Presbycusis is a disease with genetic susceptibility. According to twins studies and longitudinal studies of family cohorts, its heritability is small to moderate, with a heritability indices of between 0.35 and 0.55 (Bowl and Dawson, 2019). Unlike the single-gene genetic pathogenic pattern of congenital deafness and early-onset deafness, it is generally believed that presbycusis involves multiple genetic variants, each of which has a small impact (Wells et al., 2020).

Genome-wide association study (GWAS) is widely used for genetic composition analysis of presbycusis, and many candidate genes have been found to be associated with presbycusis (Bowl and Dawson, 2019). These genes may play an important role in signaling and maintenance of the cochlear microenvironment. Several independent studies have reported that the gene encoding glutamate metabotropic receptor 7 (GRM7) is associated with presbycusis. Mutations in GRM7 may lead to the accumulation of neurotransmitters in synaptic connections, thereby altering the susceptibility to presbycusis (Van Laer et al., 2010; Newman et al., 2012). Genetic polymorphisms in the genes coding detoxification enzymes are also linked to presbycusis, such as Uncoupling protein 2 (UCP2), Superoxide dismutase 2 (SOD2) and N-acetyltransferase 2 (NAT2) (Arsenijevic et al., 2000; Unal et al., 2005). Additionally, genetic variation may also contribute to increased susceptibility to presbycusis by environmental factors such as noise and ototoxic drugs (Prezant et al., 1993; Sliwinska-Kowalska and Pawelczyk, 2013).

Monogenic deafness-causing genes, especially those that cause delayed-onset deafness, may also be associated with presbycusis. Wells et al. (2019) performed GWAS for self-reported hearing loss adults in UK Biobank and reported 10 of the 44 associated loci included monogenic deafness genes. TMC1 variant was previously thought to be associated with progressive postlingual hearing loss and profound prelingual deafness. However, in a recent study, Boucher et al. (2020) demonstrated through in vitro transfection and in vivo animal models that the heterozygous pathogenic variants of TMC1 can cause presbycusis in a single-gene form, which updates our understanding of the inheritance pattern of presbycusis and provides a basis for potential inner ear treatments.

Noise is the second most common cause of hearing loss other than old age, and noise-induced hearing loss (NIHL) is considered a common occupational disease, with a high incidence in occupational workers who have been exposed to noise for a long time, such as workers in textile, mining, and heavy engineering industries (Nandi and Dhatrak, 2008; Natarajan et al., 2023). Both aging and acoustic trauma can lead to loss of hair cells at the base end of the cochlea. Aged animals raised in quiet environments show did not lose hair cells until well past the middle of the lifespan, and the loss was small, whereas human temporal bone specimens have found stable and large loss of hair cells throughout the life (Kujawa and Liberman, 2019). This suggest that noise exposure synergizes with aging in the development of presbycusis.

Noise damage to the auditory system is affected by intensity and duration of noise exposure and can cause permanent threshold shifts (PTS) or temporary threshold shift (TTS) (Natarajan et al., 2023). Both long-term high-intensity noise exposure and one-time exposure to hazardous noise levels can lead to PTS (Liberman, 2016; Ryan et al., 2016). Due to the repair function of the stereocilia tip links, moderate noise damage often leads to temporary hearing loss, which recovers within 24–48 h (Gerhardt et al., 1987; Jia et al., 2009). Although low-intensity noise stimulation does not directly cause hair cell loss, it may causes permanent damage to the stereocilia bundles on the hair cells and to the synaptic connections between the auditory nerve fibers (ANF) and the IHC, which results in a blockage of auditory signal transmission and decreased ability to distinguish speech in noisy background (Kujawa and Liberman, 2019). Therefore, noise exposure has a cumulative effect on damage to the auditory system, prolonged exposure to 70 dB of noise may also cause hearing damage, and long-term lower noise and short-term louder noise have the same effect on hearing (Natarajan et al., 2023).

Aminoglycoside antibiotics and chemotherapy drugs such as cisplatin and carboplatin can cause degenerative changes in the cochlea and hearing loss (Jiang et al., 2017). Additionally, through a large longitudinal cohort study lasting 10 years, Joo et al. (2020) found that loop diuretics and nonsteroidal anti-inflammatory drugs were associated with risk of progressive hearing loss, and may contributor to the incidence and severity of age-related hearing loss.

Metabolic diseases are a cluster of diseases or disorders that disrupt normal metabolism, including high blood sugar (hyperglycemia), increased blood pressure (hypertension), excess fat around the waist (obesity), and abnormal levels of cholesterol or triglycerides (dyslipidemia). In recent years, under the influence of unhealthy diet and lifestyle, the incidence of metabolic diseases and its components are on the rise, and it is most common in the elderly (Saklayen, 2018). Presbycusis and metabolic diseases are both chronic diseases with a high prevalence, and many older people suffer from them at the same time (Guo et al., 2022). In a large cohort study of 94,223 people in Korea, Rim et al. (2021) reported that obesity, hypertension, hyperglycemia and dyslipidemia were all strongly associated with hearing loss, and the number of components of the metabolic diseases is positively correlated with the rate of sensorineural hearing loss. In two cohort studies in Europe and Korea, high body mass index (BMI) and low BMI were found to be associated with hearing loss, respectively (Fransen et al., 2008; Lee et al., 2015). Furthermore, Nguyen et al. (2022) found that the mouse model of diabetes and dyslipidemia had higher hearing impairment and degeneration of the cochlear spiral ganglion and stria vascularis. Some studies have found mitochondrial dysfunction occurs in both metabolic diseases and presbycusis, and Guo et al. (2022) suggested that metabolic diseases may increase susceptibility to presbycusis by causing mitochondrial dysfunction.

Lifestyle effects on hearing are diverse, with studies showing that both smoking and passive smoking increase the risk of hearing loss, while moderate alcohol consumption has a protective effect on hearing (Dawes et al., 2014). Diet and exercise may also play a role in aging and hearing. A high antioxidant diet can reduce mitochondrial dysfunction, thereby decreasing the magnitude of the vascular atrophy and cochlear auditory nerve degeneration (Le and Keithley, 2007). Han et al. (2016) found that increasing exercise in mice was effective in attenuating cochlear degeneration and hearing loss.

Reactive oxygen species (ROS) are highly reactive chemicals produced during mitochondrial respiration or cellular response to endogenous and exogenous factors, mainly including superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxyl radical (OH-) and nitric oxide (NO-) (Pizzino et al., 2017). ROS can serve as critical signaling molecules in cell proliferation and survival, but their excessive production and accumulation can lead to oxidative stress (OS), which in turn leads to macromolecular damage, promoting diseases such as presbycusis, aging and cancer (Ray et al., 2012). In the cochlea, ROS can damage DNA, break down lipid and protein molecules, and lead to cochlear cell apoptosis (Paplou et al., 2021). Increased plasma levels of ROS in humans are associated with hearing loss, while a high antioxidant diet can reduce cochlear degeneration and hearing loss (Le and Keithley, 2007; Lasisi and Fehintola, 2011). In fact, there are antioxidant enzymes in the body that can remove ROS, such as glutathione reductase (GSR), superoxide dismutase (SOD), catalase (CAT) and methionine sulfoxide reductase (MSR). The balance of the body’s antioxidant enzymes and ROS can avoid damage to cells and tissues caused by OS (Seidman et al., 2002; Paplou et al., 2021).

The cochlea is an energy-intensive organ in which mitochondria provide energy for their sodium-potassium pump activity and ion transport through oxidative phosphorylation, while producing large quantities of ROS. The aggregation of ROS in the cochlea can lead to mutations in the mitochondrial genome, resulting in mitochondrial DNA (mtDNA) damage (Seidman et al., 2002). Mitochondrial DNA mutation is an important component of auditory system damage, and its characteristic 4,977 bp deletion occurs frequently in temporal bone tissue samples from patients with presbycusis (Zhong et al., 2011). In addition, postmortem analysis of the temporal bones of patients with presbycusis revealed defects in the expression of mitochondrial aerobic metabolism-related enzymes (Markaryan et al., 2009). For the damaged mitochondria, cells can clear and renew them through the autophagy and mitochondrial dynamics (fission and fusion events) (Wang and Puel, 2018).

However, as the body ages, the production and function of antioxidant enzymes decrease, and ischemic and hypoxic damage from local vascular lesions in the cochlea leads to increased production of ROS (Ray et al., 2012). As a result, the original balance is broken, and OS will cause cumulative damage to mitochondria and cochlear cells. In addition, mitochondrial biogenesis in the elderly is weakened, autophagy and mitochondrial dynamics are reduced, so that mitochondria are constantly depleted, so that normal cells and cochlear function cannot be maintained (Seidman et al., 2002; Wang and Puel, 2020; Figure 1).

Inflammaging is chronic and low-grade inflammation of tissues and organs that occurs during aging and can lead to conditions as diverse as cardiovascular disease, diabetes, and neurodegenerative diseases (Bazard et al., 2021b; Kociszewska and Vlajkovic, 2022). Various stimuli, including cellular debris, nutrients and pathogens, can drive sterile inflammation (Franceschi et al., 2018). The body’s immune function declines with age, mainly manifested by shift in T-cell subpopulation distribution (the number of naive T cells (especially CD8+) decreases and homeostatically proliferate into memory T cells), impaired calcium-mediated signaling and thymic atrophy, resulting in weakened immune surveillance and clearance of pathogens (Goronzy and Weyand, 2013; Yousefzadeh et al., 2021). In turn, it leads to the accumulation of inflammatory stimuli, which continuously stimulates the body to produce chronic inflammatory responses. The cochlea is not an immune-privileged organ. Systemic inflammation is associated with presbycusis, and changes in the morphology and number of macrophages can occur in the aging cochlea (Watson et al., 2017).

Macrophages are a key part of the innate immune system, presented in the cochlear spiral ligament, the auditory nerve, and the organ of Corti. Activated macrophages transform from highly branched morphology to amoeboid shape and can phagocytose cellular debris or pathogens, which are critical for maintaining the homeostasis of the cochlear microenvironment (Noble et al., 2022). In addition, the vascularization function of macrophages can regulate the permeability of the blood-labyrinth barrier (BLB) of the strial microvasculature (Noble et al., 2022). Noise trauma activates macrophages, causing changes in their shape and number (Presta et al., 2018). Analysis of temporal bone specimens of different ages revealed that aging cochlear macrophages were highly activated (Noble et al., 2019). The inflammatory response driven by macrophage activation plays an important role in the development of presbycusis by leading to cochlear degeneration and increased stria vascular permeability (Noble et al., 2022).

The intestinal tract contains a large number of microorganisms and their genetic material, and gut dysbiosis may also contribute to inflammaging. In addition to the high-fat diet can lead to the development of cochlear inflammation (Kociszewska et al., 2021). As the body ages, a series of changes occur in the intestinal tract, such as the reduced microbiota diversity, more pro-inflammatory microbiota such as LPS-producing Gram-negative bacteria, and the permeability of the intestinal barriers increases (Ragonnaud and Biragyn, 2021). Therefore, pathogens and metabolites of intestinal microorganisms can be transported to the cochlea through the systemic circulation, leading to chronic inflammation of the cochlea and the occurrence of presbycusis (Kociszewska and Vlajkovic, 2022; Figure 1).

The spiral ligament is a component of the potassium ion transport system in the lateral wall of the cochlea, which contains five types of fibrocytes, and its normal function is crucial for the maintenance of the EP (Spicer and Schulte, 1991; Lang et al., 2003; Eckert et al., 2021). Unlike sensory hair cells and neurons, which do not regenerate, spiral ligament fibrocytes typically recover rapidly after ototoxic drug and noise damage (Roberson and Rubel, 1994; Lang et al., 2003). The regenerative repair ability of fibrocytes relies on bone marrow-derived stem cells (Lang et al., 2006). However, as the body ages, stem cells are continuously depleted and their differentiation potential and proliferation rate decrease (Fehrer and Lepperdinger, 2005). Therefore, the renewal and repair ability of fibrocytes in the elderly is weakened, the spiral ligament atrophies, and metabolic presbycusis occurs (Eckert et al., 2021; Figure 1).

The management of presbycusis should first focus on prevention and avoid exposure to risk factors. While we cannot prevent aging, nor can we change our genetic background, we can minimize noise exposure, wear earplugs in noisy environments, and avoid ototoxic medications (He et al., 2019). Elderly patients should actively treat metabolic diseases and ear infections to avoid damage to their hearing (Guo et al., 2022). A good lifestyle is also essential for the prevention of presbycusis, and a reduced intake of fatty foods and a diet high in antioxidants can reduce hearing loss (Le and Keithley, 2007; Kociszewska et al., 2021). In addition, proper exercise not only strengthens immune function, but also reduces free radicals in the body. Studies have shown that long-term exercise can delay the progression of presbycusis by reducing age-related capillary loss associated with inflammation (Han et al., 2016).

Treatment of presbycusis still relies clinically on hearing amplification and cochlear implantation. Air conduction hearing aids are commonly worn in patients with mild to moderate hearing loss, active middle ear implants can be used in patients with moderate to severe hearing loss, and cochlear implants should be considered in patients with severe to profound hearing loss (Seidman et al., 2019). However, it is estimated that only 15% of eligible patients use them due to multiple factors including cost, appearance, discomfort, and lack of perceived benefit (Chien and Lin, 2012; Mahboubi et al., 2018).

In recent years, some researchers have begun to explore the treatment of presbycusis with antioxidants, anti-inflammatories, neurotrophins and other drugs (Wang and Puel, 2020). Studies by Benkafadar et al. (2019) show that EUK-207, a synthetic superoxide dismutase/catalase mimetic, reduced hair cell degeneration and age-related hearing loss in senescence-accelerated mouse-prone 8 (SAMP8) mice. Serra et al. (2022) believe that although the antioxidant melatonin cannot completely prevent presbycusis, it can delay its occurrence. Aspirin displays anti-inflammatory and antioxidant properties, and studies have shown that it can effectively reduce hearing loss in aged mice (Cazals, 2000). An ongoing clinical trial is attempting to assess its potential therapeutic effect on presbycusis in humans (Lowthian, et al., 2016). Cassinotti et al. (2022) overexpressed neurotrophin-3 (Ntf3) in mouse cochlea starting at middle age, thereby preventing age-related inner hair cell synaptopathy and slowing age-related hearing loss. Oral treatment with selegiline, a neuroprotective antiparkinsonian drug, significantly alleviated hearing loss at higher frequencies in mice with moderate hearing loss, but not in mice with rapid progressive hearing loss (Szepesy et al., 2021). We believe that the drug treatment of presbycusis has broad prospects, but the current application is still concentrated in animal models and clinical trials, and its clinical application still needs to solve problems such as efficacy, safety, administration route and dosage. In addition, gene therapy and stem cell transplantation also have potential treatment for presbycusis, which still need further research (Chen et al., 2012; Davidsohn et al., 2019).