[biomed] SRT1720 rodent trials

[Eugen Leitl]

http://blog.wired.com/wiredscience/2008/11/next-generation.html

Next-Generation Longevity Drug Works Mouse Wonders

By Brandon Keim November 04, 2008 | 5:51:25 PM Categories: Medicine & Medical
Procedures  

A potential longevity-enhancing drug has passed its final animal testing
challenge, pushing closer to reality the dream of all-purpose drugs against
diseases of aging.

Mice given the new drug, called SRT1720, gorged on high-fat food for four
months without gaining weight or developing diabetes, and ran twice as far on
a treadmill as their control-group counterparts. Similar drugs are expected
to follow down the pipeline.

"If you look at all the things that have fundamentally changed medicine in
the last 150 years, washing hands would be one, and antibiotics another. This
could be the third," said study co-author Philip Lambert, a pharmacologist at
Sirtris Pharmaceuticals, the drug's developer. "If you could keep your health
for another 10 or 15 years, that would be amazing."

SRT1720 activates one of several enzymes that regulate the function of
mitochondria — cellular power generators that convert glucose into chemical
energy. The wearing down of these generators has been linked to heart
disease, Alzheimer's disease, diabetes, cancer and other age-related
afflictions.

That same enzyme is also targeted by resveratrol, a naturally occurring
compound that reduces age-related diseases in lab animals and is already used
by longevity enthusiasts. Researchers at Sirtris showed last year that
synthetic drugs that activate the enzyme produced the same cell-level changes
as resveratrol, but the tests only lasted for two weeks. The latest study
lasted four months, suggesting that SRT1720 — and perhaps the class of enzyme
activators expected to follow — are for real.

"This shows you can make drugs that work even better than resveratrol," said
David Sinclair, co-founder of Sirtris, who compared the finding to the
synthesis of antibiotics inspired by early fungal components. "Now we've got
human-designed synthetic molecules. We're not talking about plant extracts
anymore."

Rafael de Cabo, a National Institute on Aging gerontologist who is
researching SRT1720 but was not involved in the study, published today in
Cell Metabolism, agreed with Sinclair's assessment, though he cautioned
against premature celebration.

"From rodents to humans is a long, long process," he said. "We've
demonstrated this in cells, and in mice. Now we need to move to the next
level — primates or humans."

Resveratrol is currently in clinical trials as a diabetes drug, and could be
joined next year by SRT1720, said Lambert.

The drug's side effects aren't yet apparent, but resveratrol has proven safe
in animals and — anecdotally, at least — in humans. Since SRT1720 works at
doses 1000 times lower than resveratrol, said Lambert, it should prove even
safer if effective.

He noted that the blood sugar-lowering effects from SRT1720 observed in the
study were present in mice on a high-fat diet, but not in mice on standard
fare. This suggests that SRT1720 won't produce hypoglycemia, a dangerous dip
in blood sugar that is a common side effect of diabetes treatments.

If SRT1720 and resveratrol are approved for diabetes, they will likely be
used off-label to treat other diseases, from cancer to Parkinson's, that
become more common with age and may involve age-related mitochondrial
degeneration and the resulting metabolic disarray of key tissues and organs.

That model of disease is not yet the consensus in the medical community,
which views those diseases as having multiple causes rather than a common
root, and has generally ignored mitochondrial factors in its search for
cures.

"The study again indicates that it's metabolic function that regulates
diabetes and obesity, rather than changes in the activity of structural
genes," said University of California, Irvine mitochondrial therapy pioneer
Douglas Wallace, referring to genes that code for non-mitochondrial
functions. "You have to look at tissue metabolism to understand the disease
biology. The traditional mechanism of looking at a few nuclear gene processes
is not going to be productive."

As for longevity-enhancing drugs, said Wallace, "there will be others."

Specific SIRT1 Activation Mimics Low Energy Levels and Protects against
Diet-Induced Metabolic Disorders by Enhancing Fat Oxidation [Cell Metabolism]

Image: Liver tissue from mice fed high-fat diets and, from left to right, no
dose, a low dose or a high dose of SRT1720; white patches correspond to fat /
Cell Metabolism