Examples of SIRT1 in Duodenum and Ileum

The Sinclair laboratory is driven to find genes and small molecules that can slow the pace of aging. Our work is based on the hypothesis that the pace of aging is not inexorable or predetermined, but can be altered if we know which pathways to target. There is now convincing evidence that longevity pathways exist in mammals, and that by activating them it may be possible to protect against the deterioration of major organs and tissues, thereby delaying and possibly reversing aging. Though we are focused heavily on understanding fundamental mechanisms of aging at the genetic and biochemical levels, the more pressing goal is to find new and effective ways to treat common diseases including type II diabetes, Alzheimer’s disease, cardiovascular disease, heart failure, and cancer. Ongoing work involves studies of the role of sirtuins and other longevity pathways in DNA repair, fertility, mitochondrial dysfunction, cardiac failure, muscle loss, the interactions between epigenetic and genetic instability, and memory loss. Our combined expertise spans from mouse physiology and cognition, to high-throughput molecule screening, to cutting-edge enzymology and structural biology.

Examples of Projects in the Lab:

Understanding the role of Mitochondria in Aging and Disease.

The study of mitochondria has experienced a renaissance in recent years. A large body of evidence indicates that common aging-related diseases have a mitochondrial component. Yet, surprisingly little is known about how the nuclear and mitochondrial genomes communicate and if communication breaks down during aging (Finley and Haigis, 2009). We are investigating the mechanisms by cells maintain synchrony between the nuclear and mitochondrial genomes during aging. Using novel genetic and pharmacological approaches, we are using this knowledge to restore metabolic function in aged mice back to youthful levels.

In 2007, our lab published that mitochondrial NAD+ levels dictate cell survival, which we referred to as the “Mitochondrial Oasis Hypothesis.” Following up on this work, we have formulated an exciting new hypothesis that leakage of NAD+ from mitochondria is a cause of aging and memory loss. We are also interested in identifying the majority of genes in the human genome that control mitochondrial function and mediate nuclear-mitochondrial communication. This will provide new insights into fundamental aspects of mitochondrial biology and how mitochondrial defects may be prevented or corrected. We also are interested in finding novel secreted factors that increase mitochondrial function and are candidates for signaling factors that have been recently been implicated in the systemic control of aging in simple organisms.

Can we delay menopause and female infertility?

Ovarian stem cells are a recently discovered type of cell than can give rise to oocytes in culture and produce healthy oocytes in vivo. This work may overturn the dogma that a female is born with a set number of eggs and they are simply lost over time due to damage and genome instability. We are interested in using our knowledge gained from studying aging and metabolism to understand how female infertility may be delayed or reversed. Our goals are to identify genes and small molecules that can reactivate ovarian stem cells in vivo to treat premature ovarian failure, chemotherapeutic ovarian failure (in cancer patients) and extending the healthy and fertile period of life for women.

SIRT1 in mitosis (red), Histone Ac-H4-K9 (green), DNA (blue). Photo Haim Cohen.

SIRT1 in mitosis (red), Histone Ac-H4-K9 (green), DNA (blue). Photo Haim Cohen.

Could the cell’s overreaction to DNA damage be a cause of aging?

In 2008 we published that the relocalization of chromatin factors in response to DNA damage may be a cause of aging. We called this “The Relocalization of Chromatin Modifiers (RCM) Hypothesis.” SIRT1 was shown to move from promoters to DNA breaks resulting in the expression of those genes. After DNA repair, the process was reset. During aging, however, we have evidence that this process does not fully reset, and may explain why gene expression patterns change with aging. We are testing this hypothesis directly in mice at present.

Can we develop medicines that slow aging?

The discovery of longevity genes showed that it is possible to greatly slow the pace of aging and disease by manipulating just one central pathway. This raises the possibility that we can find small molecules that can treat multiple, seemingly unrelated diseases, with a single medicine. Our lab has been highly active in this area, starting with the discovery of sirtuin activating compounds (STACs) in 2003. Since then, potent activators have been discovered and some of these are now in clinical trials, producing positive results. We have active studies to understand how STACs work and the molecular and the physiological levels using cutting-edge enzymoloical and structural methodologies and mouse genetic models in which we can delete genes at any time throughout the lifespan of the mice, and in specific organs. We recently published, for example, that the ability of resveratrol and a STAC called SRT1720 to increase mitochondrial function, require the SIRT1 gene in vivo. Small molecule screens against new longevity pathway targets are also underway and some of the compounds are undergoing pre-clinical testing in mice for their effects on aging, fertility, and other age-related diseases.

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