The shock of aging: molecular chaperones and the heat shock response in longevity and aging--a mini-review

Abstract

Background: Aging can be thought of as the collision between destructive processes that act on cells and organs over the lifetime and the responses that promote homeostasis, vitality and longevity. However, the precise mechanisms that determine the rates of aging in organisms are not known.

Objective: Macromolecules such as proteins are continuously exposed to potential damaging agents that can cause loss of molecular function and depletion of cell populations over the lifetime of essential organs. One of the key homeostatic responses involved in maintaining longevity is the induction of heat shock proteins (HSPs), a conserved reaction to damaged intracellular proteins. We aim to discuss how the interplay between protein damage and its repair or removal from the cell may influence longevity and aging.

Methods: We have reviewed experiments carried out in mammalian and non-mammalian organisms on molecular chaperones and the transcription factor (heat shock factor 1, HSF1) responsible for their expression. We have discussed mechanisms through which these molecules are regulated in cells, respond to stimuli that enhance longevity and become impaired during aging.

Results: The transcription factor HSF1 initiates the prolific induction of HSP when cells are exposed to protein damage. HSPs are molecular chaperones that protect the proteome by folding denatured polypeptides and promoting the degradation of severely damaged proteins. Activation of HSF1 is coupled functionally to fundamental pathways of longevity and orchestrates the evasion of aging through HSP induction and antagonism of protein aggregation. In addition to mediating protein quality control, some HSPs such as Hsp27 and Hsp70 directly protect cells against damage-induced entry into death pathways. However, the heat shock response declines in potency over the lifetime, and enfeeblement of the response contributes to aging by permitting the emergence of protein aggregation diseases, reduction in cellular vigor and decreased longevity.

Conclusions: Molecular chaperones play an important role in the deterrence of protein damage during aging and their expression is required for longevity. Chemical stimulation of HSP synthesis might therefore be a significant strategy in future design of antiaging pharmaceuticals.

Fig. 1.

Pathways of protein folding after exposure to protein damage during aging. Unfolded proteins accumulate in aging cells due to their exposure to damaging stresses or expression of proteins with dominant conformations that tend towards aggregation. Such proteins can, however, be folded by ATP-dependent chaperones such as Hsp70 or small HSP such as Hsp27 that function independently of ATP and tend to form high-molecular-weight folding complexes. Each pathway plays a significant role in longevity through recognition and refolding of damaged proteins.

Fig. 2.

Quality control, salvage and disposal pathways for damaged proteins. Proteins acquire multiple forms of damage over the lifetime of the organism leading to unfolding. Such alterations then trigger protein aggregation and formation of inclusion bodies (as in pathway 1). Denatured and aggregated proteins can, however, be recognized by HSPs that bind exposed hydrophobic domains in the misfolded proteins and lead to salvage and refolding of the denatured protein directly through pathway 2. However, unfolded proteins may persist in the cytoplasm and enter a third pathway (3) through binding of the Hsp70 to CHIP. Recruitment of CHIP leads to ubiquitinylation of the damaged protein and degradation by the proteasome. Pathways 2 and 3 thus compete for the denatured proteins. Another protein degradation pathway (4) is also mediated by molecular chaperones. A subset of damaged proteins is bound to Hsp70 family member Hsc70 and transported to the lysosome for degradation in CMA.

Fig. 3.

HSF1 in longevity and aging. HSF1 is activated when damaged proteins derepress its activity, permit HSP expression and stimulate repair of protein damage . HSF1 can also be directly stimulated by longevity stimuli such as the histone deacetylase SIRT1 that directly activates HSF1 by deacetylation and fosters longevity. Aging, however, is associated with a gradual decline in potency of the heat shock response and this may prevent repair of protein damage, leading to degeneration and cell death.

Fig. 4.

HSF1 regulation by damaged proteins. Damaged proteins may accumulate in cells due to exposure to proteotoxins or decline in protein degradation pathways. Such damaged proteins cause the release of HSF1 from inert cytoplasmic complexes containing Hsp90 and its co-chaperones including p23 and cyclophilins (CY), trimerization, migration to the nucleus and binding to HSP gene promoters. Full HSF1 activation involves the triggering of a complex network of posttranslational modifications that lead to hyperphosphorylation and deacetylation of key residues. Loss of HSF1 inducibility in aging may involve alterations in HSF1-chaperone complexes or in signal transduction pathways upstream of enzymes that regulate hyperphosphorylation or deacetylation.