mTORC1 and Age-Related Disease Processes

Aging is a complex process characterized by a progressive loss of physiological integrity, leading to functional decline and an increased risk for the development of chronic diseases that impact overall health. Accordingly, aging is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, declining immune response, and muscle function and neurodegenerative diseases.

A growing body of scientific evidence is elucidating the role of cellular signaling pathways that direct an organism’s response to conditions in its environment and mediate the development of chronic diseases that are tied to the aging process.

mTORC1 is linked to multiple age-related disease processes as well as healthy aging

mTORC1 is the primary sensor and integrator of the mTOR signaling pathway, which has been strongly associated with healthspan—the period of life during which one is generally free from serious and chronic disease—and diseases of aging. mTOR controls cell growth, proliferation, and survival in response to conditions in its environment, such as the availability of nutrients and growth factors. Reducing the activity of this complex—either genetically, or pharmacologically using rapamycin—has been linked to increased healthspan and longevity in multiple species, including mammals.

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A clear linkage of the mTOR pathway and, specifically, the role of mTORC1 has been established in improvements in lifespan and healthspan across a diverse number of species from yeast to mice. The data supporting this linkage has been derived from both genetic and pharmacological interventions.1 Interventions that extend lifespan and healthspan—such as calorie or dietary restriction, reduced growth factor signaling primarily through the insulin/IGF pathway, as well as pharmacological inhibition of mTORC1 by rapamycin—strongly implicate mTORC1 signaling as the common mechanism responsible for these effects.2 The use of rapamycin as an allosteric inhibitor of mTORC1 has been demonstrated in mice to reduce age-related diseases including cancer, neurodegeneration, inflammation, and other pathologies.3 The conserved nature of the effects of down-regulating the activity of the mTOR signaling pathway suggests that pharmacological approaches that achieve this safely in humans may have a broad and positive effect on healthy aging through the reduction of many chronic and debilitating diseases.

1 Johnson, S.C. et al (2013) mTOR is a key modulator of aging and age-related disease. Nature 493:338-345.

2 Longo, V.D. et al (2015) Interventions to slow aging in humans: Are we ready. Aging Cell 22 APR 2015, DOI: 10.1111/acel.12338.

3 Kennedy, B.K. and Pennypacker, J.K. (2014) Drugs that modulate aging: the promising yet difficult path ahead. Translational Research 163:456-465.
The Emerging Focus on Improving Healthspan
Most Americans suffer serious illnesses and disabilities throughout their senior years—80% of Americans 65 and older have at least one chronic condition such as cancer, cardiovascular disease, arthritis, diabetes, or Alzheimer’s disease, and 50% of Americans over 65 have two such chronic conditions.

In recent years, advances in understanding the fundamental biological mechanisms of age-related disease processes—including the link between the molecular mechanisms of aging and chronic diseases—have dramatically accelerated the potential to develop new therapeutic interventions that compress morbidity and lengthen healthy aging, or healthspan. The new field of geroscience has emerged to expand the study of the relationship between aging and age-related diseases, as an approach to discovering new ways to intervene in the aging process and delay the onset of chronic diseases.

Given that the elderly population is dramatically increasing and that age is the greatest risk factor for a majority of chronic diseases that drive both morbidity and mortality, finding medicines that target molecular mechanisms of aging to improve healthspan and age-related diseases can address one of the greatest challenges for medicine in the 21st century.