A paper published today in Nature Aging describes how cold temperatures stimulate the production of PA28γ, a protein that appears to increase lifespan in worms and cells.
An explanation for a commonly held belief
Cold temperatures have been associated with longevity for more than a hundred years [1]. The conventional explanation is that this is because cold temperatures slow down metabolism [2]; however, other experiments have shown that the longevity effects in worms are not related to this concept [3].
The researchers hypothesized that this is connected to the proteasome, which is responsible for the breakdown of protein. This mechanism is largely evolutionarily conserved among all life with nucleated cells [4], meaning that it is similar between worms and people. The human protein PA28γ, which has a worm analog of PSME-3, plays a significant role in breaking down proteins and is expressed throughout the body [5], and this was the key protein in this experiment.
Influences on basic biology in worms
The researchers used three groups of sterile worms for this experiment, kept at 15, 20, and 25 degrees Celsius. While most aspects of the proteasome and its relevant proteins were unaffected or not significantly affected by this difference in temperature, levels of PSME-3 compared to another common protein were significantly changed at 15 degrees compared to 20 and 25 degrees. The levels of mRNA that code for PSME-3 were even more sharply affected.
Using knockdown mutants that do not produce PSME-3, the researchers confirmed their findings. These worms did not receive any of the increased proteasome activity associated with cold temperatures. Investigating further, the researchers found that another protein, TRPA-1, modulates the effects of PSME-3 at cold temperatures, and worms without PSME-3 were not affected by TRPA-1 or its lack.
This and other knockdowns of proteasome complexes were found to shorten lifespan, showing that all of the proteasome is required for longevity. However, only PSME-3 was associated with longevity at cold temperatures; worms that produced PSME-3 were shown to live longer at cold temperatures, and worms that did not produce it had no such benefits.
Effects on human cells
These effects were recapitulated in the HEK293 human cell line. Shifting these cells’ temperature from the human normal of 37 degrees C to 36 degrees caused their PA28γ levels to rise, similar to the effects of cold on worms. TRPA1 was found to have similar effects to its worm analog as well.
Human disease-related proteins were found to be more strongly degraded by the increase in PA28γ. The huntingtin protein, which is responsible for Huntington’s disease, was one of these proteins, as was mutant FUS, a protein related to amyotrophic lateral sclerosis. Cold temperatures improved protein degradation in both the cytoplasm and the nucleus.
Most importantly, and in contrast to worms, PA28γ was found to increase proteasomal activity even at warm temperatures, suggesting that this may be a valid and easily accessible target for therapies.
Conclusion
This is a study on cells and worms, not mammals. However, given how much of the proteasome is evolutionarily conserved, and the similarities between the results, this line of research certainly merits further study. Mouse experiments would be the next logical step to take to determine if PA28γ is a potential target for proteostasis-related diseases.
Literature
[1] Loeb, J., & Northrop, J. H. (1916). Is there a temperature coefficient for the duration of life?. Proceedings of the National Academy of Sciences, 2(8), 456-457.
[2] Conti, B., & Hansen, M. (2013). A cool way to live long. Cell, 152(4), 671-672.
[3] Xiao, R., Zhang, B., Dong, Y., Gong, J., Xu, T., Liu, J., & Xu, X. S. (2013). A genetic program promotes C. elegans longevity at cold temperatures via a thermosensitive TRP channel. Cell, 152(4), 806-817.
[4] Finley, D. (2009). Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annual review of biochemistry, 78, 477-513.
[5] Stadtmueller, B. M., & Hill, C. P. (2011). Proteasome activators. Molecular cell, 41(1), 8-19.
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