Aging is associated with a systemic length-driven transcriptome imbalance
Posted on: 4 September 2019 , updated on: 5 September 2019
Preprint posted on 3 July 2019
Article now published in Nature Aging at http://dx.doi.org/10.1038/s43587-022-00317-6
Machine learning predicts markers of ageing: A systems biology approach points to an imbalance in RNA transcript length as the best single factor implicated in ageing, more significant than any gene alteration alone.
Selected by Monika S. Magon
Categories: cell biology, systems biology
Background
Ageing can be described as a complex progressive change in the homeostasis of molecular, cellular and physiological systems. Given the heterogeneity of its phenotypical and cellular manifestations, a wide range of studies have tried to identify molecular causes of the defects associated with ageing – with the hope that these will be druggable targets. Ageing has several hallmarks, including proteostasis, genomic instability, stem cell exhaustion, or metabolic problems1. However, high inter-species, inter-individual and even inter-organ or cell type variability, as well as little consistency between different study designs, have so far halted major breakthroughs in finding molecular mechanisms of ageing. While the search for genetic markers of ageing has found many genes dysregulated, these gene expression changes are subtle and therefore do not provide informative markers for ageing2. In this study, the authors aimed to identify an objective marker by going beyond gene expression and looking into the global transcript architecture and regulatory changes. To do so, they employed modern high throughput methods of unsupervised machine learning to analyse the transcriptome of mice as well as perform metanalysis on existing data from other species, including humans. The cutting-edge machine learning approaches allowed the authors to pinpoint a single best estimator of ageing – the balance of long and short transcripts.
Key findings
The results derived from the machine learning based investigation of mice transcriptomes demonstrate that the abundance of longer transcripts is decreased while that of the shorter ones’ is increased in ageing tissues (e.g. Figure 1 in this preprint3).
This is confirmed with meta-analysis of other studies in mice, as well as killifish, rat and human transcriptomes. The source of this homeostatic imbalance of transcript length is unknown but might be related to transcriptional regulation, posttranscriptional processing or other aspects of RNA biology. The authors point towards SFPQ, a gene that expresses a protein involved in transcriptional elongation (amongst its other functions)4. Interestingly, a meta-analysis of environmental factors known to contribute to the ageing phenotype, such as exposure to pollution, heat, pathogens, sleep deprivation, as well as the occurrence of neurodegenerative diseases, can be correlated with transcriptome imbalance. Moreover, the experimental analysis of mice of different age subjected to Influenza A, a common risk factor in ageing, caused an increased imbalance in transcript length abundance, especially in the oldest mice.
Thanks to the rigorous evaluation of the machine learning sensitivity and accuracy of predictions, as well as the use of large datasets, the authors could confirm that the imbalance in the abundance of the shortest and longest transcripts can be correlated with biological processes involved in ageing. They show that the abundance of long and short transcripts (5% of extreme lengths) arises from genes relevant to ageing, in processes such as proteostasis, chromatin organisation, mitochondrial function or neuronal activity.
Opinion and questions
In modern times, the population is ageing at an unprecedented rate. According to the World Health Organization, by 2020 the number of people aged 60 years and older will outnumber children younger than 5 years5. I believe that this manuscript will open new research avenues in ageing and stimulate a broader impact on our society in the future.
In this sense, this work presents an integrative and interdisciplinary approach, which could bring more systems biology approaches to the research of ageing. I chose to highlight this preprint also due to its relevance to a wider area of science. One could think that perhaps, in the same manner, the transcriptome length imbalance might be involved in the control of development. Besides, the transcriptional architecture might show its importance in neurodegenerative diseases, which are often seen as accelerated ageing processes6.
Moreover, as data science, machine learning and artificial intelligence advance, we will see more and more of these approaches in basic and applied science. This study sets an excellent example of the not so well adapted yet approaches in modern biology.
What comes next? While transcript length imbalance has been studied quite extensively in this preprint, it would be great to see the studies on the other identified factors associated with ageing (e.g. number of transcription factors), perhaps in a separate study.
References
- López-Otín, C., et al. The Hallmarks of Aging. Cell 153, 1194–1217 (2013).
- Cellerino, & Ori, A. What have we learned on aging from omics studies? Semin. Cell Dev. Biol. 70, 177–189 (2017).
- Stoeger, T., et al. Aging is associated with a systemic length-driven transcriptome imbalance. bioRxiv 691154 (2019).
- Takeuchi, et al. Loss of SFPQ Causes Long-Gene Transcriptopathy in the Brain. Cell Reports 23, 1326–1341 (2018).
- https://www.who.int/news-room/fact-sheets/detail/ageing-and-health
- Liu, Y., Cali, C. P. & Lee, E. B. RNA metabolism in neurodegenerative disease. Dis. Model. Mech. 10, 509–518 (2017).
doi: https://doi.org/10.1242/prelights.13649
Read preprint
(No Ratings Yet)Sign up to customise the site to your preferences and to receive alerts
Register hereAlso in the cell biology category:
Global coordination of protrusive forces in migrating immune cells
yohalie kalukula
The RNA binding protein HNRNPA2B1 regulates RNA abundance and motor protein activity in neurites
Felipe Del Valle Batalla
Pharyngeal neuronal mechanisms governing sour taste perception in Drosophila melanogaster
Matthew Davies
Also in the systems biology category:
Modular control of time and space during vertebrate axis segmentation
AND
Natural genetic variation quantitatively regulates heart rate and dimension
Girish Kale, Jennifer Ann Black
Expressive modeling and fast simulation for dynamic compartments
Benjamin Dominik Maier
Clusters of lineage-specific genes are anchored by ZNF274 in repressive perinucleolar compartments
Silvia Carvalho
preLists in the cell biology category:
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
| List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
| List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
| List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
| List by | Osvaldo Contreras |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
| List by | Ana Dorrego-Rivas |
BioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
| List by | Dey Lab, Samantha Seah |
1
Cell Polarity
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
| List by | Yamini Ravichandran |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
| List by | Maiko Kitaoka et al. |
3D Gastruloids
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
| List by | Paul Gerald L. Sanchez and Stefano Vianello |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
| List by | Dey Lab |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
| List by | Sandra Malmgren Hill |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
Cellular metabolism
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
| List by | Pablo Ranea Robles |
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
| List by | Dey Lab |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
| List by | Joseph Jose Thottacherry |
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
| List by | Dey Lab, Amanda Haage |
Also in the systems biology category:
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
| List by | Nathalie Krauth |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
Single Cell Biology 2020
A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.
| List by | Alex Eve |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
| List by | Dey Lab |
Pattern formation during development
The aim of this preList is to integrate results about the mechanisms that govern patterning during development, from genes implicated in the processes to theoritical models of pattern formation in nature.
| List by | Alexa Sadier |