Age-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD. Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed “chronic” senescence. Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.

Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor–associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants ofIRAK3, which encodes IRAK-M, were associated with an increased likelihood of developing AMD. In human samples and mouse models, IRAK-M abundance in the RPE declined with advancing age or exposure to oxidative stress and was further reduced in AMD.Irak3-knockout mice exhibited an increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M led to a disruption in RPE cell homeostasis, characterized by compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of adeno-associated virus (AAV)–expressing humanIRAK3rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration inIrak3-knockout mice. Our data show that replenishment of IRAK-M in the RPE may redress dysregulated pro-inflammatory processes in AMD, suggesting a potential treatment for retinal degeneration.

Age is a primary risk factor for chronic conditions, including age‐related macular degeneration (AMD). Impairments in autophagy processes are implicated in AMD progression, but the extent of autophagy's contribution and its therapeutic potential remain ambiguous. This study investigated age‐associated transcriptomic changes in autophagy pathways in the retinal pigment epithelium (RPE) and evaluated the protective effects of topical trehalose, an autophagy‐enhancing small molecule, against light‐induced outer retinal degeneration in mice. Transcriptomic analysis of human RPE/choroid and mouse RPE revealed consistent downregulation of autophagy pathways with age, alongside variable changes as AMD severity progressed. Given the age‐ and AMD‐associated perturbation of autophagy pathways, we examined trehalose treatment in vitro, which enhanced autophagic flux and restored mitochondrial respiratory function in primary murine RPE cells exposed to oxidative stress. In vivo, topical trehalose improved autophagy‐lysosome activity in mouse RPE, as demonstrated by elevated LC3B turnover and SQSTM1/p62 degradation. Furthermore, trehalose eyedrops protected mice from light‐induced damage to the RPE and photoreceptors, preserving outer nuclear layer thickness, RPE morphology, and junctional F‐actin organization. Taken together, the data support that age‐related decline and severe dysregulation in autophagy contributed to AMD progression. By restoring autophagic flux, topical trehalose demonstrates therapeutic potential to address early autophagy‐related pathological changes in AMD.

Age is a primary risk factor for chronic conditions, including age-related macular degeneration (AMD). Impairments in autophagy processes are implicated in AMD progression, but the extent of autophagy’s contribution and its therapeutic potential remain ambiguous. This study investigated age-associated transcriptomic changes in autophagy pathways in the retinal pigment epithelium (RPE) and evaluated the protective effects of topical trehalose, an autophagy-enhancing small molecule, against light-induced outer retinal degeneration in mice. Transcriptomic analysis of human RPE/choroid and mouse RPE revealed consistent downregulation of autophagy pathways with age, alongside variable changes as AMD severity progressed. Given the age- and AMD-associated perturbation of autophagy pathways, we examined trehalose treatment in vitro , which enhanced autophagic flux and restored mitochondrial respiratory function in primary murine RPE cells exposed to oxidative stress. In vivo , topical trehalose improved autophagy-lysosome activity in mouse RPE, demonstrated by elevated LC3B turnover and SQSTM1/p62 degradation. Furthermore, trehalose eyedrops protected mice from light-induced damage to the RPE and photoreceptors, preserving outer nuclear layer thickness, RPE morphology, and junctional F-actin organization. Taken together, the data support that age-related decline and severe dysregulation in autophagy contributed to AMD progression. By restoring autophagic flux, topical trehalose demonstrates therapeutic potential to address early autophagy-related pathological changes in AMD.

Unchecked, chronic inflammation is a constitutive component of age-related diseases, including age-related macular degeneration (AMD). Here we identified interleukin-1 receptor-associated kinase (IRAK)-M as a key immunoregulator in retinal pigment epithelium (RPE) that declines with age. Rare genetic variants of IRAK-M increased the likelihood of AMD. IRAK-M expression in RPE declined with age or oxidative stress and was further reduced in AMD. IRAK-M-deficient mice exhibited increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M disrupted RPE cell homeostasis, including compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of AAV-expressing IRAK-M rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in IRAK-M- deficient mice. Our data support that replenishment of IRAK-M expression may redress dysregulated pro-inflammatory processes in AMD, thereby treating degeneration. One Sentence Summary: IRAK-M is a protective molecule and promising therapeutic target for macular degeneration

With rising life expectancy, age-related diseases such as age-related macular degeneration (AMD) increasingly threaten the quality of life in older adults. This chapter contributes to the discourse on longevity and geriatrics by focusing on strategies to preserve vision, a key determinant of independence in aging populations. AMD, a progressive neurodegenerative retinal disease, is a leading cause of vision loss in the elderly. The dry form (dAMD), which accounts for 85–90% of cases, is marked by drusen accumulation beneath the retinal pigment epithelium (RPE), leading to RPE and photoreceptor degeneration. Its pathogenesis involves a multifactorial interplay of aging, genetic predisposition, oxidative stress, and immune dysregulation. Currently, there are no effective treatments for dAMD; anti-complement therapies for geographic atrophy (GA), the late stage of dAMD, have shown limited functional benefit in patients. Topical therapies offer promising advantages, including non-invasiveness, localized action, reduced systemic toxicity, and potential for cost-effective, patient-friendly interventions. However, developing effective eye drop formulations for dAMD remains a significant challenge, largely due to limited drug penetration to the posterior segment of the eye. Advances in understanding dAMD pathophysiology, coupled with novel delivery platforms, are essential to circumventing these barriers. A growing pipeline of small molecules and peptides targeting inflammation, autophagy, mitochondrial dysfunction, amyloid-beta toxicity, and choroidal circulation is currently under preclinical and clinical investigation. This chapter reviews the evolving therapeutic landscape for dAMD, emphasizing the potential of topical treatments to enhance patient care and support healthy aging.