang, J.; Lin, H.; Zhang, W.; Zheng, Y. Transcriptomic analysis highlights cochlear inflammation associated with age-related hearing loss in C57BL/6 mice using next generation sequencing. PeerJ 2020, 8, e9737.
  107. Coppe, J.P.; Desprez, P.Y.; Krtolica, A.; Campisi, J. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annu. Rev. Pathol. 2010, 5, 99–118.
  108. Tchkonia, T.; Zhu, Y.; van Deursen, J.; Campisi, J.; Kirkland, J.L. Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities. J. Clin. Investig. 2013, 123, 966–972.
  109. Chinta, S.J.; Woods, G.; Rane, A.; Demaria, M.; Campisi, J.; Andersen, J.K. Cellular senescence and the aging brain. Exp. Gerontol. 2015, 68, 3–7.
  110. Salminen, A.; Ojala, J.; Kaarniranta, K.; Haapasalo, A.; Hiltunen, M.; Soininen, H. Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur. J. Neurosci. 2011, 34, 3–11.
  111. Salvador, E.; Burek, M.; Löhr, M.; Nagai, M.; Hagemann, C.; Förster, C.Y. Senescence and associated blood-brain barrier alterations in vitro. Histochem. Cell Biol. 2021, 156, 283–292.
More