Moderate cold exposure contributes to the extension of lifespan by alleviating the aggregation of disease-related proteins

Growing evidence demonstrate that cold stimulation as a nonpharmacological strategy can be applied to prevent the development of ageing. However, the optimal ambient temperature to mammals and the mechanism for low temperature to extend lifespan remain poorly understood. In this editorial, we highlight the data presented by Hyun et al. suggesting that a beneficial role of moderate cold temperature in reducing disease-related aggregation thereby age-related deteriorations^[1].

It is known that extreme low temperature is detrimental for organisms contributing to 'excess winter mortality' due to respiratory, heart and cerebrovascular diseases^[2]. A large number of ecological time-series studies indicates a U-shaped relationship between ambient temperature and mortality, with the lowest rate on days in which the average temperatures range from 15℃ to 25℃^[3]. Previous data report that cold exposure can resolve obesity-induced inflammation and insulin resistance, as well as improves glucose tolerance through the activation of brown adipose tissue and liver^[4-5]. In a study with obesity mice, the cold temperature was set to 5℃ for a duration of 7 days. However, contrasting evidence suggests that a cold environment, particularly between 4℃ to 6℃, may increase cardiovascular risks, such as hypertension and cardiac arrhythmia, by stimulating the sympathetic nervous system in rodents^[6]. Given these varying findings, the effects of cold conditions below 10℃ on different disease progressions remain controversial, potentially influenced by the duration of cold exposure and the original state of the organisms.

Understanding the underlying mechanisms could lead to the broader use of cold interventions in addressing agingassociated mortality. The interaction between longevity and low temperature has garnered increasing attention. Several studies have identified that moderate cold temperatures promote an adaptive immune response, thereby increasing the sensitivity to cancer therapy^[7]. Exposure to moderate cold temperature ranging from 12℃ to 16℃ leads to a mild decrease of 0.5℃ and 0.03℃ in the body temperature of rodents and humans, ultimately prolonging lifespan and supporting the notion of temperature reduction as a conserved mechanism for longevity^[8]. Understanding the underlying mechanisms could lead to the broader use of cold interventions in addressing ageing-associated mortality. For instance, a study by Hyun and colleagues involved exposure of C. elegans models to moderate low temperature (15℃), standard temperature (20℃), and mild heat stress (25℃), respectively. They found that 15℃ was sufficient to induce lifespan extension compared with the control and heat-induced worms. Furthermore, the authors examined the role of the cold-sensitive channel, transient receptor potential ankyrin-1 (TRPA-1), which is associated with lifespan regulation. Worms lacking TRPA-1 exhibited lower trypsin-like activity at moderate cold temperatures compared to wild-type worms. Additionally, TRPA-1 loss attenuated the induction of psme-3 mRNA at 15℃, indicating that TRPA-1 modulates PA28γ at the transcriptional level. These findings suggest that moderate cold condition exerts a beneficial influence on longevity via regulating TRPA-1.

Contrary to the conventional view that cold-induced longevity is primarily attributed to the slowdown of chemical reactions and metabolism, C. elegans studies have suggested that it is a multi-regulated process involving more than just passive changes in chemical reactions^[9]. To explore this further, the authors investigated whether moderate cold temperatures could influence proteasome activity, a determinant of cell function and viability linked to aging mortality. Their results demonstrated that the worm orthologue of PA28γ/PSME3 is required for moderate cold-induced longevity and attenuates age-related deficits in protein degradation by the 26S proteasome. Additionally, PA28γ in relation to moderate cold temperatures prevents the aggregation of disease-related proteins in C. elegans models, mimicking ageing-related mortality conditions such as Huntington's disease and amyotrophic lateral sclerosis (ALS).

The researchers expanded their investigations by simulating a moderate reduction in temperature (36℃) in cultured human cells, akin to the physiological status during sleep when the human body can reach a moderate cold temperature of 36℃. Shifting HEK293 human cells from 37℃ to 36℃ led to an increase in PA28γ protein expression and its assembly into proteasome-activator complex. This activation of trypsinlike activity was found to be TRPA1- and PA28γ-dependent. To validate the role of TRPA1- and PA28γ in longevity, the researchers transfected human cells with overexpressed polyQexpanded HTT (the protein underlying Huntington's disease), which resulted in the accumulation of polyQ aggregates. Remarkably, culturing the cells at 36℃ substantially reduced the amounts of Q100-HTT protein and its aggregation in a TRPA1-/ PA28γ-dependent manner. Additionally, PA28γ overexpression also increased trypsin-like proteasome activity and prevented protein aggregation at 37℃. These results demonstrate an evolutionary conserved effect of moderated cold temperatures in proteasome regulation, which has implications for aging and age-related diseases.

This review article highlights the importance of controlling ambient temperatures for overall health. The findings elucidate that moderate cold temperatures prolong lifespan in C. elegans by inducing a ubiquitin-independent, PA28γ-dependent trypsinlike proteasome activity, which effectively alleviates protein aggregation and ageing-related mortality. Furthermore, this pathway is conserved in humans, suggesting the possibility of manipulating it to extend human health span. Further investigations are warranted to identify the optimal temperature for extending lifespan and to understand the molecular basis of proteasome activity that can potentially prevent ageing progression.