Examples of SIRT1 in Duodenum and Ileum

The Sinclair research group is driven to understand why we age and to find novel approaches to slow and reverse 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 what leads to the progressive loss of mitochondrial fitness during aging. We investigate the cellular mechanisms that could be employed to maintain the mitochondrial homeostasis and ultimately prolong healthspan.

One of our research avenues led to the discovery of ongoing asynchrony 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. We established 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 hypothesis that leakage of NAD+ from mitochondria is a cause of aging and memory loss.

We are also interested in identifying new genes and signaling cascades in the human genome that control mitochondrial function. We are developing novel genome mining algorithms, using advanced sequencing and proteomics tools, and high throughput screening methods to map the most complete network of mitochondrial regulators. This work 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?

High efficiency of DNA repair is essential for cell survival and the prevention of cancer, yet it declines with age for reasons that are unclear. We introduced  “The Relocalization of Chromatin Modifiers (RCM) Hypothesis” which assumes that relocalization of chromatin factors in response to DNA damage may be a cause of aging. We discovered that SIRT1 moves away from promoters to DNA breaks resulting in gene expression changes. In young cells this process is reset just upon completion of DNA repair. However, we have evidence that during aging the resetting process is less efficient, and thus contributes to altered gene expression patterns at the onset of aging.

Our work on SIRT1 led us to an exciting finding that the level of nicotinamide adenine dinucleotide (NAD+), cofactor of SIRT1, declines with age. We study the mechanisms by which the NAD+ level affects DNA repair and look for therapeutic targets to improve this process. In particular we focus on delineating the biology of NAD+-depleting and producing enzymes as a direct tools to control the NAD+ level in the cells toward the increased healthspan.

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 enzymological 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 published, for example, that the ability of resveratrol and a STAC called SRT1720 to increase mitochondrial function, require the SIRT1 gene in vivo. We have an active program to find molecules that raise NAD levels. We are testing them for their effects on aging and other age-related diseases. Human clinical trials with NAD-boosting molecules are planned for 2017.

Website Design by Boston Web Designers