An unbiased screen of the entire human genome found a heart gene that, with a toxic domain removed, restores vision in aged mice and reduces their overall frailty

An unbiased screen of the entire human genome found a heart gene that, with a toxic domain removed, restores vision in aged mice and reduces their overall frailty

A team from MIT and Harvard tested nearly the entire human genome for the ability to protect retinal cells from aging. The strongest protector turned out to be NKX2-5, a gene normally active only in the heart. After engineering the protein, a single subretinal injection restored vision in aged mice, and intravenous delivery improved their grip strength and general condition.

The retinal pigment epithelium beneath the photoreceptors works under constant oxidative and photic stress throughout life and accumulates damage with age. This damage is one of the causes of age-related macular degeneration, the leading cause of blindness in older adults, affecting roughly 200 million people worldwide. Protective factors are usually sought one hypothesis at a time. On September 30 a preprint appeared on bioRxiv from a team that tested nearly all 13,000 human genes at once.

The team was led by Ryan Lu at MIT. They inserted genes one by one into retinal cells, damaged the cells with a compound that recapitulates aging in this tissue, and scored which survived. They found nine protective genes: some acted as antioxidants, one protected through an inflammatory pathway but caused the cells to lose their shape, and a third class (just three genes, including NKX2-5) slowed the biological age of the cell as measured by molecular clocks.

From this trio Lu chose NKX2-5, the strongest protector and the most unexpected: a gene normally active in the heart that is never turned on in the retina at all. Its tinman family arose more than 500 million years ago, before the first vertebrates and before any heart-like organs existed. Activating it in the retina does not convert the cell into a cardiac cell, because its usual partners in the cardiac program remain silent there. The protein has a second, hidden function that is separate from its cardiac role.

"The biggest surprise was NKX2-5," Lu wrote

In 15-month-old mice a single subretinal injection of the gene restored visual acuity to near-young levels within a month. But when the gene was expressed for longer than two months, the retina began to thin and the electrical response to light weakened: the beneficial gene proved toxic under prolonged expression.

To identify which part of the protein was harmful, the team deleted the homeodomain, the region by which NKX2-5 binds to the DNA of cardiac genes and also captures the inflammatory protein CARD10. Without the homeodomain the protection remained and the toxicity disappeared. The truncated version, NKX2-5ΔHD, restored aged mice to the visual acuity of young animals and held the effect for at least six months. In young mice the homeodomain-deleted gene caused no retinal damage even after 14 months of expression.

The same safe version was delivered intravenously to the oldest males, 25-month-old mice. After three months their paw grip strength increased and their frailty index decreased, although how the gene affected the muscles is not yet clear. A lifespan study in these mice is ongoing.

"When Kat and I were running this screen in early 2022, we both learned that we carry a risk allele for age-related macular degeneration. It almost feels like fate," Lu wrote of his screening co-author

Lu himself developed another route to the same goal, the ER-100 therapy, which is already in human trials and temporarily reprograms optic nerve cells. NKX2-5 provides a second, independent path: a single transplanted heart gene instead of cellular reprogramming.

Evolution seals genes like these inside one organ. Transplanting them into a different aging tissue activates their hidden protective program. An unbiased genomic screen brings them to light, and protein engineering turns the finding into a safe candidate.