Senior Scholar Award in Aging
Frederick W. Alt, Ph.D
Center for Blood Research, Boston

The Biology of Mammalian Sir2 Homologs and their Role in Lifespan Determination

Aging occurs in almost all organisms, yet the molecular basis of aging is poorly understood. In addition, many diseases, including cancers, occur much more frequently in aged populations. Therefore, an understanding of the molecular and cellular events that accompany aging would undoubtedly contribute immensely to human health. One way to unravel the complex process of aging is to study molecules that are important in the aging process. Sir2 is a molecule found in all organisms that appears to play an important role in determining how quickly aging occurs. Increasing the amount of Sir2 has been shown to increase lifespan in yeast and worms. Sir2 acts in several different ways to increase lifespan. The fact that Sir2 regulates aging in organisms as different from one another as yeast and worms implies that Sir2 may play a similar role in humans.

In the past, our lab has been involved in studies of immunology and cancer. In our studies, we have often made mice lacking specific genes involved in these processes. We are now taking a similar approach to studying the function of mammalian Sir2 proteins in aging and aging-related disorders. In mammals, there are seven family members of Sir2, called SIRT1-SIRT7. We have made mouse strains, lacking each of these genes. In work that has recently been published, we have found that mice lacking a particular version of Sir2, called SIRT1 often die after birth, with defects in the eye and heart. We have also found that cells from these mice are hypersensitive to radiation. In ongoing studies, we have evidence that mice lacking several other SIRT genes are alive and appear healthy, at least when they are young. These mice will be prime candidates for testing the effects of Sir2 on aging. We intend to study all these mice closely as they age, particularly looking for any evidence of rapid aging or cancer. Ultimately, we hope to generate mice that have increased levels of Sir2, in the hopes that these animals might have an extended lifespan.

In addition to characterizing mice lacking Sir2, we are also carrying out experiments on cells. We are attempting to identify molecules in the cell that interact with Sir2. We have already discovered several molecules that may interact with Sir2. Further studies of these interactions will likely tell us much about what Sir2 does in the cell and how it extends lifespan. Oxygen free radicals, which are damaging molecules that are generated all the time in the cell, are thought to be an important cause of aging. We are therefore looking to see whether Sir2 may play a role in how the cell resists oxidative damage. We have also made Sir2 in the test tube and we are studying how it behaves. We hope that our experiments will help provide insight into how aging occurs.

Contact Dr. Alt.