Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Aug 1;12(5):1304-1322.
doi: 10.14336/AD.2021.0115. eCollection 2021 Aug.

tRNA-derived fragments as New Hallmarks of Aging and Age-related Diseases

Ya Yuan  1 , Jiamei Li  1 , Zhi He  1 , Xiaolan Fan  1   2 , Xueping Mao  1   2 , Mingyao Yang  1   2 , Deying Yang  1   2
Affiliations
Review

tRNA-derived fragments as New Hallmarks of Aging and Age-related Diseases

Ya Yuan et al. Aging Dis. .

Abstract

tRNA-derived fragments (tRFs), which are non-coding RNAs produced via tRNA cleavage with lengths of 14 to 50 nucleotides, originate from precursor tRNAs or mature tRNAs and exist in a wide range of organisms. tRFs are produced not by random fracture of tRNAs but by specific mechanisms. Considerable evidence shows that tRFs are detectable in model organisms of different ages and are associated with age-related diseases in humans, such as cancer and neurodegenerative diseases. In this literature review, the origin and classification of tRFs and the regulatory mechanisms of tRFs in aging and age-related diseases are summarized. We also describe the available tRF databases and research techniques and lay a foundation for the exploration of tRFs as biomarkers for the diagnosis and treatment of aging and age-related diseases.

Keywords: age-related diseases; aging; regulation mechanisms; tRFs.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interests The authors have no conflicts of interest to declare.

Figures

Figure 1.
Figure 1.
Classification of tRFs.
Figure 2.
Figure 2.
Regulatory mechanisms of tRFs. A) tRFs interact with proteins to regulate gene expression. B) tRFs target genes to inhibit the proliferation of cancer cells and affect early neural development. C) tRFs affect protein synthesis by regulating protein levels and inhibiting translation initiation and progression. D) tRFs participate in cell cycle regulation by promoting the progression of prostate cancer cells from the G2 phase to the M phase and inhibiting the formation and activity of apoptotic bodies. E) tRFs are associated with the post-transcriptional methylation of tRNAs. Hypo-methylation of tRNA or lack of NSun2 enables the accumulation of 5′tRFs, and these 5′tRFs activate stress-response pathways.
Figure 3.
Figure 3.
Hallmarks of aging and tRFs associated with aging hallmarks. Blue box, upregulated in disease; green box, downregulated in disease. Aging features the following 9 hallmarks: loss of proteostasis, stem cell exhaustion, altered intercellular communication, deregulated nutrient sensing, cellular senescence, telomere attrition, mitochondrial dysfunction, genomic instability and epigenetic alterations. Researchers have found that tRFs are associated with many of these hallmarks.
Figure 4.
Figure 4.
tRFs in age-related diseases. ?, upregulated in disease; ?, downregulated in disease.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

  • Profiling of Differentially Expressed MicroRNAs in Saliva of Parkinson's Disease Patients.
    Jiang Y, Chen J, Sun Y, Li F, Wei L, Sun W, Deng J, Yuan Y, Wang Z. Jiang Y, et al. Front Neurol. 2021 Nov 26;12:738530. doi: 10.3389/fneur.2021.738530. eCollection 2021. Front Neurol. 2021. PMID: 34899562 Free PMC article.
  • Influence of Maternal BLV Infection on miRNA and tRF Expression in Calves.
    Goldkamp AK, Lahuis CH, Hagen DE, Taxis TM. Goldkamp AK, et al. Pathogens. 2023 Nov 3;12(11):1312. doi: 10.3390/pathogens12111312. Pathogens. 2023. PMID: 38003777 Free PMC article.
  • Emerging roles of transfer RNA fragments in the CNS.
    Winek K, Soreq H. Winek K, et al. Brain. 2025 Aug 1;148(8):2631-2645. doi: 10.1093/brain/awaf130. Brain. 2025. PMID: 40294208 Free PMC article. Review.
  • Transfer RNA‑derived small RNAs: A class of potential biomarkers in multiple cancers (Review).
    Mao C, Yuan W, Fang R, Wu Y, Zhang Z, Cong H. Mao C, et al. Oncol Lett. 2024 May 1;28(1):293. doi: 10.3892/ol.2024.14427. eCollection 2024 Jul. Oncol Lett. 2024. PMID: 38737976 Free PMC article. Review.
  • Biomarkers of aging.
    Aging Biomarker Consortium; Bao H, Cao J, Chen M, Chen M, Chen W, Chen X, Chen Y, Chen Y, Chen Y, Chen Z, Chhetri JK, Ding Y, Feng J, Guo J, Guo M, He C, Jia Y, Jiang H, Jing Y, Li D, Li J, Li J, Liang Q, Liang R, Liu F, Liu X, Liu Z, Luo OJ, Lv J, Ma J, Mao K, Nie J, Qiao X, Sun X, Tang X, Wang J, Wang Q, Wang S, Wang X, Wang Y, Wang Y, Wu R, Xia K, Xiao FH, Xu L, Xu Y, Yan H, Yang L, Yang R, Yang Y, Ying Y, Zhang L, Zhang W, Zhang W, Zhang X, Zhang Z, Zhou M, Zhou R, Zhu Q, Zhu Z, Cao F, Cao Z, Chan P, Chen C, Chen G, Chen HZ, Chen J, Ci W, Ding BS, Ding Q, Gao F, Han JJ, Huang K, Ju Z, Kong QP, Li J, Li J, Li X, Liu B, Liu F, Liu L, Liu Q, Liu Q, Liu X, Liu Y, Luo X, Ma S, Ma X, Mao Z, Nie J, Peng Y, Qu J, Ren J, Ren R, Song M, Songyang Z, Sun YE, Sun Y, Tian M, Wang S, Wang S, Wang X, Wang X, Wang YJ, Wang Y, Wong CCL, Xiang AP, Xiao Y, Xie Z, Xu D, Ye J, Yue R, Zhang C, Zhang H, Zhang L, Zhang W, Zhang Y, Zhang YW, Zhang Z, Zhao T, Zhao Y, Zhu D, Zou W, Pei G, Liu GH. Aging Biomarker Consortium, et al. Sci China Life Sci. 2023 May;66(5):893-1066. doi: 10.1007/s11427-023-2305-0. Epub 2023 Apr 11. Sci China Life Sci. 2023. PMID: 37076725 Free PMC article. Review.
See all "Cited by" articles

References

    1. López OC, Blasco M, Partridge L, Serrano M, Cell KGJ (2013). The hallmarks of aging. Cell, 153:1194-1217. - PMC - PubMed
    1. Wyss-Coray T (2016). Ageing, neurodegeneration and brain rejuvenation. Nature, 539:180-186. - PMC - PubMed
    1. Gomes AP, Ilter D, Low V, Endress JE, Fernández-García J, Rosenzweig A, et al.. (2020). Age-induced accumulation of methylmalonic acid promotes tumour progression. Nature, 585(7824):283-287 - PMC - PubMed
    1. Wang H, Fau Z, Xiang HF, Zhang XH (2020). Molecules in the blood of older people promote cancer spread. Nature, 585(7824):187-188. - PubMed
    1. Lee Y, Shibata Y, Malhotra A, Genes DAJ, development (2009). A novel class of small RNAs: tRNA-derived RNA fragments (tRFs). Genes Dev, 23:2639-2649. - PMC - PubMed

LinkOut - more resources