Is it hot in here, or is it just SIRT1? Sirtuins activate heat shock transcription

Longevity is correlated with stress resistance. This makes abundant sense: Aging is (among other things) the decreasing ability to maintain cellular homeostasis over time. Cellular stress responses, broadly speaking, detect suboptimal conditions and activation of gene expression aimed at correcting the problem — a fairly reasonably definition of maintaining homeostasis. So it seems reasonable that more robust stress responses (or high basal expression of stress response target genes) would be associated with delayed aging and extended lifespan; indeed, this relationship has been used more than once to screen for long-lived mutants.

The heat shock proteins (HSPs), originally characterized (and therefore named) in the context of cellular responses to high-temperature stress, appear to play a critical role in regulation of lifespan, as illustrated by two examples from C. elegans: Expression levels of hsp-16.2, which vary stochastically even within clonal populations, are correlated with lifespan. Consistent with this, heat shock factor (HSF), the transcription factor that governs the heat shock response, is required for the lifespan extension caused by daf-2 mutations. (Mechanistically, HSF may serve this function by activating target genes that drive disaggregation and degradation of malfolded proteins.)

The heat shock response has now been connected to another major player in lifespan regulation: SIRT1, the most well-studied member of the sirtuin family. In mammals, HSF is subject to acetylation, which diminishes its ability to bind DNA and activate transcription – but this modification can be removed by the longevity assurance factor SIRT1, which is a protein deacetylase. From Westerheide et al. (see also the Perspectives piece in the same issue of Science):

Stress-Inducible Regulation of Heat Shock Factor 1 by the Deacetylase SIRT1

Heat shock factor 1 (HSF1) is essential for protecting cells from protein-damaging stress associated with misfolded proteins and regulates the insulin-signaling pathway and aging. Here, we show that human HSF1 is inducibly acetylated at a critical residue that negatively regulates DNA binding activity. Activation of the deacetylase and longevity factor SIRT1 prolonged HSF1 binding to the heat shock promoter Hsp70 by maintaining HSF1 in a deacetylated, DNA–binding competent state. Conversely, down-regulation of SIRT1 accelerated the attenuation of the heat shock response (HSR) and release of HSF1 from its cognate promoter elements. These results provide a mechanistic basis for the requirement of HSF1 in the regulation of life span and establish a role for SIRT1 in protein homeostasis and the HSR.

The relationship between a master regulator of aging (SIRT1) and an effector pathway (HSF and its target genes) is another example of an emerging trend in the biogerontological literature: the unification of separate longevity control mechanisms. (By “unification”, I don’t mean that these separate mechanisms are shown to be literally equivalent; I simply mean that our increasing knowledge of the connections between genes and their functions has revealed that many phenomena previously thought to act independently are in fact coordinated by regulatory factors).

These findings may also give mechanistic insight into a curious observation from a couple of years ago: resveratrol, an activator of SIRT1, induces the heat shock response. (When we discussed that study, I lamented that the authors hadn’t determined whether SIRT1 was required for the effect — in light of this paper, it does seem that they missed a pretty big boat.) It now seems reasonable to explain those data as follows: resveratrol activates SIRT1, which deacetylates HSF, which in turn binds DNA more efficiently and increases transcription of heat shock response genes. A strong prediction of this model is that HSF should be necessary for any lifespan extension resulting from resveratrol treatment.


One comment

  1. Thanks for your work.
    Might I suggest you also Tag these Disaggregation of malfolded proteins AND
    Degradation of malfolded proteins. Seems to be getting to the crux of a line of thinking about aging.

    …And so what are those calorie restricted critters dying of? Do the malfolded and non-degraded proteins catch up with them anyway or is something else?

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