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Review
. 2011 May 17;30(13):2520-31.
doi: 10.1038/emboj.2011.162.

Cellular stress response pathways and ageing: intricate molecular relationships

Affiliations
Review

Cellular stress response pathways and ageing: intricate molecular relationships

Nikos Kourtis et al. EMBO J. .

Abstract

Ageing is driven by the inexorable and stochastic accumulation of damage in biomolecules vital for proper cellular function. Although this process is fundamentally haphazard and uncontrollable, senescent decline and ageing is broadly influenced by genetic and extrinsic factors. Numerous gene mutations and treatments have been shown to extend the lifespan of diverse organisms ranging from the unicellular Saccharomyces cerevisiae to primates. It is becoming increasingly apparent that most such interventions ultimately interface with cellular stress response mechanisms, suggesting that longevity is intimately related to the ability of the organism to effectively cope with both intrinsic and extrinsic stress. Here, we survey the molecular mechanisms that link ageing to main stress response pathways, and mediate age-related changes in the effectiveness of the response to stress. We also discuss how each pathway contributes to modulate the ageing process. A better understanding of the dynamics and reciprocal interplay between stress responses and ageing is critical for the development of novel therapeutic strategies that exploit endogenous stress combat pathways against age-associated pathologies.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
General and organelle-specific stress response pathways influenced by the ageing process. Depending on the type of macromolecule and the site of damage, distinct stress response pathways, such as autophagy, heat shock response, UPRmt, UPRER, remodelled proteasome and the DNA damage response are initiated. Ageing broadly affects stress response pathways in multiple steps. For simplicity, only proteins with functions modulated by ageing are depicted. Double arrows denote bi-directional communication with the nucleus, which involves generation of stress signals in the stressed organelle or the cytoplasm, transduction of the signals to the nucleus and upregulation of stress-relieving proteins, which in turn function to ameliorate damage. Question marks denote lack of information about specific molecules mediating the effects of ageing. Although, a typical Golgi stress response pathway has not been described yet, several types of stress and also ageing may influence gene expression in the nucleus and cell homeostasis by impinging on Golgi function. BER, base-excision repair; BiP, Ig-binding protein; CHOP, C/EBP homologous protein; CMA, chaperone-mediated autophagy; DAF-16, abnormal dauer formation 16; DVE-1, defective proventriculus 1; GRP94, glucose-regulated protein 94; HSF1, heat shock factor 1; HSP, heat shock protein; HR, homologous recombination; IGF-1, insulin growth factor 1; LAMP-2A, lysosome-associated membrane protein 2A; NER, nucleotide-excision repair; NHEJ, non-homologous end joining; PERK, PKR-like ER kinase; UPRER/mt, unfolded protein response endoplasmic reticulum/mitochondrion; XBP-1, X-box-binding protein 1.
Figure 2
Figure 2
Crosstalk between stress response pathways implicated in ageing. TOR and SIRT1 serve as central hubs in the stress response network connecting autophagy, DNA damage and the heat shock response. Protein misfolding, triggered by stress, depletes the pool of chaperones. Excess nutrition or reduced chaperone availability cause imbalance between mTORC1 assembly and disassembly, resulting in elevated signalling. The deacetylase SIRT1 targets multiple transcriptional regulators (p53, FOXO and HSF1), participating in distinct stress response pathways. SIRT1 activity is modulated by nutrient availability and is altered during ageing. Similarly, the efficiency of HSF1 activation and autophagosome clearance is impaired during ageing. As a consequence, heat shock protein production is perturbed. Excessive oxidative stress aggravates the symptoms of ageing and age-related pathologies. Activation of TOR increases transcription of SESN. SESN expression is dependent on ROS accumulation and involves JNK and FOXO. SESN is also the target of the tumour suppressor p53, which is activated upon genotoxic stress. Increased SESN activity inhibits TOR signalling by activating AMPK and TSC2. AMPK, adenosine monophosphate-activated protein kinase; FOXO, forkhead box O; HSF1, heat shock factor 1; HSP, heat shock protein; JNK, c-Jun N-terminal kinase; ROS, reactive oxygen species; SESN, sestrin; SIRT1, sirtuin1; TOR, target of rapamycin; TSC2, tuberous sclerosis complex 2.

References

    1. Abravaya K, Myers MP, Murphy SP, Morimoto RI (1992) The human heat shock protein hsp70 interacts with HSF, the transcription factor that regulates heat shock gene expression. Genes Dev 6: 1153–1164 - PubMed
    1. Akerfelt M, Morimoto RI, Sistonen L (2010) Heat shock factors: integrators of cell stress, development and lifespan. Nat Rev Mol Cell Biol 11: 545–555 - PMC - PubMed
    1. Anckar J, Hietakangas V, Denessiouk K, Thiele DJ, Johnson MS, Sistonen L (2006) Inhibition of DNA binding by differential sumoylation of heat shock factors. Mol Cell Biol 26: 955–964 - PMC - PubMed
    1. Anckar J, Sistonen L (2007) Heat shock factor 1 as a coordinator of stress and developmental pathways. Adv Exp Med Biol 594: 78–88 - PubMed
    1. Anselmi B, Conconi M, Veyrat-Durebex C, Turlin E, Biville F, Alliot J, Friguet B (1998) Dietary self-selection can compensate an age-related decrease of rat liver 20 S proteasome activity observed with standard diet. J Gerontol A Biol Sci Med Sci 53: B173–B179 - PubMed

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