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.