Bilkei-Gorzo Andras, Schurmann Britta, Schneider Marion, Kraemer Michael, Nidadavolu Prakash, Beins Eva C, Müller Christa E, Dvir-Ginzberg Mona, Zimmer Andreas
Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, Bonn 53125, Germany.
Pharmaceutical Institute, University of Bonn, Bonn 53121, Germany.
ACS Pharmacol Transl Sci. 2024 Aug 14;7(9):2637-2649. doi: 10.1021/acsptsci.4c00002. eCollection 2024 Sep 13.
Brain aging is associated with cognitive decline, reduced synaptic plasticity, and altered metabolism. The activity of mechanistic target of rapamycin (mTOR) has a major impact on aging by regulating cellular metabolism. Although reduced mTOR signaling has a general antiaging effect, it can negatively affect the aging brain by reducing synaptogenesis and thus cognitive functions. Increased mTOR activity facilitates aging and is responsible for the amnestic effect of the cannabinoid receptor 1 agonist Δ-tetrahydrocannabinol (THC) in higher doses. Long-term low-dose Δ-THC had an antiaging effect on the brain by restoring cognitive abilities and synapse densities in old mice. Whether changes in mTOR signaling and metabolome are associated with its positive effects on the aging brain is an open question. Here, we show that Δ-THC treatment has a tissue-dependent and dual effect on mTOR signaling and the metabolome. In the brain, Δ-THC treatment induced a transient increase in mTOR activity and in the levels of amino acids and metabolites involved in energy production, followed by an increased synthesis of synaptic proteins. Unexpectedly, we found a similar reduction in the mTOR activity in adipose tissue and in the level of amino acids and carbohydrate metabolites in blood plasma as in animals on a low-calorie diet. Thus, long-term Δ-THC treatment first increases the level of energy and synaptic protein production in the brain, followed by a reduction in mTOR activity and metabolic processes in the periphery. Our study suggests that a dual effect on mTOR activity and the metabolome could be the basis for an effective antiaging and pro-cognitive medication.
大脑衰老与认知能力下降、突触可塑性降低以及新陈代谢改变有关。雷帕霉素的作用靶点（mTOR）的活性通过调节细胞代谢对衰老产生重大影响。虽然mTOR信号传导减弱具有普遍的抗衰老作用，但它可能会通过减少突触形成从而影响认知功能，对衰老的大脑产生负面影响。mTOR活性增加会加速衰老，并且是高剂量大麻素受体1激动剂Δ-四氢大麻酚（THC）产生遗忘效应的原因。长期低剂量的Δ-THC通过恢复老年小鼠的认知能力和突触密度，对大脑产生抗衰老作用。mTOR信号传导和代谢组的变化是否与其对衰老大脑的积极影响相关，仍是一个悬而未决的问题。在这里，我们表明Δ-THC治疗对mTOR信号传导和代谢组具有组织依赖性的双重作用。在大脑中，Δ-THC治疗导致mTOR活性以及参与能量产生的氨基酸和代谢物水平短暂增加，随后突触蛋白合成增加。出乎意料的是，我们发现脂肪组织中的mTOR活性以及血浆中氨基酸和碳水化合物代谢物的水平与低热量饮食的动物相似地降低。因此，长期的Δ-THC治疗首先会增加大脑中的能量水平和突触蛋白产量，随后降低外周的mTOR活性和代谢过程。我们的研究表明，对mTOR活性和代谢组的双重作用可能是一种有效的抗衰老和促认知药物的基础。
