In a new study published in Nature Aging, researchers have shown that aging is associated with a decreased expression of long transcripts over multiple tissues across several animal species .
It is well known that aging is accompanied by changes in the expression of many genes. Therefore, numerous studies have focused on identifying crucial ‘longevity’ genes and correcting their expression levels in aged animals as a way to potentially rejuvenate them.
Such techniques as real-time quantitative PCR (qPCR or RT-PCR) and RNA sequencing (RNA-seq) are used to compare gene expression levels in different conditions, including aging. More often than not, the research is then reduced to a specific set of genes or pathways for practical reasons.
In this study, the researchers sought to explore aging-associated gene expression changes at a global level instead of evaluating individual genes. They analyzed transcriptomic data for mice and checked if their conclusions held true across several species, including humans.
First, the scientists performed RNA-seq on various tissues taken from male mice at 4, 9, 12, 18, and 24 months old. Gene expression changes were inferred by comparing the expression level of each gene at a given age to its expression at 4 months of age in the corresponding tissue.
Next, the researchers applied a machine learning technique to identify which molecular features were associated with the age-related gene expression changes in mice. They show that the length of mature transcripts, i.e. after they’ve been processed and are now ready to be used for protein synthesis, is the most informative feature.
Importantly, with increased age, long transcripts demonstrate a decrease in expression for most tissues. In other words, the abundance of transcripts from long genes compared to short genes changes in old mice. The researchers coined this phenomenon “length-associated transcriptome imbalance”. They confirmed this observation using two other experimental techniques: proteomics and NanoString.
Of mice, men, rats, and killifish
To investigate if the length-associated transcriptome imbalance is a conserved feature across different species, the researchers reverted to previously published studies. They analyzed transcriptomic data from two mouse studies, one rat study, and a killifish study.
Although the amount of available data, e.g. the number of tissues, varied for these species, the results confirmed an age-dependent transcriptome imbalance. For all the organisms considered, approximately 80% of tissues demonstrated an age-related decrease in long transcripts.
Next, the researchers analyzed several sets of single-cell data during mouse aging to investigate if specific cell types or tissues were responsible for the observed transcriptome imbalance. They did not detect any variability and concluded that it was an organism-wide phenomenon.
Finally, the researchers analyzed data available for human tissues. The results were mostly consistent with the previous findings: in both middle-aged (40 to 59) and older adults (60 to 79), a decreased expression of long transcripts was observed. In humans but not mice, one tissue seems particularly prone to this transcriptome imbalance: the brain.
Another set of analyses revealed that the length of both mouse and human genes correlates with their ‘longevity power’. Indeed, the ‘anti-longevity’ genes mostly encode the shortest transcripts, while the longest transcripts are the products of ‘pro-longevity’ genes.
Reversing transcriptome imbalance
The outstanding question, then, is: can or even should anything be done about this age-dependent transcriptome imbalance? Fortunately, the researchers addressed this too. They looked into 11 interventions previously shown to be able to extend mouse lifespan within the Interventions Testing Program of the NIA.
According to the data they analyzed, seven of these anti-aging interventions increase the abundance of long transcripts, including rapamycin, resveratrol, senolytics, and FGF21. On the other hand, metformin and eating every other day were not effective in this respect.
In addition, the researchers highlight that length-associated transcriptome imbalance can be reverted by partial reprogramming, as evidenced by their analysis of a study on retinal ganglion cell rejuvenation .
Aging is among the most important risk factors for morbidity and mortality. To contribute toward a molecular understanding of aging, we analyzed age-resolved transcriptomic data from multiple studies. Here, we show that transcript length alone explains most transcriptional changes observed with aging in mice and humans. We present three lines of evidence supporting the biological importance of the uncovered transcriptome imbalance. First, in vertebrates the length association primarily displays a lower relative abundance of long transcripts in aging. Second, eight antiaging interventions of the Interventions Testing Program of the National Institute on Aging can counter this length association. Third, we find that in humans and mice the genes with the longest transcripts enrich for genes reported to extend lifespan, whereas those with the shortest transcripts enrich for genes reported to shorten lifespan. Our study opens fundamental questions on aging and the organization of transcriptomes.
This study uncovered a conserved molecular feature of age-associated global transcriptome changes. It is, however, unclear if the transcriptome imbalance is specific to aging. Similarly to cellular enlargement, it could have several molecular origins, including DNA damage and loss of proteostasis. It is nevertheless promising that length-associated transcriptome imbalance is amenable to anti-aging interventions. Future studies should shed light on the role and causes of aging-related transcriptome imbalance.
 Stoeger, T. et al. Aging is associated with a systemic length-associated transcriptome imbalance. Nature Aging 1–16 (2022)
 Lu, Y. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020)