Exploring Heat Shock Proteins and Longevity Via Hormesis

Many mild forms of environmental stress extend healthy life in laboratory species: yeast, flies, worms, and mice. None of the really interesting processes are fully understood at this point, but enough has been learned to think that there are numerous overlapping mechanisms involved. Thus we should expect to see that there is at least some overlap in the biochemical details of responses to calorie restriction, mild heat stress, exercise, and others including low toxin doses, despite the fact that they overall produce what look to be very different shifts in metabolism.

The activity of heat shock proteins is one shared mechanism seen in a number of different forms of life extension. As the name might imply these are proteins first cataloged in connection with the metabolic response to excessive heat, but they also turn out for cold, oxygen deprivation, and some other circumstances that stress cells. Heat shock proteins play a role in cellular housekeeping, helping to prevent harmful accumulations of misfolded proteins, among other tasks.

Hormesis is the name given to circumstances whereby beneficial results occur as a result of mild levels of damage and stress. Some of the benefit of calorie restriction, exercise, and so forth, arises due to the triggering of hormetic processes: a little damage spurs all sorts of cellular maintenance for an extended time, resulting in a net gain in integrity and less damage than would otherwise exist. Extended healthy longevity is the observable result. Heat shock proteins are just one of the mechanisms involved here - there are numerous others.

In the near future I imagine that some fraction of the researchers presently investigating drugs that might slow aging will move on to try to produce pharmaceutical means to trigger the beneficial side of hormesis. This seems like a plausible goal, especially in the case of heat shock proteins, given what is known today, but there doesn't seem to be a great deal of movement in this direction at the present time.

Here are a couple of recent papers from research groups looking into the mechanisms and connections associated with heat shock proteins and their effect on aging and longevity.

The long-term effects of a life-prolonging heat treatment on the Drosophila melanogaster transcriptome suggest that heat shock proteins extend lifespan

Heat-induced hormesis, i.e. the beneficial effect of mild heat-induced stress, increases the average lifespan of many organisms. This effect, which depends on the heat shock factor, [decreases] mortality rate weeks after the stress has ceased. To identify candidate genes that mediate this lifespan-prolonging effect late in life, we treated flies with mild heat stress (34°C for 2 hours) 3 times early in life and compared the transcriptomic response in these flies versus non-heat-treated controls 10-51 days after the last heat treatment.

We found significant transcriptomic changes in the heat-treated flies. Several hsp70 probe sets were up-regulated 1.7-2-fold in the mildly stressed flies weeks after the last heat treatment. This result was unexpected as the major Drosophila heat shock protein, Hsp70, is reported to return to normal levels of expression shortly after heat stress. We conclude that the heat shock response, and Hsp70 in particular, may be central to the heat-induced increase in the average lifespan in flies that are exposed to mild heat stress early in life.

Integrin-linked kinase modulates longevity and thermotolerance in C. elegans through neuronal control of HSF-1

Integrin-signaling complexes play important roles in cytoskeletal organization and cell adhesion in many species. Components of the integrin-signaling complex have been linked to aging in both Caenorhabditis elegans and Drosophila melanogaster, but the mechanisms underlying this function are unknown.

Here, we investigated the role of integrin-linked kinase (ILK), a key component of the integrin-signaling complex, in lifespan determination. We report that genetic reduction of ILK in both C. elegans and Drosophila increased resistance to heat stress, and led to lifespan extension in C. elegans without majorly affecting cytoskeletal integrity. In C. elegans, longevity and thermotolerance induced by ILK depletion was mediated by the heat-shock factor-1 (HSF-1), a major transcriptional regulator of the heat-shock response (HSR).


Trying to disentangle how misfolded proteins are removed is perplexing, e.g.,
"Inhibiting IGF1 Signaling Reduces Misfolded Protein Aggregation in Aging"
- However, "Activation of proteasome by insulin-like growth factor-I may enhance clearance of oxidized proteins in the brain"
- Perhaps, alternating between acute CR (which boosts proteasomes) and chronic CR (boosts autophagy) is worth considering. See -
"Relationship between the proteasomal system and autophagy"

A quick web search seems to indicate that many polyphenols/flavonoids inhibit proteasomes. Hard to know what to make of that.
Also, a recent press release speculates a trial drug "could be a revolutionary new technique to cure a wide range of human diseases—from cystic fibrosis to cataracts to Alzheimer's disease—that are caused by 'misfolded' protein molecules."

Posted by: Lou Pagnucco at December 10th, 2013 11:11 PM

I am not convinced that hormesis has been demonstrated to extend life in mice. The only mild stressor to robustly extend life in mice is CR: exercise extends mean but not maximum lifespan, and other putative cases used sick, ill-cared-for, and otherwise short-lived animals. To go from one intervention that happens to both be a mild stressor and a life-extender to a class effect is petitio principii at best.

Posted by: Michael at December 11th, 2013 8:48 AM

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