Bidirectional Effect\nof Long-Term Δ<sup>9</sup>‑Tetrahydrocannabinol Treatment\non mTOR Activity and Metabolome

Brain aging is associated with cognitive decline, reduced\nsynaptic\nplasticity, and altered metabolism. The activity of mechanistic target\nof rapamycin (mTOR) has a major impact on aging by regulating cellular\nmetabolism. Although reduced mTOR signaling has a general antiaging\neffect, it can negatively affect the aging brain by reducing synaptogenesis\nand thus cognitive functions. Increased mTOR activity facilitates\naging and is responsible for the amnestic effect of the cannabinoid\nreceptor 1 agonist Δ<sup>9</sup>-tetrahydrocannabinol (THC)\nin higher doses. Long-term low-dose Δ<sup>9</sup>-THC had an\nantiaging effect on the brain by restoring cognitive abilities and\nsynapse densities in old mice. Whether changes in mTOR signaling and\nmetabolome are associated with its positive effects on the aging brain\nis an open question. Here, we show that Δ<sup>9</sup>-THC treatment\nhas a tissue-dependent and dual effect on mTOR signaling and the metabolome.\nIn the brain, Δ<sup>9</sup>-THC treatment induced a transient\nincrease in mTOR activity and in the levels of amino acids and metabolites\ninvolved in energy production, followed by an increased synthesis\nof synaptic proteins. Unexpectedly, we found a similar reduction in\nthe mTOR activity in adipose tissue and in the level of amino acids\nand carbohydrate metabolites in blood plasma as in animals on a low-calorie\ndiet. Thus, long-term Δ<sup>9</sup>-THC treatment first increases\nthe level of energy and synaptic protein production in the brain,\nfollowed by a reduction in mTOR activity and metabolic processes in\nthe periphery. Our study suggests that a dual effect on mTOR activity\nand the metabolome could be the basis for an effective antiaging and\npro-cognitive medication.