Effects of hunger on neuronal histone modifications slow aging in Drosophila

Abstract

Hunger is an ancient drive, yet the molecular nature of pressures of this sort and how they modulate physiology are unknown. We find that hunger modulates aging in Drosophila . Limitation of branched-chain amino acids (BCAAs) or activation of hunger-promoting neurons induced a hunger state that extended life span despite increased feeding. Alteration of the neuronal histone acetylome was associated with BCAA limitation, and preventing these alterations abrogated the effect of BCAA limitation to increase feeding and extend life span. Hunger acutely increased feeding through usage of the histone variant H3.3, whereas prolonged hunger seemed to decrease a hunger set point, resulting in beneficial consequences for aging. Demonstration of the sufficiency of hunger to extend life span reveals that motivational states alone can be deterministic drivers of aging.

Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory Phenotype

“…[ 71–74 ] To investigate the effects of alterations in BCAA metabolism on the aging process, we turned to Drosophila melanogaster , which has a shorter lifespan and shares conserved signaling pathways in cellular senescence and aging with mammals. [ 75–77 ] Furthermore, recent Drosophila studies demonstrated that BCAA‐restricted diet extends lifespan, [ 78,79 ] highlighting the role of BCAA metabolism during physiological aging in Drosophila .…”

“…We used female fruit flies in these experiments, based on our preliminary findings that they were more responsive to the BCAA‐restricted diet and showed a greater lifespan extension compared to male flies, which is consistent with a previous study. [ 79 ] Strikingly, overexpression of either transporter significantly shortened fly lifespan (Figure 4c) and led to age‐related decline in climbing ability (Figure 4d). [ 83 ] Additionally, overexpression of dSlc6a15‐a or dSlc6a15‐b induced cellular senescent hallmarks, including upregulation of the cyclin‐dependent kinase inhibitor dacapo ( d p21) (Figure 4e), and increased expression of the inflammatory cytokine unpaired 2 ( Upd2 ) (Figure 4f) in elderly flies.…”

“…[ 109 ] For example, recent research revealed that BCAT regulates isoleucine abundance in neurons to influence the feeling of hunger and affect the lifespan of fruit flies. [ 79 ] Moreover, SLC6A15 knockdown was shown to impact appetite and weight gain in mice, [ 110 ] which may affect their life span and metabolic health in the long term. These findings highlight the need for further research to explore the complex roles of BCAA regulators in organismal aging.…”

Enhanced Branched-Chain Amino Acid Metabolism Improves Age-Related Reproduction inC. elegans

“…For instance, in mouse and human studies, reducing dietary isoleucine or valine, but not leucine, enhances metabolic health in mice, while higher isoleucine intake in humans correlates with increased BMI 51 . In Drosophila , a decrease in isoleucine, but not valine, leucine, or their combinations, was found to be crucial for stimulating feeding behavior 52 . These suggest that individual BCAAs have specific influences on various phenotypes.…”

Transiently restricting individual amino acids protectsD. melanogasteragainst multiple stressors

“…Isoleucine restriction has recently garnered more attention than that of other amino acids, because of the generally protective effects that result from restricting its intake. When it is restricted in the diet, female flies live longer (Weaver et al 2023) and so do male and female heterogenous mice, who also have improved metabolic health (Green et al 2023). We also recently found that female flies subjected to two short bouts of isoleucine deprivation have extended lifespan (Fulton et al 2024).…”