For many years, it has been known that lower temperatures encourage longevity in various animals.
The exact mechanism underlying this has remained a mystery, but recent study indicates low temperatures can trigger a biological process that enhances the removal of protein aggregations that are misfolded.
Alzheimer’s disease and other neurodegenerative disorders are among the aging-related diseases that have been linked to misfolded proteins.
The identification of this mechanism may improve our knowledge of how to treat human disorders brought on by protein misfolding.
Since more than 50 years ago, it has been recognised that lower temperatures make people live longer, but the exact mechanisms by which this is true have remained a mystery.
In recent years, researchers have uncovered the mechanism underlying the extended worm lifespan and demonstrated how it affects human cells.
Researchers from Cologne, Germany, published their findings in the journal Nature Aging and found that a molecule that breaks down protein clumps is more active at lower temperatures.
This activity may contribute to a decrease in the prevalence of dangerous misfolded proteins, which are thought to contribute to the development of a number of aging-related diseases like Alzheimer’s disease.
Transforming attitudes towards ageing
A few decades ago, it was thought that the buildup of poisons from oxidation was the cause of ageing. This changed in the 1990s once it was discovered that the genetic model organism C. elegans, a species of worm, could live longer at lower temperatures, according to Professor David Vilchez, the study’s primary author and director of the CECAD Research Center at the University of Cologne.
“We chose to concentrate on cold temperatures because it was recognized [more than 50 years ago] that cold temperatures can increase longevity Hence, it was discovered in flies, Drosophila proved in C. elegans, also proved in fish, and most recently proved in mice. Thus, it is actually one of the best methods for extending longevity for many people.
The potential for this discovery to offer insight on the mechanisms underlying ageing didn’t become obvious until the process’ genetic regulation was revealed in 2012 in a publication published in Cell, according to Prof. Vilchez.
There is a notion that claims that since 1860, human body temperatures have been declining by 0.03°C every decade, despite the fact that all of these research have been conducted on animal models. Others have linked this result to the fact that life expectancy has been rising since then, however this is just a correlation and the explanation has not been established.
Removing aggregations of improperly folded proteins
Researchers grew worms at 25oC and then relocated them to surroundings set at 15 degreeC, 20 degreeC, and 25 degreeC to study how cold temperatures affected the worms. They discovered that the activity of the molecule in charge of removing misfolded proteins from cells significantly increased at lower temperatures.
Subsequent investigation revealed that this was caused by the activation of a cell channel that functions at lower temperatures to promote the production of certain proteins implicated in the cellular process.
The quantity of misfolded proteins in worm cells was later shown to decrease at lower temperatures.
Researchers employed worms with changed genomes to mimic crucial aspects of two aging-related human disorders, Huntington’s disease and amyotrophic lateral sclerosis, in order to further examine this (ALS). These models were simple to create because, in contrast to multifactorial diseases like Alzheimer’s, each of these disorders are brought on by mutations in a single gene.
In worm models of Huntington’s disease and ALS, they discovered that the same mechanism was triggered at low temperatures and prevented the aggregation of improperly folded proteins.
Aid in the treatment of Huntington’s disease
An area of the Huntingtin gene, which codes for a particular amino acid, the building block of proteins, is repeated excessively in people with Huntington’s disease.
Dr. Natalia Pessoa Rocha, a researcher on Huntington’s disease at the University of Texas Health Science Center in Houston who was not involved in the study, described the polyglutamine tail that results from the extra amino acids on the protein. This might lead to proteins folding incorrectly.
Although the protein can fold, if it misfolds, it can collect into hazardous aggregates for cells. This is a very well-known mechanism in the aggregation of misfolded proteins that occurs in Alzheimer’s, Parkinson’s, and other neurodegenerative illnesses. Hence, this characterizes Huntington’s,” she stated.
Researchers discovered that lowering the temperature of human cells to 36 oC resulted in the same cell process being triggered, in addition to discovering that cold temperatures increase the clearance of misfolded proteins in worms.
At 35oC, however, the opposite was discovered, indicating that moderately low temperatures are the best for inducing this process in human cells. It was also discovered that overexpression of the genes in charge of this mechanism induced this pathway, which led to an increase in the molecules that help cells get rid of misfolded proteins.
In order to lessen the protein aggregation linked to sickness, etc., we were able to express the protein in human cells in vitro and truly simulate what happens at cold temperatures.
Future research on aging
Although it is a long way off, Prof. Vilchez stated that the results of this study may assist to direct future research towards treating neurodegenerative illnesses brought on by protein misfolding by identifying a molecule in the process that might be utilised as a medication target.
It is an extremely significant paper. They could pinpoint a crucial target for every disease caused by a protein problem. Not just Huntington’s, but particularly Alzheimer’s Parkinson’s, and other disorders, as I told you,” he said.
Nonetheless, there is still much to be done to convert this into human terms. People are almost always highly thrilled when a new target is there, so we need to be careful about how we convey this message, according to Dr. Pessoa Rocha. When human cells’ temperature was lowered to 36 °C, the same cell process was induced.
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