A Caution on mTOR Inhibitors: Loss of mTORC2 in the Hypothalamus Harms Mice

Inhibition of mTOR, and specifically of the mTORC1 protein complex these days, while trying to avoid inhibition of the mTORC2 complex, is a strategy for modestly slowing aging. It is what I would consider a good example of a worse strategy, in that it aims to adjust the operation of metabolism to make it more resilient to the damage of aging, rather than attempting to repair the damage of aging. It will thus produce benefits to health and longevity that are small in the grand scheme of what is possible. This is true of near all of the initiatives arising from the study of the metabolic response to calorie restriction and other stresses, in which cell maintenance processes such as autophagy are upregulated to beneficial effect.

Another issue with adjusting metabolism into a new state, rather than repairing damage to try to reset metabolism to a known good state, is that it will likely have detrimental side-effects that are hard to map and categorize, as metabolism is enormously complex. The research here offers an example of the type, a discovery made many years in to the development of mTOR inhibitors as therapeutics. While systemic mTOR inhibition appears beneficial in mice, researchers have now shown that loss of mTORC2 in the hypothalamus is detrimental.

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that plays critical roles in the regulation of growth, metabolism, and aging. The mTOR protein kinase is found in two distinct protein complexes; mTOR complex 1 (mTORC1) integrates numerous environmental and hormonal cues, including the availability of amino acids, to regulate key anabolic processes including ribosomal biogenesis, protein translation, and autophagy, while mTOR complex 2 (mTORC2) plays a role in cytoskeletal organization and is a key effector of insulin/PI3K signaling. The pharmaceutical rapamycin, which acutely and robustly inhibits mTORC1, extends the lifespan in organisms including yeast, worms, flies, and mice, even when begun late in life or when treatment is intermittent.

While it has long been presumed that inhibition of mTORC1 by rapamycin mediates its beneficial effects on longevity, we and others have found that prolonged treatment with rapamycin also inhibits mTORC2, both in cell culture and in vivo in mice. However, inhibition of mTORC2 by rapamycin is limited to specific cell lines and tissues, most likely determined by the relative expression of FK506-binding proteins (FKBPs). In the nematode Caenorhabditis elegans, mTORC2 regulates metabolic processes via several distinct signaling pathways and can have positive or negative effects on lifespan depending on the tissue that is targeted, the temperature, and the food source.

Over the last decade, significant progress has been made in understanding the roles of both mTOR complexes in the regulation of key metabolic tissues. Less well understood is the role of mTOR complex signaling in the brain. mTOR Complex 1 is clearly an important regulator of neuronal behavior; hypothalamic mTORC1 is a key sensor of nutrient sufficiency and acute activation of hypothalamic mTORC1 suppresses food intake. In contrast, the role of brain mTORC2 signaling in the regulation of metabolism, health, and longevity has been less studied. mTORC2 signaling in the brain plays important roles in whole body metabolism, but the specific neuronal populations mediating these effects and the long-term implications for health and longevity remain to be elucidated.

Here, we show that loss of hypothalamic mTORC2 signaling in mice decreases activity level, increases the set point for adiposity, and renders the animals susceptible to diet-induced obesity. Hypothalamic mTORC2 signaling normally increases with age, and mice lacking this pathway display higher fat mass and impaired glucose homeostasis throughout life, become more frail with age, and have decreased overall survival. We conclude that hypothalamic mTORC2 is essential for the normal metabolic health, fitness, and lifespan of mice. Our results have implications for the use of mTORC2-inhibiting pharmaceuticals in the treatment of brain cancer and diseases of aging.


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