micro-RNA as a buffer against age-related changes in gene expression

As we know from too many studies to cite here, gene expression changes dramatically over the course of aging. Chaperone expression rises; anabolic pathways fall; and myriad other alterations take place, many in a tissue-specific manner.

It’s in that context that a recent result from Williams et al. is surprising: In mouse lung, the expression proflie of micro-RNAs (miRNAs) seems to remain relatively constant over the course of aging:

microRNA expression in the aging mouse lung

MicroRNAs (miRNAs) are a novel class of short double stranded RNA that mediate the post-transcriptional regulation of gene expression. Previous studies have implicated changes in miRNA expression in the regulation of development and the induction of diseases such as cancer. However, although miRNAs have been implicated in the process of aging in C. elegans, nothing is known of their role in mammalian tissues. Results: To address this question, we have used a highly-sensitive, semi-quantitative RT-PCR based approach to measure the expression profile of 256 of the 493 currently identified miRNAs in the lungs from 6 month (adult) and 18 month (aged) old female BALB/c mice. We show that, despite the characteristic changes in anatomy and gene expression associated with lung aging, there were no significant changes in the expression of 256 miRNAs. Conclusion: Overall, these results show that miRNA transcription is unchanged during lung aging and suggests that stable expression of miRNAs might instead buffer age related changes in the expression of protein-encoding genes.

miRNAs are unusual genes: Rather than encoding proteins, these short RNAs serve to regulate the stability and/or translation of other transcripts within the cell; they hybridize to mRNAs and either target them for degradation or prevent their efficient translation into protein. Mammalian genomes contain hundreds of miRNA genes, and since each miRNA can potentially regulate many transcripts, it’s becoming clear from a huge body of recent work that miRNAs are a key player in the story of how genomic information gets converted into protein (and thus phenotype).

One type of article in the recent bumper crop of miRNA papers follows the following formula: The authors look at the miRNA expression profile in their condition of interest, compare it to some reasonable-sounding baseline, and characterize the miRNAs that differ significantly between the two states. Invariably, tens (or even hundreds) of miRNAs differ. The authors then go on to cherry-pick a particularly robustly regulated miRNA, identify a target, and make an argument about the biological significance of the regulatory program. On my desk alone, there are dozens of such papers, on subjects ranging from cancer to development, in at least five different vertebrate species.

Given that, it’s genuinely shocking to see a phenomenon as variegated as aging — one that is, moreover, already known to be associated with a wide range of gene expression changes — come up empty on the miRNA front. Hence, what others of the glass-half-empty school might term a “negative result” sounds to me (and to the authors) like real news.

The authors propose that the constant levels of miRNAs serve to attenuate age-related alterations in gene expression that occur at the transcriptional level. It’s likely that some of the changes in transcription are maladaptive, not so much regulated events as stochastic perturbations run amok (see our earlier articles, Genomic instability and transcriptional noise and Stochastic effects on lifespan determination). Maintaining constant levels of particular miRNAs (ones that target the genes most likely to undergo perturbation, or whose unscheduled expression are the most harmful) would buffer this deleterious random noise. Even though certain transcripts were being inappropriately expressed, the miRNA buffer would prevent them from being translated into protein, thereby preserving cellular homeostasis.

This idea lends itself to some testable hypotheses: The proteomes of cells with inefficient miRNA processing should be less robust (i.e., more prone to perturbation) and these cells should fare poorly late in the lifespan. Lowering levels of miRNA might even accelerate cellular aging. While it’s not possible to make an entirely miRNA-free animal, tissue-specific conditional mutants in the miRNA processing machinery might allow us to test whether miRNA plays a role in slowing age-related decline.

A corollary of this model might allow us to address a puzzle in the study of gene expression during aging. Granted that some fraction of the genome is regulated differently in old vs. young cells — are these changes protective (as in the case of heat shock proteins), neutral (i.e, programmed responses to other changes that don’t affect cellular homeostasis), or maladaptive (in the sense of causatively responsible for age-related decline)? If the constancy of the miRNA profile is protective and adaptive, then one would predict that miRNA targets whose transcript levels increase in old cells would be likely to encode genes in the third category: genes whose expression is actively detrimental to the cell, and whose translation should be restrained in order to maintain proper cellular function and increase the chances of survival.

One comment

  1. I am perplexed by the suggested conclusion that:

    “Overall, these results show that miRNA transcription is unchanged during lung aging and suggests that stable expression of miRNAs might instead buffer age related changes in the expression of protein-encoding genes.”

    If a specific tissue type is aging over time, yet there are no measured changes in miRNA expression, is it not more likely that miRNAs have little or nothing to do with aging rather than assume a “buffering” role? I do not mean in any way to downplay the importance of miRNAs. I merely don’t understand how the authors of that publication would first jump to a conclusion that flatline miRNA expression would be actively playing a role in the aging process. Am I missing something?

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