Researchers: Yan-Ping Zhang, Wen-Hong Zhang, Pan Zhang, Qi Li, Yue Sun, Jia-Wen Wang, Shaobing O Zhang, Tao Cai, Cheng Zhan, Meng-Qiu Dong
Twenty-nine years following the breakthrough discovery that a single-gene mutation of daf-2 doubles Caenorhabditis elegans lifespan, it remains unclear where this insulin/IGF-1 receptor gene is expressed and where it acts to regulate ageing. Using knock-in fluorescent reporters, we determined that daf-2 and its downstream transcription factor daf-16 are expressed ubiquitously. Using tissue-specific targeted protein degradation, we determined that intracellular DAF-2-to-DAF-16 signaling in the intestine plays a major role in lifespan regulation, while that in the hypodermis, neurons, and germline plays a minor role. Notably, intestine-specific loss of DAF-2 activates DAF-16 in and outside the intestine, causes almost no adverse effects on development and reproduction, and extends lifespan by 94% in a way that partly requires non-intestinal DAF-16. Consistent with intestine supplying nutrients to the entire body, evidence from this and other studies suggests that altered metabolism, particularly down-regulation of protein and RNA synthesis, mediates longevity by reduction of insulin/IGF-1 signaling.
References
- mTOR as a central regulator of lifespan and aging.
- Key proteins and pathways that regulate lifespan.
- Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans.
- DAF-16 target identification in C. elegans: past, present and future.
Topic: Insulin-like growth factor 1 (IGF-1) in aging (Graph Available)