Biology subjects

Cao, K.-Y.

Publications and source records attributed to Cao, K.-Y..

4 recordsLinked to original sources

bioRxiv2026

Evolutionarily Conserved Decline of tRNA Mannosyl-Queuosine Links Translational Regulation to Aging and Is Reversed by Queuine

Aging arises from interconnected molecular defects, yet upstream regulatory mechanisms that coordinate these hallmarks remain incompletely defined. While epitranscriptomic regulation has emerged as a critical layer of gene control, the contribution of tRNA-specific modifications to aging remains largely unexplored. Here, we systematically profile tRNA modifications across multiple organs, species, and senescence models and identify mannosyl-queuosine (manQ), a wobble-position modification of tRNAAsp, as the first tRNA-specific modification that consistently declines with age. ManQ depletion is evolutionarily conserved and tightly correlates with functional deterioration. Mechanistically, loss of manQ impairs translational fidelity, leading to proteome imbalance, collapse of proteostasis, and aberrant expression of senescence-associated proteins, including GPNMB. These translational defects intersect with established aging hallmarks and accelerate cellular and organismal aging. We further demonstrate that circulating queuine, a microbiota-derived precursor required for manQ biosynthesis, declines with age in rodents and humans. Queuine deficiency promotes senescence, whereas supplementation restores manQ levels, improves translational accuracy, suppresses p16/p21-driven senescence programs, and re-establishes proteostatic balance. Across species, queuine supplementation extends lifespan and enhances healthspan. In Drosophila, it increases median lifespan by 47% and improves stress resistance and memory. In naturally aging mice, long-term oral administration extends lifespan by 15.3%, reduces DNA methylation age, improves cognitive and motor performance, strengthens antioxidant defenses, remodels the gut microbiota, and alleviates inflammation and metabolic dysfunction without detectable toxicity. Collectively, these findings establish tRNA epitranscriptomic remodeling as a previously unrecognized layer of aging regulation and identify restoration of manQ through queuine supplementation as a multi-system strategy to delay aging.

pharmacology and toxicology↗

bioRxiv2025

Targeted intervention of senescence induced by a 5' half fragment of tRNASec(NCA) with antisense oligonucleotide extends healthspan and lifespan in mice

In light of increasing attention being paid to aging research globally, the accumulation of aging hallmarks and their corresponding targeting therapeutics have been substantially revealed. However, uncovering the genuine drivers within epigenetic alterations that lead to aging remains a formidable challenge. In this study, we identified tRNASec(NCA) as the most severely damaged tRNA species in the kidneys of naturally aged mice. This damage not only dysregulated selenoproteins with anti-aging effects, but also generates a 5'-tRNA fragment cleaved at the 34th position, which accumulates in an age-dependent manner. Mechanistically, the 5'-tRNASec(NCA) half interacts and activates Toll-like receptor 7, thereby triggering innate immune responses and promoting cellular senescence in both mice and human cells. Moreover, in a naturally aged mice model, administration of an antisense oligonucleotide (ASO) targeting the 5'-tRNASec(NCA) half remarkably ameliorates aging markers, enhances telomere length, and extends healthspan and lifespan. In addition, ASO-5'-tRNASec(NCA) half plays another role in directly targeting and downregulating BCAT1 via the RNAi pathway to intervene in the senescence process. Our findings underscore tRNA damage as a novel aging hallmark, and targeting the damage-induced products presents a novel strategy for aging intervention, thus expanding our knowledge of the aging process.

genetics↗

bioRxiv2020

Cytotoxic effects of tRNA-derived fragments and tRNA halves from non-pathogenic Escherichia coli strain on colorectal cancer cells

Transfer RNAs (tRNAs) purified from non-pathogenic E. coli strain (NPECS) possess cytotoxic properties on colorectal cancer cells. In the present study, the bioactivity of tRNA halves and tRNA fragments (tRFs) derived from NPECS are investigated for their anticancer potential. Both tRNA halves and tRF mimics studied exhibited significant cytotoxicity on colorectal cancer cells, with the latter being more effective suggesting that tRFs may be important contributors to the bioactivities of tRNAs derived from gut microbiota. Through high-throughput screening, EC83 mimic, a double-strand RNA with a 22 nt 5-tRF derived from tRNA-Leu(CAA) as antisense chain, was identified as one with the highest potency (IC50=52 nM). Structure-activity investigations revealed that 2-O-methylation of the ribose of guanosine may enhance the cytotoxic effects of EC83 mimic via increasing the stability of its tertiary structure. Consistently, 4-thiouridine substitution reversed this increased stability and the enhanced cytotoxic effects. This provides the first evidence that the bioactivity of tRF mimics would be impacted by chemical modifications. Furthermore, the present study provides the first evidence to suggest that novel tRNA fragments derived from the gut microbiota may possess anti-cancer properties and have the potential to be potent and selective therapeutic molecules. IMPORTANCEWhile the gut microbiota has been increasingly recognized to be of vital importance to human health and disease, the current literature shows that there is a lack of attention given on the non-pathogenic Escherichia coli strain. Moreover, the biological activities of tRNA fragments (tRFs) derived from bacteria have rarely been investigated. The findings from this study revealed tRFs as a new class of bioactive constituents derived from gut microorganisms, suggesting that studies on biological functional molecules in intestinal microbiota should not neglect tRFs. The research of tRFs would play an important role in biological research of gut microorganisms, including bacteria-bacteria interaction, gut-brain axis, gut-liver axis, etc. Furthermore, the guidance on the rational design of tRF therapeutics provided in this study indicates that further investigations should pay more attention to these therapeutics from probiotics. The innovative drug research of tRFs as potent druggable RNA molecules derived from intestinal microorganisms would open a new area in biomedical sciences.

microbiology↗

bioRxiv2019

Cross-kingdom regulation of tRNAs/tRFs derived from Chinese yew

Plants containing countless chemical constituent have benefited mankind since the origin of life. Although secondary metabolites in plants, such as morphine, artemisinin and taxol, have been developed as therapeutic drugs for clinical therapy, few study focuses on the pharmacological activities of plant small RNAs with function of cross-kingdom regulations. Yew is widely considered as a \"superstar\" plant due to the discovery of paclitaxel, or taxol, which is a well-known natural drug for the treatment of multiple types of cancer1. Here we show the surprising finding that an RNA fragment, named tRF-T11, derived from tRNAHis(GUG) of Chinese yew strongly suppressed human ovarian cancer progression. In A2780 cells, tRF-T11 mimic (a double-stranded RNA with tRF-T11 as antisense chain) exhibited potent cytotoxicity comparable to that of taxol, but no significant cytotoxicity to normal ovarian surface epithelial cells. Moreover, the cytotoxicity of tRF-T11 mimic is 80-fold stronger than that of taxol in taxol-resistant A2780 cells. Bioinformatic and molecular biological studies revealed that tRF-T11 targets transient receptor potential cation channel subfamily A member 1 (TRPA1) to inhibit its expression levels. In a further in vivo investigation, the growth rate of ovarian tumor xenografts in nude mice was significantly reduced by treatment with tRF-T11 mimic, and the TRPA1 protein expression in tumors treated with tRF-T11 mimic was also down-regulated. Our findings are the first to provide evidence that plant-derived tRFs can regulate the expression of target genes in vitro and in vivo, indicating that they may become as a new source of druggable siRNA. Moreover, this discovery demonstrated a pilot example of an innovative approach for not only identifying pharmacologically-active tRFs from plants, but also for improving the efficiency and possibilities of discovering new drug target.

cell biology↗