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 genes^4,5. 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.

SIRT1-Activating Compounds (STACs)
From the multiple beneficial effects of CR in primates and humans, it is apparent that drugs developed to treat diseases of aging may also help treat a wide variety of severe human diseases, including metabolic, neurological, and cardiovascular diseases and cancer. The field of aging research is moving from the discovery of key genes that control the aging process to the development of small molecules that modulate these genetic pathways. One of the first such molecules is resveratrol, found in red wine, which belongs to a family of chemically related molecules that activate SIRT1⁶. Resveratrol and other “sirtuin-activating compounds” (STACs) extend the life span of yeast, worms, flies, fish, and obese mice, with physiological changes that resemble those caused by CR.

In the past few years, significant research efforts have led to the generation of druglike, synthetic STACs, unrelated to resveratrol, that are 1,000-fold more potent activators of SIRT1. Animals treated with novel STACs display many of the beneficial effects of calorie restriction, including an improvement in metabolic and cardiovascular parameters, linked to an increase in mitochondrial biogenesis.

Development of Small-Molecule Drugs That Treat Diseases of Aging
The development process for drugs that modulate aging pathways is no different than that for a typical drug, although the end product could have much broader applications (figure 2). To date, the SIRT1 activator resveratrol has reached phase Ib clinical trials as a treatment for type 2 diabetes and cancer. These trials are one to three months in length. We envisage, within the next two to three years, the initiation of longer human trials, on the order of three to nine months, that test resveratrol against other severe disorders, such as Huntington’s disease and obesity. Trials lasting nine to twelve months, which test the compound against chronic disorders such as metabolic syndrome or Alzheimer’s, may begin within the next four to six years. Finally, looking out seven or more years, we anticipate that drugs that modulate aging pathways may be tested in long-term human trials that last one to several years and measure biomarkers of human aging.

Figure 2. Potential timeline for human clinical trials of drugs to treat diseases of aging. Top: Estimate of the length of a clinical trial testing a drug that targets aging genes as a treatment for a particular disease. The durations of the trials move from months at the left end of the spectrum to years at the right. Bottom: Estimate of the time it may take for a drug that targets aging genes, as a treatment for a given disease, to enter human clinical trials. At left, shorter clinical trials of treatments for diabetes, cancer, and mitochondrial disorders have already been initiated. At right, long-term clinical trials lasting years, measuring human biomarkers of aging, will likely be initiated in the next seven years.

Potential Societal Impact of Drugs to Treat Diseases of Aging
Rapid advances in the field of aging research in the past five years have prompted economists and epidemiologists to calculate the potential impact of drugs that broadly treat diseases of aging. A recent paper from RAND⁷ comparing several promising experimental therapies concluded that drugs that treated diseases of aging by mimicking CR would be the most cost effective, costing perhaps one-tenth as much per additional year of healthy life as more common medical interventions for specific diseases such as cancer, stroke, and heart disease (figure 3). Given the progress of clinical work on such drugs and the long list of reputable scientists who are backing that work, it is feasible that drugs that are broadly effective against diseases of aging could hit the market within the next decade. Success is by no means guaranteed, but it is worth pondering the remarkable fact that serious drug development has entered a space that was until recently the realm of science fiction.

Figure 3. Cost-benefit analysis of selected future therapies (adapted from Goldman et al., 2005 RAND study). The estimated cost per additional year of healthy life for drugs targeting diseases of aging, $8,790, is roughly one-half the cost of stroke treatment, one-tenth the cost of cardiac defibrillators, and one-fifteenth the cost of diabetes prevention.

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