A bridge between CR, DNA damage, and transcriptional dysregulation in aging?

In past years, I was fond of comparing biogerontology to the tale of the blind men and the elephant: everyone was approaching the problem from different directions, unable to see the big picture — and reaching conclusions that had more to do with the direction of approach (i.e., initial biases) than the fundamental importance of any given observation.

But this analogy is becoming increasingly less apt, and we may be on the verge of the era of unifying theories in the biology of aging.

What causes aging? The various subfields of biogerontology answer this question in very different ways. To vastly oversimplify: In one corner we have metabolism, including the related stories of sirtuins and calorie restriction; in another corner, we have DNA damage and stochasticity of gene expression. (Already we’re seeing the unifying tendency of recent findings: a few years ago I might have put those four items in four separate corners, but on the basis of recent reports I feel comfortable starting to bin them together. There are those, however, who would argue I’m being premature if not outright inaccurate in so doing.) In both corners, one could make a legitimate claim that the phenomenon in question has serious explanatory power regarding a fundamental mechanism of aging or longevity assurance — but is there a connection between the two?

Quite possibly. A major paper from Oberdoerffer et al. has investigated the role of sirtuins (specifically, yeast Sir2 and mammalian SIRT1) in chromatin. Over the course of their elegant study, the authors trace the parallels between sirtuins’ roles in yeast and human genome stability — and in the process, build a bridge between sirtuin activity, DNA damage, and transcriptional dysregulation:

SIRT1 Redistribution on Chromatin Promotes Genomic Stability but Alters Gene Expression during Aging

Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in the desilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizes to DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the aging mouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability and suppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin-modifying proteins may be a conserved mechanism of aging in eukaryotes.

In both yeast and mammals, Sir2/SIRT1 relocalizes from its original location to sites of DNA damage. This may be a good thing — the sirtuin appears to be involved in recruiting DNA repair factors to break sites — but it has a negative consequence: The departure of Sir2/SIRT1 from its original perch can result in transcriptional derepression (recall that SIR genes were originally identified in S. cerevisiae as silent information regulators). The extent of such derepression will depend on SIRT1 levels/activity and also the extent of the damage — but it’s fairly obvious that the resulting transcriptional changes will have a stochastic component.

This probably isn’t such a bad thing when cells are young and damage is rare — but as either chronological or replicative age increases, damage becomes more prevalent (and even persistent), and the transcriptional changes due to SIRT1 relocalization could become quite severe.

That’s only part of the story: At damage sites, SIRT1 is promoting DNA repair and genomic stability (though evidence for the latter presented here is rather indirect, inferred from tumor spectra and cancer survival in a mouse model).

At both silenced promoters and DNA breaks, more SIRT1 (or SIRT1 activity; there’s a subtle but important distinction having to do with whether the protein is playing a stoichiometric or catalytic role) appears to be a good thing: More protein means that the “dilution” resulting from SIRT1 relocalization will result in less net loss from sites of transcriptional repression; similarly, higher levels of SIRT1 result in lower levels of genomic instability in response to DNA damage, presumably because there’s more SIRT1 around to do its thing at break sites. To complete their unifying bridge, the authors close the paper with a speculation that calorie restriction’s effect on lifespan might be mediated by increasing SIRT1 levels or activity in both arenas.

According to the authors’ interpretation, SIRT1 is performing two important functions — controlling transcription and ensuring efficient DNA repair — both of which (the authors claim) are essential for longevity assurance. This seems very reasonable, though the formal logic is slightly strained: just because SIRT1 improves genomic stability, prevents transcriptional derepression and extends lifespan doesn’t mean that the (now clearly related) former two functions are in any way related to the latter one. Sorting out causation will be a challenge, requiring some high-impact genetics — perhaps involving an approach that uncouples SIRT1’s silencing function at promoters with its affinity for or activity in damage sites. Probably crazy hard, but not impossible, and logically rather important to the model.

(See also the treatment of this article at ScienceNOW.)


  1. I agree with you, very interesting and potentially an important paper. Nice to have things start coming together. Hopefully things will continue this way and we finally get a cohesive understanding.

    thanks for doing such a good job covering this paper.


  2. If my layman’s interpretation is correct, the paper –
    “Is caspase-dependent apoptosis only cell differentiation taken to the extreme?”
    – conjectures that, rather than simply being caused by collateral metabolic damage, “transient DNA single strand breaks” and “alterations in nuclear morphology” are a purposeful part of a stochastic differentiation program.

    A corroborating paper is
    “Enzyme plays key role in cell fate”

    Is this plausible?
    Do less “differentiated” cells exhibit fewer chromatin modifications?

  3. the problem with all these theories is they do not explain why animals which never stop growing never age.

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