'Fountain of youth' research uncovers aging genes

Elixir and Sirtris are dedicated to bottle the genie which could hold the promise of everlasting youthfulness.

7 November  2006
DELHI, INDIA

Two biopharmaceutical companies are in big race to bring forth a magic potion to restore eternal youth and longevity. 

Elixir Pharmaceuticals Inc., a Kendall Square company, has recently come out with a pathbreaking research on yeast uncovering the genes that regulate aging.

Elixir Pharmaceuticals' researchers Drs. Rory Curtis, Bard J. Geesaman and Peter S. DiStefano in their "Aging and Metabolism: Drug Discovery Opportunities," appearaed in Nature Reviews Drug Discovery the findings describing the intimate links between these pathways of aging and those of metabolic disease, such as type 2 diabetes and obesity.

The authors elaborated how these insights open the door to novel classes of drugs, which can be developed to not only treat diabetes and obesity, but also effectively slow the aging process and extend lifespan. John Kopchick, Ph.D., Goll-Ohio Eminent Scholar and Professor of Molecular Biology, Department of Biomedical Sciences, Konneker Research Center, Ohio University, commented, "Their conclusions article provided an elegant and comprehensive survey of the essential connections between metabolic disease pathways and aging. The potential of this research is profound: Modulating these pathways may not only uncover yet unknown therapeutic targets and/or drugs to treat metabolic disorders, researcher said.

Elixir is also researching sirtuins, but it’s seeking ways to treat diabetes and obesity by targeting ghrelin, a protein released in the stomach that regulates hunger and metabolic functions.

Much research has focused on the role of insulin resistance in aging. According to the authors, "in situations where plentiful high-calorie food is combined with a sedentary existence, the pancreas increases insulin secretion above normal levels in order to dispose of sustained excess blood glucose which, over time, leads to the deposition of visceral fat." 

Two major effects result from such conditions. Increased visceral fat initiates a metabolic cascade that impairs insulin signaling in the body, and greater levels of insulin cause visceral fat to secrete substances that reduce insulin sensitivity in tissues. As the authors note, "Eventually, this feed-forward cycle leads to an altered metabolic state involving very high levels of insulin (hyperinsulinemia) induced by resistance to insulin, even under fasting conditions. This state triggers a constellation of related complications, collectively referred to as metabolic syndrome."

According to the Nature authors, many of the genes implicated in the modulation of lifespan are well-conserved from lower organisms right up through humans. In addition, these genes code for receptors, enzymes and transporters, and are therefore suitable targets for drug development. These include: 1) the SIR2/SIRT class of deacetylases, known to increase lifespan when over-expressed in yeast and flies, 2) insulin/insulin-like growth factor receptor, which increases lifespan in worms and mice when deleted in certain tissues, 3) AMP kinase, an enzyme that acts as a
fuel sensor and is a target of the anti-diabetic drug metformin, and 4) INDY ('I'm not dead yet'), a cell surface transporter known to increase lifespan in flies when mutated.

Dr. Kopchick stated, "The article by DiStefano et al. will stimulate a paradigm shift in our thinking about aging and age-related disorders. As pointed out by the authors, we are beginning to recognize that metabolic syndrome, in addition to being a precursor of serious diseases such as type 2 diabetes and cardiovascular disease, may be a sign of premature aging.

Equally in the race is Cambridge, Mass-based Sirtris Pharmaceuticals. Research published in Nature by Sirtris scientists is first demonstration in mammals that resveratrol, a sirtuin activator, can treat diseases of aging, such as diabetes doses first diabetes patient in human clinical study with improved formulation of resveratrol. 

Sirtris, the leading sirtuin therapeutics company, announced that SRT501, its initial clinical candidate which is a proprietary formulation of resveratrol with improved bioavailability, has been administered to patients with type 2 diabetes in a human Phase 1b clinical study.

Sirtris is studying SRT501 as a drug candidate for type 2 diabetes, based in part on the scientific evidence that sirtuin activation, by means of compounds like resveratrol, has been shown to have a positive effect on key clinical measures for diabetes. In an article published today in Nature, "Resveratrol improves health and survival of mice on a high-calorie diet," resveratrol was shown in mice to promote normal cellular function and extend healthy lifespan, including an increase in insulin sensitivity, a decrease in insulin growth factor-1 levels, and an increase in the number of cellular mitochondria. The authors of the Nature article include principal investigator David Sinclair, Ph.D., Associate Professor of Pathology and Co-Director of the Paul F.

"This study indicates that SIRT1 is associated with extension of healthy lifespan in obese mice and if this is translated into humans, it could have an enormous impact on medicine." said David Sinclair. "I believe that the measures of health improvement in this study, such as increased insulin sensitivity and decreased IGF-1 levels, show the potential for sirtuin activation to treat metabolic diseases, such as diabetes."

SRT501 is the first small molecule to enter human clinical trials that is designed to target SIRT1, the best characterized of the recently-discovered family of sirtuin enzymes. Activation of SIRT1 is believed to be a key pathway by which resveratrol regulates such processes as glucose and insulin production, fat metabolism, and cell survival. Sirtris has applied this scientific discovery to the development of SRT501, which activates SIRT1, for the treatment of diseases of aging such as metabolic and mitochondrial disorders. In addition, Sirtris has a robust pipeline of small molecule drug candidates that are potent SIRT1 activators and are chemically distinct from resveratrol.

"Based on the continuing scientific evidence, as shown in this most recent Nature article, we are continuing to advance drug candidates, such as SRT501, to translate the science of sirtuins into new treatments for diseases of aging, such as diabetes," said Christoph Westphal, M.D., Ph.D., Chief Executive Officer of Sirtris Pharmaceuticals. "We are excited about the ability of SRT501 to activate SIRT1 as a potential treatment for diabetes. In addition, we are developing a strong pipeline of sirtuin activators that are more potent and are targeted for a broad range of diseases of aging."

Sirtris has exclusively in-licensed from Harvard University a broad portfolio of intellectual property relating to the therapeutic potential of activating sirtuins, largely based on the work of Dr.

David Sinclair. In the current human clinical study of SRT501, Sirtris has designed this phase 1b trial to evaluate the safety and pharmacokinetics of SRT501 in 90 patients with Type 2 diabetes using daily oral administration of SRT501 for 28 days.

Sirtuins are a recently discovered family of enzymes that promote normal cellular function. In particular, sirtuins improve the function of mitochondria which generate energy in cells. When organisms face adversity, sirtuins are activated as part of a natural process that maintains healthy function.

Therefore, sirtuins are attractive drug targets which may be therapeutically beneficial for diseases in which mitochondria are dysfunctional, often observed in diseases of aging. These diseases include metabolic diseases such as type 2 Diabetes and other mitochondrial disorders. Sirtuin therapeutics offer the potential for a novel class of drugs that can treat significant diseases of aging in a new way.

So researchers are developing drugs to treat or prevent aging-related diseases like diabetes or obesity. The current explosion of anti-aging research dates to the 1930s when scientists discovered that dramatically reducing an animal’s caloric intake will pile on extra years. But a near-starvation diet is beyond reach for most. However, the Food and Drug Administration does not consider aging a condition that requires treatment.