Article in Eureka Alert

5/1/2012

BOSTON – May 1, 2012 – Scientists at Joslin Diabetes Center have identified a key mechanism of action for the TOR (target of rapamycin) protein kinase, a critical regulator of cell growth which plays a major role in illness and aging. This finding not only illuminates the physiology of aging but could lead to new treatments to increase lifespan and control age-related conditions, such as cancer, type 2 diabetes, and neurodegeneration.

Over the past decade, studies have shown that inhibiting TOR activity, which promotes cell growth by regulating protein synthesis, increases lifespan in a variety of species including flies and mice; in recent years research has focused on uncovering the precise mechanisms underlying this effect. The Joslin study, published in the May 2 issue of Cell Metabolism, reports that TOR has a direct impact on two master gene regulator proteins – SKN-1 and DAF-16 –which control genes that protect against environmental, metabolic and proteotoxic stress. The TOR kinase acts in two signaling pathways, TORC1 and TORC2. When TORC1 is inhibited, SKN-1 and DAF-16 are mobilized, leading to activation of protective genes that increase stress resistance and longevity. This new finding was demonstrated in experiments with C. elegans, a microscopic worm used as a model organism, but activation of protective genes was also observed in mice. Most findings in C. eleganshave turned out to be applicable to mice and humans.

"We uncovered a critical mechanism in the relationship between TOR and aging and disease. There is a homeostatic relationship between protein synthesis and stress defenses: when protein synthesis is reduced, stress defenses increase," says lead author T. Keith Blackwell, MD, PhD, co-head of the Joslin Islet Cell & Regenerative Biology Section and Professor of Pathology at Harvard Medical School. The Blackwell lab studies the aging process and how it is influenced by insulin and other metabolic regulatory mechanisms.

TOR activity, which is essential for early development but can lead to age-related decline, is implicated in a variety of chronic diseases, including diabetes, cardiovascular disease, cancer and neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. In diabetes, TOR has both positive and negative effects: It promotes beta cell growth and insulin production but inappropriate TORC1 activity leads to insulin resistance and beta cell demise, as well as fat accumulation. At the same time, insufficient TORC2 activity can lead to insulin resistance.

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