Brain IRS2 signaling coordinates life span and nutrient homeostasis.
Reduced insulin-like signaling extends the life span of Caenorhabditis elegans and Drosophila. Here, we show that, in mice, less insulin receptor substrate-2 (Irs2) signaling throughout the body or just in the brain extended life span up to 18%. At 22 months of age, brain-specific Irs2 knockout mice were overweight, hyperinsulinemic, and glucose intolerant; however, compared with control mice, they were more active and displayed greater glucose oxidation, and during meals they displayed stable superoxide dismutase-2 concentrations in the hypothalamus. Thus, less Irs2 signaling in aging brains can promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice.
Taguchi
Akiko
A
Howard Hughes Medical Institute, Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Wartschow
Lynn M
LM
White
Morris F
MF
D000375:Aging; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002940:Circadian Rhythm; D003433:Crosses, Genetic; D004032:Diet; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008136:Longevity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050177:Overweight; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010750:Phosphoproteins / Q000378:metabolism*; D012119:Respiration; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D005947:Glucose; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C526298:Irs2 protein, mouse