Histone acetylation promotes long-lasting defense responses and longevity following early life heat stress

Abstract

Early exposure to some mild stresses can slow down the aging process and extend lifespan, raising the question of how early life stress might impact the somatic health of aged animals. Here, we reveal that early life heat experience triggers the establishment of epigenetic memory in soma, which promotes long-lasting stress responses and longevity in C . elegans . Unlike lethal heat shock, mild heat activates a unique transcriptional program mimicking pathogen defense responses, characterized by the enhanced expression of innate immune and detoxification genes. Surprisingly, the expression of defense response genes persists long after heat exposure, conferring enhanced stress resistance even in aged animals. Further studies identify the histone acetyltransferase CBP-1 and the chromatin remodeling SWI/SNF complex as epigenetic modulators of the long-lasting defense responses. Histone acetylation is elevated by heat stress and maintained into agedness thereafter. Accordingly, histone acetylation levels were increased on the promoters of defense genes. Moreover, disruption of epigenetic memory abrogates the longevity response to early hormetic heat stress, indicating that long-lasting defense responses are crucial for the survival of aged animals. Together, our findings provide mechanistic insights into how temperature stress experienced in early life provides animals with lifetime health benefits.

Short-Term Mild Temperature-Stress-Induced Alterations in the C. elegans Phosphoproteome

“…Many studies have studied the effects of mild stresses on extending the lifespan [ 8 , 9 ]. However, very little work has investigated how short-term mild stresses could have long-term beneficial effects.…”

“…Exposure to severe stresses often causes tissue damage and ultimately shortens the lifespan, while mild stresses usually promote defenses against damage and therefore promote longevity [ 5 , 6 , 7 ]. More importantly, studies in animals have shown that mild early-life stress, such as heat stress, could significantly extend the lifespan of animals [ 8 , 9 ], suggesting that stress in early life could be beneficial for health promotion throughout the animal’s lifespan. However, the exact biological mechanisms behind this phenomenon are largely unknown.…”

“…However, severe short-term heat stress (36 °C) will not shorten the life of nematodes but will rather prolong life [ 24 ]. Notably, in the larval stage and early adult stage, suitable mild heat stress (25 °C), under laboratory conditions, can extend the lifespan of the nematode as well [ 8 , 9 ]. In addition, under mild heat stress (25 °C), heat-sensitive activated tax-2 / tax-4 ion channels are distributed in ASJ neurons, and then insulin-like peptides are secreted to inhibit the activity of DAF-16/FOXO, resulting in a shortened lifespan [ 21 ].…”

“…In addition, under mild heat stress (25 °C), heat-sensitive activated tax-2 / tax-4 ion channels are distributed in ASJ neurons, and then insulin-like peptides are secreted to inhibit the activity of DAF-16/FOXO, resulting in a shortened lifespan [ 21 ]. Moreover, epigenetic regulators ( cbp-1 and swsn-1 ) and a stress-activated protein kinase ( pmk-1 ) enhance pathogen resistance, promoting longevity following early hermetic heat stress [ 9 ]. Overall, these results further indicate that temperature changes occurring in the early stage of life can significantly influence life at later stages, suggesting that proteins’ responses to early temperature changes might be potentially related to the regulation of the life cycle.…”

The flip side of sirtuins: the emerging roles of protein acetyltransferases in aging

“…Third, lifespan extension in model organisms, through either dietary/caloric restriction or pharmacological mimetics of dietary restriction, requires CBP and p300 [30][31][32][33][34][35][36]. Finally, studies in C. elegans have directly demonstrated that reduced expression of CBP or p300 shortens lifespan [37][38][39][40].…”