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. elegans have
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, includingdiabetes, 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.
The new
results on TOR and SKN-1 suggest that SKN-1 might have a positive effects
in Type 2
diabetes: "Turning on this pathway could be important in defending
against the effects of high glucose, and promoting beta cell health" says
Blackwell.
In the
study, TOR activity was inhibited by genetic interference and the TOR-inhibitor
rapamycin, a naturally occurring compound which is used as an immunosuppressant
in organ transplants, and has been shown to increase lifespan in mice.
Using
rapamycin or related drugs to treat diseases affected by TOR has been a subject
of intense interest among scientists and clinicians. The study found that
rapamycin inhibits both TORC1 and TORC2, which will interest scientists
investigating rapamycin as a pharmaceutical. "We need to increase
understanding of rapamycin and its effects on TOR activity to determine how
targeting TOR or processes it controls can help treat diseases that involve TOR
and derangement of metabolism. We also need to look at therapies that work on
TORC1 and TORC2 independently," said Blackwell. However, one caveat with
TOR inhibition is that the kinase plays such a central role in the basic
physiology of growing and dividing cells.
The new
results suggest that in some situations we might want to bypass TOR itself, and
directly harness beneficial processes that are controlled by SKN-1 or DAF-16.
Future
research will focus on gaining a deeper understanding of how TOR acts on
beneficial defense pathways and affects aging and disease. "In science, we
are always looking for ways to interfere with mechanisms that promote aging and
disease in ways that are beneficial to people," says Blackwell.
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