Introduction: Cold exposure is a challenging environmental stimulus for humans, particularly in vulnerable populations such as older adults. Decrements in cold tolerance observed in older adults may be mediated by an age-related reduction in the stress-induced cytoprotective mechanism of autophagy, which enhances cell survival by eliminating damaged cellular components. However, it is unknown how autophagy and accompanying cytoprotective pathways (i.e., heat shock proteins) respond to cold conditions in humans.
Purpose: The purpose of this thesis was to evaluate the impact of aging on autophagic activity during cold exposure and assess strategies to reverse age-related autophagic dysfunction.
Methods: We examined the influence of age on autophagy during acute cold exposure utilizing ex vivo, in vitro, and in vivo models in young (19-29 years) and older (54-76 years) adults. Autophagic activity in all investigations was assessed in peripheral blood mononuclear cells (i.e., immune cells) via Western blotting. Simulated hypothermic conditions (equivalent to 4-35°C core temperature) were evaluated using ex vivo whole-blood exposure. In vivo cold stress was achieved using cold-water immersions to elicit a physiologically relevant decrease in core temperature by 0.5 and 1.0°C. Techniques that potentially reversed autophagic impairments during cold exposure were assessed including, 1) an in vitro treatment of a known autophagic stimulator (rapamycin) in immune cells obtained from young and older males, and 2) an in vivo cold acclimation in young males with cold-water immersions (14°C for 60 min) repeated on 7 consecutive days.
Results: Simulated hypothermia (4-35°C) induced autophagic dysfunction regardless of age or sex. Moderate cold stress (a 0.5°C reduction in core temperature) stimulated autophagy in young males. However, intense cold exposures (equivalent to ≥ 1.0°C decrease in core temperature) elicited signs of autophagic dysfunction and a shift towards apoptotic cell death. Additionally, older adults displayed evidence of autophagic dysfunction during each cold exposure, although age-related autophagic dysfunction was mitigated with acute rapamycin treatment. Further, cold acclimation robustly improved autophagic responses to cold exposure.
Conclusion: Despite an observed age-related impairment in autophagic responses during cold exposure, this thesis provided the first evidence in humans that autophagic dysregulation during cold exposure can be reversed through the administration of autophagic stimulators and through cold acclimation.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/45895 |
| Date | 29 January 2024 |
| Creators | King, Kelli Elizabeth |
| Contributors | Kenny, Glen P. |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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