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C. H. Westphal MD, PhD1; M. A. Dipp, MD, PhD1; L. Guarente PhD2; D. A. Sinclair PhD3

1 Sirtris Pharmaceuticals
2 MIT
3 Harvard Medical School and Glenn Institute of Aging

Abstract
For thousands of years, society has been seeking a means to extend healthy life span. Yet the key genes that dictate life span were discovered only within the last decade. The challenge now is to utilize these discoveries to develop drugs to treat broadly prevalent diseases of aging, such as type 2 diabetes and cancer. From this perspective, we discuss the promising drug targets identified thus far in the field of aging research. Some of these targets appear to underlie the beneficial effects of calorie restriction, the most robust means to extend healthy life span in mammals. Insights gained from human clinical trials of calorie restriction, and from therapeutic interventions in animal models of diseases of aging, delineate a potential development path for drugs that treat diseases of aging.

Genes and Diets That Dictate the Pace of Aging
Only 20 years ago, aging was considered too complex for pharmacological intervention, involving thousands of genes and pathways. However, geneticists studying model organisms such as yeast and worms discovered several genes that can dramatically extend healthy life span1. There are proaging genes such as IGF-1 and antiaging genes such as SIRT1.

While genes that control aging have only recently been discovered, scientists have known for many decades that a simple change in diet can dramatically slow the pace of aging. “Calorie restriction” (CR), the diet wherein calories are reduced 20 to 40 percent, is the most robust means of extending healthy life span in mammals, and several of the key longevity pathways seem to underlie the beneficial effects of this diet. CR also improves health parameters in higher organisms including humans3.

In rodents, CR has been known for decades to forestall numerous diseases of aging, including diabetes, neurodegeneration, cardiovascular disorders, cancer, and several other diseases. Studies in calorie-restricted primates indicate that key aging parameters are improved, such as glucose levels, insulin sensitivity, and blood pressure. Many of these beneficial effects have now been seen in humans on a six-month CR diet2. Given the striking effects of CR on all these species, a broad scientific effort has been aimed at finding the key mechanisms of CR and molecules that can mimic its health benefits3.

Links between SIRT1 and Calorie Restriction
One of the leading candidates for a gene that underlies the effect of CR is SIRT1, the founding member of the seven-member “sirtuin” family of genes4,5. Calorie restriction activates SIRT1, leading to an increase in the number and function of mitochondria. Mitochondria are the “powerhouses of the cell” that are responsible for ATP production and also for clearance of by-products such as lactic acid. SIRT1 controls aspects of physiology that are consistent with CR, including fat metabolism, glucose metabolism, and cell survival. Because it is difficult for people to maintain compliance with calorie-restricted diets, a more practical approach to treating disease would be to develop small molecules that mimic CR by activating SIRT1. This represents a novel approach to treating diseases of aging, such as type 2 diabetes and cancer (figure 1).

Figure 1. Therapeutic potential of drugs that target longevity pathways. Targeting genes that are linked to aging has the potential to treat a broad range of diseases.

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