Lower Body Temperature Supports Healthy Aging

Researchers from the University of Cologne’s CECAD Cluster of Excellence in Aging Research have uncovered one of the mechanisms by which a lower body temperature increases life expectancy. The study is published in Nature Aging.

Lower temperature, longer lifespan

When exposed to extremely cold temperatures, the human body starts to lose heat faster than it’s produced – this is hypothermia, a condition that can be dangerous or even fatal. A moderate decrease in body temperature, however, can elicit positive health effects in organisms across the animal kingdom, particularly when it comes to aging.

Two cornerstone studies led by Walford and colleagues in the 1960s–1970s discovered that a 5 and 6 °C drop in body temperature increased the lifespan of Cynolebias, a short-lived fish, by 43 and 75%, respectively. In laboratory experiments, when the nematode Caenorhabditis elegans (C. elegans) is developed and aged at 15 °C – considered a “low” temperature – it outlives wild-type worms that are developed and aged at 25 °C, a “high” temperature. In humans, a 2019 study led by Professor Julie Parsonnet at Stanford University found that the average American’s body temperature has declined since the Industrial Revolution. As Parsonnet describes, in the 160 years that have passed since this period, individuals have “gotten taller, gotten fatter, they’ve gotten colder and they live longer.”

While various studies – conducted across many species – have demonstrated associations between lower body temperature and longevity, sometimes referred to as the “temperature law”, the molecular mechanisms underpinning the associations are yet to be deciphered.

The new study, led by Professor David Vilchez, principal investigator in the faculty of medicine at CECAD, proposes one possible mechanism behind the association, which centers around protein clearance.

Cold temperatures enhance protein clearance

Aging is considered a primary risk factor for neurological disorders characterized by pathological protein aggregation, such as Alzheimer’s, Parkinson’s and Huntington’s disease and amyotrophic lateral sclerosis (ALS). Vilchez and colleagues turned to C. elegans and human cell models of Huntington’s and Parkinson’s disease to explore how body temperature impacts the effectiveness of proteasomes, protein complexes that degrade damaged or unrequired proteins via proteolysis. The research team focused specifically on the proteosome activator PA28γ/PSME3 in human cells, and its worm orthologue – PSME-3 – in C. elegans.

“We find that cold temperature (15 °C) selectively induces the trypsin-like activity of the proteasome in C. elegans through PSME-3,” the authors write. “Notably, exposure of human cells to moderate cold temperature (36 °C) also activates trypsin-like activity through PA28γ/PSME3, reducing disease-related protein aggregation and neurodegeneration.”

The data suggests that the cold temperatures increase proteosome activity, enabling the clearance of the harmful protein aggregations. “Taken together, these results show how over the course of evolution, cold has preserved its influence on proteasome regulation – with therapeutic implications for aging and aging-associated diseases,” says Vilchez.

Regardless of the temperature conditions, Vilchez and colleagues found that by genetically over-expressing the proteosome activator, the proteasome activity could be further boosted. This may provide novel therapeutic targets for aging and aging-associated diseases at the normal body temperature of 37 °C, the research team suggests. “We believe that these results may be applied to other age-related neurodegenerative diseases as well as to other animal species,” Vilchez concludes.

Reference: Lee HJ, Alirzayeva H, Koyuncu S, Rueber A, Noormohammadi A, Vilchez D. Cold temperature extends longevity and prevents disease-related protein aggregation through PA28γ-induced proteasomes. Nat Aging. 2023. doi:10.1038/s43587-023-00383-4.

This article is a rework of a press release issued by the German Federal Ministry of Education and Research. Material has been edited for length and content.