A genome-scale ORF screen for resilience factors that protect the RPE and restore vision in aged mice
Lu, Y. R. R.; Shen, H.; Kajderowicz, K.; Ai, J.; Chen-Neumann, Y. H.; Hu, Y.; Tyshkovskiy, A.; Lou, Q.; Dong, T.; Grauvogel, L.; Chen, Z.; Cameron, J. C.; Li, X.; Shirahama, S.; Bligh, M.; Hou, S.; Chin, J.; Costa, M. W.; Ryu, J.; Sharma, R.; Mann, M.; Bharti, K.; Bowes Rickman, C.; Gladyshev, V. N.; Gregory-Ksander, M.; Ksander, B.; Weissman, J.
Show abstract
Aging is a complex phenomenon, yet therapeutic discovery has largely relied on testing individual hypothesis-driven targets. Here, we performed a genome-scale open reading frame (ORF) screen for oxidative-stress resistance in retinal pigment epithelium (RPE) cells, which are vulnerable to oxidative damage during aging. The screen identified nine protective ORFs including antioxidant factors and an epithelial-to-mesenchymal transition regulator. Notably, we also identified three factors that reduce transcriptomic age including the cardiac transcription factor NKX2-5. NKX2-5 conferred robust oxidative resilience in vitro and in vivo. Domain dissection revealed that its homeodomain is dispensable for resilience, enabling development of NKX2-5{Delta}HD, which retained protective activity without detectable toxicity over 14 months. In middle-aged mice, subretinal NKX2-5{Delta}HD restored visual and electrophysiological function, and its systemic delivery improved grip strength and reduced frailty in late-aged mice. These findings highlight the value of unbiased, genome-scale gain-of-function screening, as resilience factors normally expressed in other contexts can be reengineered as potential therapeutics for age-related decline in other tissues.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging. 97%
- Oxidative stress causes a reversible decrease of deubiquitylases activity in old vertebrate brains 96%
- Transient non-integrative nuclear reprogramming promotes multifaceted reversal of aging in human cells 96%
Similar papers in this journal
Similar papers in this journal
- A Trans-Omic Mendelian Randomization Study of Parental Lifespan Uncovers Novel Aging Biology and Drug Candidates for Human Healthspan Extension 96%
- Age-associated transcriptomic and epigenetic alterations in mouse hippocampus 95%
- In vivo chemical reprogramming is associated with a toxic accumulation of lipid droplets hindering rejuvenation 94%
Similar papers in this journal
- Swim exercise in C. elegans extends neuromuscular and intestinal healthspan, enhances learning ability, and protects against neurodegeneration 96%
- Single-cell transcriptomics reveals expansion of cytotoxic CD4 T-cells in supercentenarians 95%
- Systematic Approach Identifies Multiple Transcription Factor Perturbations That Rejuvenate Replicatively Aged Human Skin Fibroblasts 94%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.