HSP70 to the rescue

Hormesis is a process through which moderate stress induces a body response that is protective against insults, confers health and possibly even longevity benefits.  The process of hormesis is thought to be mediated primarily via heat shock proteins (HSPs).  An introduction to these topics is provided in the blog entry Hormesis and age retardation.  Also, see my blog entry Stress and longevity for a further discussion of how moderate stresses confer longevity.  In this blog entry I thought I would further explore how hormesis and heat shock proteins work, focusing primarily on the HSP70 superfamily of proteins.  Frankly, I was shocked (sort of by intellectual heat) to discover the complexity of the biomolecular processes involved and gave up on the process a few times until I finally decided to dig into it.  In this blog entry I will attempt a simplified explanation of how hormesis and the HSP70 chaperone proteins work to exercise their health benefits.  Even simplified the topic is still complex, so please fasten your mental seat belts.

First of all, heat stress, oxidative stress and other kinds of stress can cause the improper unfolding of proteins in the endoplasmic reticulum in cells.  “Proteins in the endoplasmic reticulum (ER) require an efficient system of molecular chaperones whose role is to assure their proper folding and to prevent accumulation of unfolded proteins,  triggering what is known as the “unfolded protein response” (UPR). UPR is a functional mechanism by which cells attempt to protect themselves against ER stress, resulting from the accumulation of the unfolded/misfolded proteins.” The quote is from the 2004publication Endoplasmic Reticulum Stress and Unfolded Protein Response in Inclusion Body Myositis Muscle.

The UPR is an ancient response shared among many living things.  “The unfolded protein response (UPR) is a cellular stress response — that has been found to be conserved between all mammalian species, as well as yeast and worm organisms.   The UPR is activated in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum. In this scenario, the UPR has two primary aims: initially to restore normal function of the cell by halting protein translation (genetics) and activate the signaling pathways that lead to increasing the production of molecular chaperones involved in protein folding. If these objectives are not achieved within a certain time lapse or the disruption is prolonged, the UPR aims to initiate programmed cell death (apoptosis)(ref).”  While you are at it, by the way, you might want to check out The Incorrect protein folding theory of aging discussed in my treatise.  The basic notion is that stress often leads to the misfolding of proteins, a process that can accelerate with age creating dysfunctional conditions and vulnerability to a number of diseases.  Misfolded proteins cannot perform their intended functions and can create active mischief.  In a nutshell, the role of the HSP70 heat shock proteins is to mobilize when large numbers of misfolded proteins show up due to stress, and to fold them up properly again.  So, HSP70 proteins play important roles in health maintenance and possibly also in longevity.

On a macroscopic level HSP70 proteins are known to play a number of important roles.  See for example the 2008 paper Inducible heat shock protein 70 and its role in preconditioning and exercise.  Preconditioning has been shown to confer cellular protection via expression Hsp, which may be of benefit in preventing protein damage following subsequent periods of exercise.”  The 2002 review paper Neuroprotection: heat shock proteins states “This chapter highlights the involvement of HSP70 involvement in the pathophysiology of cerebral ischaemia, from the original reports of HSP70 expression after cerebral ischaemia to evidence of HSP70 neuroprotection and the potential mechanisms which might mediate this cellular protection.” 

 The neuroprotective mechanisms of HSP70 are multiple as is pointed out in the 2002 review publication Heat shock proteins and neuroprotection.  In response to many metabolic disturbances and injuries including stroke, neurodegenerative disease, epilepsy and trauma, the cell mounts a stress response with induction of a variety of proteins, most notably the 70 kD heat shock protein (Hsp70). The possibility that stress proteins might be neuroprotective was suspected because Hsp70, in particular, was induced to high levels in brain regions that were relatively resistant to injury. Hsp70 expression was also correlated with the phenomenon of induced tolerance. With the availability of transgenic animals and gene transfer, has it become increasingly clear that such heat shock proteins do indeed protect cells from injury. Several reports have now shown that selective overexpression of Hsp70 leads to protection in several different models of nervous system injury. This review will cover these studies, along with potential mechanisms by which Hsp70 might mediate cellular protection.” 

HSP70 is of course only one of several heat shock protein families.  Other HSP proteins may exercise similar or complimentary effects.  The example, HSP90 is discussed in the 2010 publication Heat shock protein 90 in neurodegenerative diseases.

The 2004 publication Many mechanisms for hsp70 protection from cerebral ischemia tells “In addition to the well-studied role of Hsp70 as a molecular chaperone assisting in correct protein folding, several new mechanisms by which Hsp70 can prevent cell death have been described. Hsp70 is now known to regulate apoptotic cell death both directly by interfering with the function of several proteins that induce apoptotic cell death as well as indirectly by increasing levels of the anti-death protein bcl-2. Despite these new insights into the ways in which Hsp70 functions as an anti-death protein, further surprises are likely as we continue to gain insight into the functioning of this multifaceted protein.”

The HSP70 superfamily consists of multiple members, and each member seems to have distinct properties in terms of structure, cellular localization, function and response to stress(ref).   “In humans, 17 genes for the HSP superfamily are grouped into the HPS110 family and the HSP 12 family(ref).”  And these families in turn have identified subfamilies.  The functions of the HS{70 superfamily proteins are regulated and/or modified by co-chaperones, particularly in the J-family and in the BAG family.  Again, the pathways appear to be ancient and conserved across a variety of species and the interactions are complex and in several cases not well understood.

Much of our limited knowledge of what goes on comes from study of what goes on in other much-simpler species, an example being the ascidian Ciona intestinalis.  See the 2010 publication Stress response in the ascidian Ciona intestinalis: transcriptional profiling of genes for the heat shock protein 70 chaperone system under heat stress and endoplasmic reticulum stress.  .  “Most stress-inducible genes are conserved between Ciona and vertebrates, as expected from a close evolutionary relationship between them. The present study characterized the stress responses of HSP70 chaperone system genes in Ciona for the first time and provides essential data for comprehensive understanding of the functions of the HSP70 chaperone system.”

How do HSP70s basically work?  The 2005 paperThe 2005 paper HSP70 chaperones: cellular functions and molecular mechanism has this to say: “Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a large variety of protein folding processes in the cell by transient association of their substrate binding domain with short hydrophobic peptide segments within their substrate proteins. The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus, ATP binding and hydrolysis are essential in vitro and in vivo for the chaperone activity of Hsp70 proteins. This ATPase cycle is controlled by co-chaperones of the family of J-domain proteins, which target Hsp70s to their substrates, and by nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this chaperone cycle. For specific tasks the Hsp70 cycle is coupled to the action of other chaperones, such as Hsp90 and Hsp100.”

Most of the studies related to HSP70 appear to be highly focused and related to strange species far removed from humans, for example 2010 study Molecular cloning and expression of two HSP70 genes in the Wuchang bream (Megalobrama amblycephala Yih), the 2007 publication An inducible 70 kDa-class heat shock protein is constitutively expressed during early development and diapause in the annual killifish Austrofundulus limnaeus the 2004 study Expression of cytoprotective proteins, heat shock protein 70 and metallothioneins, in tissues of Ostrea edulis exposed to heat and heavy metals, and Sequencing and expression pattern of inducible heat shock gene products in the European flat oyster, Ostrea edulis and the 2008 study Inducible and constitutive heat shock gene expression responds to modification of Hsp70 copy number in Drosophila melanogaster but does not compensate for loss of thermotolerance in Hsp70 null flies.  It is very challenging, to say the least, to draw together the conclusions of these studies into a coherent picture relevant to humans except that, mostly but not always, “a phylogenetic analysis of the HSP70 family members from oyster and other bivalves revealed a substantial conservation in the evolutionary pattern among constitutive and inducible gene products, from invertebrates to higher vertebrates(ref).”

A maddening thing that keeps showing up in my longevity studies is that everything seems somehow to be connected to just about everything else, and HSP70 seems to be no exception.  For example it seems to have a role in the mitochondria as discussed in the 2010 publication Understanding the functional interplay between mammalian mitochondrial Hsp70 chaperone machine components.  “Mitochondria biogenesis requires the import of several precursor proteins that are synthesized in the cytosol. The mitochondrial heat shock protein 70 (mtHsp70) machinery components are highly conserved among eukaryotes, including humans. However, the functional properties of human mtHsp70 machinery components have not been characterized among all eukaryotic families. To study the functional interactions, we have reconstituted the components of the mtHsp70 chaperone machine (Hsp70/J-protein/GrpE/Hep) and systematically analyzed in vitro conditions for biochemical functions. We observed that the sequence-specific interaction of human mtHsp70 toward mitochondrial client proteins differs significantly from its yeast counterpart Ssc1. Interestingly, the helical lid of human mtHsp70 was found dispensable to the binding of P5 peptide as compared with the other Hsp70s. We observed that the two human mitochondrial matrix J-protein splice variants differentially regulate the mtHsp70 chaperone cycle. Strikingly, our results demonstrated that human Hsp70 escort protein (Hep) possesses a unique ability to stimulate the ATPase activity of mtHsp70 as well as to prevent the aggregation of unfolded client proteins similar to J-proteins. We observed that Hep binds with the C terminus of mtHsp70 in a full-length context and this interaction is distinctly different from unfolded client-specific or J-protein binding. In addition, we found that the interaction of Hep at the C terminus of mtHsp70 is regulated by the helical lid region. However, the interaction of Hep at the ATPase domain of the human mtHsp70 is mutually exclusive with J-proteins, thus promoting a similar conformational change that leads to ATPase stimulation. Additionally, we highlight the biochemical defects of the mtHsp70 mutant (G489E) associated with a myelodysplastic syndrome.”  This study illustrates that although the HSP pathway is highly conserved across multiple species, evolutionary changes have occurred, for example in how the mitochondrial HSP70 works in yeast and humans. 

The research literature related to HSPs consists of at least hundreds of documents and those cited here provide only a small sample.  Some summary conclusions are:

:·       The hormetic actions of HSPs appear to be evolutionarily conserved and apply to thousands of species, yeasts and plants as well as animal. They actions have to do with reaction to and protection against stresses of various kinds on the cellular level.

·       The same or almost the same HSP genes exist across numerous species.  A great deal of knowledge of human HSP70 comes from study of oysters.

·       In some particular  cases, however, HSP genes in humans might not be quite the same or work differently.

·       HSP70 works through complicated biological mechanisms and one of its functions is to properly refold proteins in the endoplasmic reticulum that have been unfolded due to stress.

·       As pointed out in earlier blog entries, the hormetic responses of HSP70 in humans may be evoked by exercise, taking cur cumin or certain other supplements, or many other mild stressors.  The results are often health-giving and possibly exercise  longevity effects on the organism.

·       Knowledge of heat shock proteins and the mechanisms of hormesis is primitive, perhaps comparable to knowledge of the American Continent among Europeans in 1600. 

·       There is much to be learned and a lot of current research on these subjects.   Perhaps new surprises are in store about new ways to harness HSP responses for disease prevention and life extension.  We will see.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at www.vincegiuliano.com and an extensive site of my art at www.giulianoart.com. Please note that I have recently changed my mailbox to vegiuliano@agingsciences.com.
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