Dietary 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. In Caenorhabditis 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 FOXA) 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 of C. elegans DR, using the eat-2 genetic model, and demonstrate broad changes in metabolic gene expression in eat-2 DR animals, which requires both mxl-2 and pha-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 in eat-2;mxl-2 animals compared to wild-type, which was not observed in eat-2 animals with pha-4 loss. Surprisingly, we discovered more than 2000 genes synthetically dysregulated in eat-2;mxl-2, out of which the promoters of down-regulated genes were substantially enriched for PQM-1 and ELT-1/3 GATA TF binding motifs. We further show functional deficiencies of the mxl-2 loss in DR outside of lifespan, as eat-2;mxl-2 animals 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. While eat-2 animals do not show a significantly different metabolic rate compared to wild-type, we also find that loss of mxl-2 in DR does not affect the rate of oxygen consumption in young animals. The gene expression signature of eat-2 mutant 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-2 animals 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 distinct roles in promotion of benefits in response to different pro-longevity stimuli.

饮食限制（DR）是在较长时间内减少总体食物消耗的过程，已被证明可以延长进化多样化物种的寿命，并延缓人类与年龄相关的疾病的发生。在秀丽隐杆线虫中，作为专性异二聚体发挥作用的 Myc 家族转录因子 (TF) MXL-2 (Mlx) 和 MML-1 (MondoA/ChREBP) 以及 PHA-4（与 FOXA 直系同源）对于完整的转录因子都是必需的。 DR 的生理益处。然而，对 DR 的适应性转录反应以及 MML-1::MXL-2 和 PHA-4 的作用仍然难以捉摸。我们使用eat-2遗传模型鉴定了线虫DR 的转录特征，并证明eat-2 DR 动物中代谢基因表达的广泛变化，这需要mxl-2和pha-4 。虽然 DR 基因表达中对这些因素的要求重叠，但我们发现与野生型相比，许多 DR 基因在eat-2;mxl-2动物中表现出相对基因表达的相反变化，而在eat-2中未观察到这种变化pha-4缺失的动物。令人惊讶的是，我们发现eat-2;mxl-2中有超过 2000 个基因综合失调，其中下调基因的启动子显着富集 PQM-1 和 ELT-1/3 GATA TF 结合基序。我们进一步表明 DR 中mxl-2损失在寿命之外的功能缺陷，因为eat-2;mxl-2动物表现出明显较小的巢尺寸并产下一定比例的死蛋，这表明 MML-1::MXL-2 具有在长期粮食短缺的情况下，维持身体资源分配与繁殖之间的平衡的作用。 虽然与野生型相比， eat-2动物没有表现出显着不同的代谢率，但我们还发现 DR 中mxl-2的损失不会影响幼年动物的耗氧率。 eat-2突变动物的基因表达特征与能量利用和资源分配的优化一致，而不是诱导与急性代谢应激相关的典型基因表达变化，例如TORC1抑制后诱导自噬。一致地， eat-2动物对压力没有显着的抵抗力，这进一步支持了这样的观点，即慢性 DR 可能通过有效利用有限的资源而不是广泛上调压力反应来有益于健康和寿命，并且还表明 MML-1:: MXL-2 和 PHA-4 在响应不同的长寿刺激而促进益处方面可能具有不同的作用。