Treatment of age-related visual impairment with a mitochondrial therapeutic

Abstract

ABSTRACTAge-related visual decline and disease due to neural dysfunction are major sources of disability that have resisted effective treatment. In light of evidence that visual impairment and mitochondrial dysfunction advance with age, we characterized age-related decline of spatial visual function in mice, and investigated whether improving mitochondrial function could treat it. Impaired photopic acuity measured with a virtual opto-kinetic system emerged near 18 months, and declined to ∼40% below normal by 34 months. Daily application of the synthetic peptide SS-31, which has high selectivity for mitochondrial membranes that contain cardiolipin, and promotes efficient electron transfer, was able to mitigate visual decline from 18 months. Daily application from 24 months, when acuity was reduced by ∼16%, reversed visual decline and normalized function within 2 months; recovered function that persisted for at least 3 months after treatment was withdrawn. A single treatment at 24 months also delayed subsequent visual decline. Daily application from 32 months took longer to affect change, but enabled substantial improvement within 2 months. The effects of age and SS-31 treatment on contrast sensitivity was similar to those on acuity, systemic and eye drop applications of SS-31 had comparable effects, scotopic spatial visual function was largely unaffected by age or treatment, and altered function was independent of variation in optical clarity. These data indicate that SS-31 treatment adaptively alters the aging visual system, and provide a rationale to investigate whether mitochondrial dysfunction is a treatable pathophysiology of human visual aging and age-related visual disease.TRANSLATIONAL IMPACTClinical issueAge-related visual impairment is a major source of disability. Aging invariably leads to optical dysfunction related to inflexibility (presbyopia) or clouding (cataracts) of the lens, and neural dysfunction; each of which compromises the ability to resolve detail (acuity) and differences in luminance (contrast sensitivity) in visual scenes. Age is also a predisposition to develop blinding visual diseases that have a neurological origin, such as glaucoma, diabetic retinopathy, and age-related macular degeneration. Whereas, age-related optical problems can often be corrected with eyewear or surgical lens replacement, we lack sufficient understanding of the natural course of visual aging and the neural processes that regulate it to effectively treat age-related visual dysfunction and disease linked to neural dysfunction.ResultsMitochondria are cellular organelles that enable energy metabolism, and essential cellular signaling processes. Mitochondrial function declines with age in the visual system and is linked with the development of age-related visual disease. Here, the authors present evidence that improving mitochondrial function can treat age-related visual decline. They report that a loss of acuity emerged in mice near 18 months (early old age) and declined with age until 34 months (extreme old age) when it was reduced by ∼60%. Daily administration of the mitochondria-acting peptide, SS-31, from 18 months largely prevented subsequent age-related visual decline. Application from 24 months, when moderate visual impairment was present, led to complete recovery of visual acuity within 2 months, which persisted for at least 3 months after SS-31 was withdrawn. A single dose at 24 months was also able to delay visual decline. Moreover, 2 months of SS-31 administration from 32 months, after much more severe visual dysfunction was manifest, substantially improved function by 34 months.Implications and future directionsThe study reveals that spatial measures of visuomotor function can identify age-related visual decline in mice that is largely preventable and reversible early in its course, by treatment with a mitochondrial-acting peptide. That visual dysfunction late in life is partially reversible with the peptide, also indicates that treating mitochondrial dysfunction has the potential to provide a benefit at any age. In addition, that restored function endured after the peptide was withdrawn indicates that improving mitochondrial function elicits long-lasting beneficial changes in the aging visual system. By linking mitochondrial dysfunction with visual aging, the data also suggests that improving mitochondrial function is a promising approach for treating age-related visual disease.