TheC. elegansMyc-family of transcription factors coordinate a dynamic adaptive response to dietary restriction

Abstract

AbstractDietary restriction (DR), the process of decreasing overall food consumption over an extended period of time, has been shown to increase longevity across evolutionarily diverse species and delay the onset of age-associated diseases in humans. InCaenorhabditis elegans, the Myc-family transcription factors (TFs) MXL-2 (Mlx) and MML-1 (MondoA/ChREBP), which function as obligate heterodimers, and PHA-4 (orthologous to forkhead box transcription factor A) are both necessary for the full physiological benefits of DR. However, the adaptive transcriptional response to DR and the role of MML-1::MXL-2 and PHA-4 remains elusive. We identified the transcriptional signature ofC. elegansDR, using theeat-2genetic model, and demonstrate broad changes in metabolic gene expression ineat-2DR animals, which requires bothmxl-2andpha-4. While the requirement for these factors in DR gene expression overlaps, we found many of the DR genes exhibit an opposing change in relative gene expression ineat-2;mxl-2animals compared to wild-type, which was not observed ineat-2animals withpha-4loss. We further show functional deficiencies of themxl-2loss in DR outside of lifespan, aseat-2;mxl-2animals exhibit substantially smaller brood sizes and lay a proportion of dead eggs, indicating that MML-1::MXL-2 has a role in maintaining the balance between resource allocation to the soma and to reproduction under conditions of chronic food scarcity. Whileeat-2animals do not show a significantly different metabolic rate compared to wild-type, we also find that loss ofmxl-2in DR does not affect the rate of oxygen consumption in young animals. The gene expression signature ofeat-2mutant animals is consistent with optimization of energy utilization and resource allocation, rather than induction of canonical gene expression changes associated with acute metabolic stress -such as induction of autophagy after TORC1 inhibition. Consistently,eat-2animals are not substantially resistant to stress, providing further support to the idea that chronic DR may benefit healthspan and lifespan through efficient use of limited resources rather than broad upregulation of stress responses, and also indicates that MML-1::MXL-2 and PHA-4 may have different roles in promotion of benefits in response to different pro-longevity stimuli.