Physiological responses to daylong heat exposure in young and older adults: Part II - Autophagy and the acute cellular stress response.

With rising global temperatures, heat-related mortality is increasing, particularly among older adults. While this is often attributed to declines in thermoregulatory function, little is known regarding the effect of age on the cellular processes associated with mitigating heat-induced cytotoxicity. We compared key components of the cellular stress response in 19 young (19-31 years; 10 female) and 37 older adults (61-78 years; 10 female) during 9 hours of heat exposure (40°C, 9% relative humidity). Mean body temperature (T) was calculated from core and skin temperatures. Changes in proteins associated with autophagy, apoptotic signaling, acute inflammation, and the heat shock response were assessed via Western blot in peripheral blood mononuclear cells harvested before and after exposure. T increased 1.5 (SD 0.3)°C and 1.7 (0.3)°C in the young and older adults, respectively. We observed similar elevations in autophagy-related proteins (LC3-II and LC3-II/I) between young and older adults (both P≥0.121). However, the older adults displayed signs of autophagic dysfunction, evidenced by a 3.7-fold [95% CI: 2.4, 5.6] greater elevation in the selective autophagy receptor p62 (P<0.001). This was paired with elevations in apoptotic responses, with a 1.7-fold [1.3, 2.3] increase in cleaved caspase-3 in the older relative to young adults (P<0.001). Older adults also exhibited diminished heat shock protein 90 responses (0.7-fold [0.5, 0.9] vs young, P=0.011) and, at any given level of thermal strain (T area under the curve), elevated tumor necrosis factor-α (1.5-fold [1.0, 2.5] vs young, P=0.008). Attenuated autophagic responses may underlie greater vulnerability to heat-induced cellular injury in older adults.