Can We Develop Medicines That Slow Aging?

Why do we grow old? Why does aging cause disease? Can we slow aging or even reverse it? These are some of the greatest unsolved questions in biology. Advances in technology are allowing us to probe these questions more deeply and more rapidly than ever. By tackling these questions, researchers led by Dr. David Sinclair of Harvard Medical School aim to develop medicines that may one day prevent and/or treat multiple common diseases at once. Their ultimate goal is to allow people to live healthier, disease-free lives. They focus on genes (e.g. sirtuins) and small molecules (e.g. resveratrol) that mimic exercise and calorie restriction, a diet that slows the pace of aging in animals.

The researchers use mouse models to test genes and small molecules for their ability to protect against common age-related diseases such as cancer, heart disease, Alzheimer’s disease, cardiovascular disease, infertility, and type II diabetes. At the cellular level we study epigenetics, cellular metabolism and mitochondrial function, neuroprotection, and cellular senescence.

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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. The Sinclair Lab has 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.

The Sinclair Lab 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.

The Sinclair Lab at Harvard Medical School

The Sinclair Lab studies genes that slow the pace of aging. Work ranges from the isolation of novel stem cells from mouse and humans, to assessing small molecules that slow the pace of aging when fed to mice. Their goal is to uncover new biological processes that can translated into radically different medicines to promote longer, more productive lives.

A focus is on the Sirtuin genes and how they they protect against aging and also common diseases such as cancer, heart disease, inflammation, neurodegeneration and diabetes. The Sinclair Lab has mouse models to assess these diseases and how well genetic and pharmacological agents can slow them.

They are expanding into new areas such as understanding how cells control cellular energetics and female fertility, the role of chromatin in DNA repair in aging, and novel genes that control our innate defenses against deterioration and disease.

They are a team with complementary skills who work together to solve key scientific questions about mammalian biology and human health. Skills in the lab range from enzymology and biochemistry, to genetics and systems biology, to mouse models and human genetics. A screen of the human genome has recently been completed in collaboration with the Elledge Lab, aimed at identifying mitochondrial enhancers that promote human longevity, opening up entirely new areas of investigation for incoming graduate students.

David Sinclair, Ph.D., Department of Genetics, Harvard Medical School

David A. Sinclair, Ph.D. is a Professor in the Department of Genetics at Harvard Medical School and a co-joint Professor in the Department of Physiology and Pharmacology at the University of New South Wales. He is the co-Director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging and a Senior Scholar of the Ellison Medical Foundation. He obtained his Ph.D. in Molecular Genetics at the University of New South Wales, Sydney in 1995. He worked as a postdoctoral researcher at M.I.T. with Dr. Leonard Guarente where he co discovered a cause of aging for yeast as well as the role of Sir2 in epigenetic changes driven by genome instability. In 1999 he was recruited to Harvard Medical School where his laboratory’s research has focused primarily on understanding the role of sirtuins in disease and aging, with associated interests in chromatin, energy metabolism, mitochondria, learning and memory, neurodegeneration, and cancer. He has also contributed to the understanding of how sirtuins are modulated by endogenous molecules and pharmacological agents such as resveratrol. Dr. Sinclair is co-founder of several biotechnology companies and is on the scientific advisory board of several others. He is also co-founder and co-chief editor of the journal Aging. He has received numerous awards including The Australian Commonwealth Prize, a Helen Hay Whitney Postdoctoral Award, a Leukemia Society Fellowship, a Ludwig Scholarship, a Harvard-Armenise Fellowship, an American Association for Aging Research Fellowship, The Nathan Shock Award from NIH, Scholarships from The Ellison Medical Foundation, The Merck Prize, the Genzyme Outstanding Achievement in Biomedical Science Award, a "Bio-Innovator award" and the David Murdock-Dole Lectureship.

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Source: Harvard Medical School Department of Genetics

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