Senior Scholar Award in Aging
James L. Sherley, M.D., Ph.D.
Massachusetts Institute of Technology

Identification of Chemical “Age Spots” on Immortal DNA Strands in Adult Stem Cells

Modern societies are the beneficiaries of a previous century of extraordinary acceleration of advances in science and medicine. Yet, there is still a significant burden of disease and illness. One reason for the persistence of sickness and poor health is that, despite extensive knowledge of human biology and physiology, there remain many essential aspects of human life that are poorly understood. In the next century, research to better elucidate the mysteries of human life will yield greater benefits for health and well-being.

Chief among the unsolved mysteries of human life that contribute to chronic diseases and poor health is aging. Like all mammals, humans age. Though some aspects of aging are understood, many others remain unclear. Of particular relevance to our research is the paradox of cellular aging.

The basic building blocks of the body are microscopic self-contained living units called cells. Trillions of cells with different functional capabilities are grouped together in the body to form organs and tissues. Aging of cellular tissues and organs is hard to understand, because newly formed cells continuously replace old cells. This process, called cell renewal occurs continuously in most cellular tissues and organs throughout life. The main focus of this research is investigation of a cellular process that may account for the paradoxical aging of adult tissues that undergo continuous cell renewal.

New cells in adult tissues are produced by the division of specialized cells called stem cells. Before an adult stem cell divides to produce a second cell that can replace older tissue cells, it duplicates all of its components, including its genetic material DNA. However, the process of duplicating DNA results in errors in the new copies of the genetic code. If these copy errors were retained in the stem cell's DNA, they could result in diseases like cancer. We recently confirmed a long-standing hypothesis that when adult stem cells divide they transfer all new DNA copies to the new second cell and keep the original error-free DNA, called immortal DNA strands. Other cells are less likely to form cancers because, unlike adult stem cells, which divide for the entire human life span, they stop dividing, perform their function, and die.

This remarkable strategy for avoiding cancer-causing genetic errors in adult stem cells may have one drawback, stem cell aging. Whereas adult tissue stem cells can renew all of their other cellular materials, they retain the same immortal DNA strands. We postulate that with time these long-lived DNA strands undergo chemical changes that lead to the malfunction or death of adult stem cells. Loss of adult stem cell function will erode tissue function and limit longevity. Thus, time-dependent chemical reactions in adult stem cell immortal DNA strands may be a major cause of aging in human tissues.

We refer to the predicted chemical changes in immortal DNA strands in adult stem cells as DNA "age spots". The main goal of this research is to confirm the existence of DNA age spots and determine their chemical nature. Understanding the nature of immortal DNA strand age spots may yield strategies for intervening in aging processes and reducing their effects on human health and life expectancy.

Contact Dr. Sherley.