Treatment of age-related visual impairment with a mitochondrial therapeutic
Bibliographic record
Abstract
ABSTRACT Age-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and normalized function within 2 months; recovered function that persisted for at least 3 months after treatment was withdrawn.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 IMPACT Clinical issue Age-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. Results Mitochondria 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 directions The 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".