Increased Mammalian Lifespan and a Segmental and Tissue-Specific Slowing of Aging after Genetic Reduction of mTOR Expression

• Published in: Cell reports (Cambridge) Vol. 4; no. 5; pp. 913 - 920
• Main Authors: Wu, J. Julie, Liu, Jie, Chen, Edmund B., Wang, Jennifer J., Cao, Liu, Narayan, Nisha, Fergusson, Marie M., Rovira, Ilsa I., Allen, Michele, Springer, Danielle A., Lago, Cory U., Zhang, Shuling, DuBois, Wendy, Ward, Theresa, deCabo, Rafael, Gavrilova, Oksana, Mock, Beverly, Finkel, Toren
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2013; Elsevier
• Subjects: Aging - physiology; Animals; Female; Glucose - metabolism; Homeostasis; Longevity - physiology; Male; Mammals; Mice; Signal Transduction; TOR Serine-Threonine Kinases - biosynthesis; TOR Serine-Threonine Kinases - deficiency; TOR Serine-Threonine Kinases - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.07.030

We analyzed aging parameters using a mechanistic target of rapamycin (mTOR) hypomorphic mouse model. Mice with two hypomorphic (mTORΔ/Δ) alleles are viable but express mTOR at approximately 25% of wild-type levels. These animals demonstrate reduced mTORC1 and mTORC2 activity and exhibit an approximately 20% increase in median survival. While mTORΔ/Δ mice are smaller than wild-type mice, these animals do not demonstrate any alterations in normalized food intake, glucose homeostasis, or metabolic rate. Consistent with their increased lifespan, mTORΔ/Δ mice exhibited a reduction in a number of aging tissue biomarkers. Functional assessment suggested that, as mTORΔ/Δ mice age, they exhibit a marked functional preservation in many, but not all, organ systems. Thus, in a mammalian model, while reducing mTOR expression markedly increases overall lifespan, it affects the age-dependent decline in tissue and organ function in a segmental fashion.
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•In mammals, decreased mTOR expression produces a profound increase in lifespan•Reduced mTOR expression results in lower rates of spontaneous tumor formation•Age-related benefits of reduced mTOR expression are tissue specific
Recent evidence suggests that mTOR may regulate lifespan in a wide range of organisms, including mammals. Unfortunately, few good mouse models of reduced mTOR activity exist. Here, Finkel and colleagues characterize a hypomorphic model of mTOR expression. Mice expressing reduced levels of mTOR live significantly longer than their wild-type littermates. Of note, while overall lifespan is extended, careful phenotyping of this model demonstrates that reducing mTOR activity slows the rate of tissue and organ aging in a segmental fashion.