Hypothalamic mTORC2 is essential for metabolic health and longevity

Area of Science:

• Cell Biology
• Metabolism and Aging
• Neuroscience

Background:

• The mechanistic target of rapamycin (mTOR) is a key regulator of cell growth and metabolism, existing in two complexes: mTORC1 and mTORC2.
• Rapamycin, a known lifespan-extending drug, inhibits both mTORC1 and mTORC2, though its longevity effects are often attributed to mTORC1.
• mTORC2 signaling's role in longevity is complex, varying with environmental factors in some species.

Purpose of the Study:

• To investigate the specific role of hypothalamic mTORC2 signaling in regulating metabolic health, activity, and lifespan in mice.
• To determine the impact of impaired hypothalamic mTORC2 signaling on age-related changes in body composition and glucose homeostasis.
• To elucidate the contribution of hypothalamic mTORC2 to overall survival and frailty.

Main Methods:

• Utilized a mouse model with disrupted hypothalamic mTORC2 signaling.
• Assessed parameters including activity levels, adiposity, susceptibility to diet-induced obesity, and glucose homeostasis.
• Monitored age-related changes in fat mass, frailty, and overall survival.

Main Results:

• Loss of hypothalamic mTORC2 signaling led to decreased activity levels and increased adiposity set points.
• Mice lacking this pathway were more prone to diet-induced obesity and exhibited impaired glucose homeostasis.
• Hypothalamic mTORC2 deficiency resulted in increased frailty with age and significantly reduced overall survival.

Conclusions:

• Hypothalamic mTORC2 signaling is essential for maintaining normal metabolic health, physical fitness, and lifespan in mice.
• Dysregulation of hypothalamic mTORC2 contributes to age-related metabolic decline and reduced longevity.
• These findings suggest potential therapeutic targets for aging-related diseases and brain cancers involving mTORC2 inhibition.