Aging Cells Shift Preference Toward Short Genes, Revealing New Anti-Aging Therapeutic Targets
核心洞察
A Northwestern Medicine study in PNAS reveals that aging tissues exhibit a length-biased shift in gene expression, favoring short stress-response genes while long neurodevelopmental genes decline.
RNA polymerase II (搜索) transcription activity and frequency decrease with age, and interactions with the Mediator complex (搜索) are reduced in aged mouse liver and brain tissues.
Long-read sequencing uncovered increased aberrant splice isoforms and intron-retention events in aged mouse brains, pointing to splicing defects as a hallmark of aging.
Aging fundamentally alters how cells transcribe DNA into messenger RNA, according to a new Northwestern Medicine study published in the Proceedings of the National Academy of Sciences (PNAS). The research demonstrates that as organisms age, cells develop a measurable preference for expressing shorter genes, while the transcription of long genes—particularly those critical for neuronal function—steadily declines. These findings open a new window into the molecular mechanisms of aging and point toward novel targets for anti-aging drug development.
The study, led by senior author Ali Shilatifard, PhD, chair and Robert Francis Furchgott Professor of Biochemistry and Molecular Genetics at Northwestern University, employed a multimodal approach to examine RNA extracted from liver, kidney, and brain tissue cells of young (11 weeks old) and old (72 weeks old) mice. Parallel analyses were conducted using publicly available total RNA-seq data from young and aged human patient tissue samples.
Transcriptional Decline Across Aging Tissues
Short-read RNA sequencing revealed a reduction in overall transcription activity and frequency in aging tissues, with no changes observed in elongation rates. Subsequent transcriptomic analysis uncovered a consistent pattern: aging tissues preferentially expressed short genes, while long genes saw diminished output.
In the aging mouse brain specifically, short stress-response genes were upregulated, and long neurodevelopmental genes were downregulated. These results were mirrored in human tissue samples, underscoring the translational relevance of the findings.
The researchers also discovered that interactions between RNA polymerase II (搜索)—the multiprotein complex responsible for transcribing DNA into mRNA—and the Mediator complex (搜索), which relays regulatory signals from transcription factors to RNA polymerase II, were decreased in chromatin extracted from aged mouse liver and brain tissues.
Splicing Defects Emerge as a Hallmark of Aging
By integrating short-read and long-read RNA sequencing, the team gained deeper insight into why longer genes may be disproportionately affected during aging.
"Specifically, long-read sequencing revealed an increase in aberrant splice isoforms in the aged mouse brain, particularly mono-exonic isoforms, along with intron-retention events," said study co-author Marta Iwanaszko, PhD, research associate professor of Biochemistry and Molecular Genetics, who designed the study's computational methodology and supervised the analysis.
Introns are normally spliced out of mRNA transcripts before translation into proteins. Their retention can cause major problems for protein function and, consequently, for the cell.
Elongation Factors ELOA (搜索) and SPT6 (搜索) in the Spotlight
The study builds on the team's prior discovery that the elongation factor ELOA (搜索) regulates short genes during cellular senescence. In the current work, the investigators found that physiological aging causes a length-biased reduction in long neuronal genes alongside increased splicing defects, and they demonstrated that expression of the elongation factor SPT6 (搜索) decreases with age.
"Building on our recent discovery that the elongation factor ELOA (搜索) regulates short genes during cellular senescence, we found that physiological aging causes a length-biased reduction in long neuronal genes alongside increased splicing defects. In this study, we also demonstrate that the expression of elongation factor SPT6 (搜索) decreases with age," said Saeid Parast, PhD, a postdoctoral fellow in the Shilatifard laboratory and co-first author of the study.
Parast added: "Future work will explore how these and other transcription elongation factors balance aging, as ELOA (搜索) may drive stress gene expression while the loss of SPT6 (搜索) shuts down long neuronal genes."
Toward Anti-Aging Therapeutics
The findings highlight potential transcriptional control targets for anti-aging drug development. The authors noted that further work is warranted to identify the specific elongation factors essential for transcription of long genes.
"The present study does not assess elongation factor occupancy in brain tissue, or whether age-dependent changes in these elongation factors might correlate with (or potentially drive) the preferential loss of long neurodevelopmental gene expression," the authors wrote. "A more thorough mechanistic understanding of elongation control in aging could enable approaches to maintain or increase RNAPII processivity in hope of preventing or reversing aging at the cellular level."
Madhurima Das, PhD, a research associate in the Shilatifard laboratory, served as co-first author alongside Parast. Additional co-authors include Yue He, a student in the Driskill Graduate Program in Life Sciences, and Issam Ben-Sahra, PhD, the Thomas D. Spies Professor of Genetic Metabolism.
The work was supported by National Institutes of Health grants R35CA197569, DP2HG012442, R50CA265372, T32CA281953, and R24GM137786.