Moreno Tatiana M, Brown Michelle E, Kumsta Caroline
Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States.
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States.
MicroPubl Biol. 2025 Apr 25;2025. doi: 10.17912/micropub.biology.001520. eCollection 2025.
Inhibition of mTORC1, a conserved nutrient-sensing complex, extends lifespan across model organisms, but the effects of mTORC1 hyperactivation are less understood. RagA, a GTPase essential for mTORC1 activation, can be locked in its active GTP-bound state through gain-of-function mutations, such as Q63L in RAGA-1. We found that transgenic expression of mutation ( ) decreases lifespan without hyperactivating mTORC1, suggesting mTORC1-independent effects or transgene toxicity. In contrast, we show that a CRISPR-generated Q63L mutation at the endogenous locus ( hyperactivates mTORC1 without affecting lifespan, challenging the paradigm that mTORC1 hyperactivation accelerates aging. Thus, genetic context and potential compensatory mechanisms may contribute to mTORC1-mediated lifespan regulation, at least in metazoans.
mTORC1是一种保守的营养感应复合体，对其抑制可延长多种模式生物的寿命，但mTORC1过度激活的影响却鲜为人知。RagA是mTORC1激活所必需的一种GTP酶，可通过功能获得性突变（如RAGA - 1中的Q63L）锁定在其活性GTP结合状态。我们发现，该突变的转基因表达会缩短寿命，而不会使mTORC1过度激活，这表明存在mTORC1非依赖性效应或转基因毒性。相比之下，我们表明，通过CRISPR在内源基因座产生的Q63L突变会过度激活mTORC1，但不影响寿命，这对mTORC1过度激活会加速衰老的范式提出了挑战。因此，至少在后生动物中，遗传背景和潜在的补偿机制可能有助于mTORC1介导的寿命调节。
