Dr. Ronald A. DePinho
President, University of Texas MD Anderson Cancer Center
We are in a period in history that is redefining the human experience, a period of major scientific advances that have increased life expectancy and positioned us to understand and control many diseases. The pace of progress has accelerated dramatically in recent years as a result of major technological and conceptual advances, enabling us to understand biological and disease processes on the most elemental levels, and illuminating preventive and therapeutic strategies for many diseases. Our understanding of the instigators of cancer, heart disease, diabetes and other disease has provided an unprecedented opportunity to be more proactive, as opposed to reactive, in managing public health.
The importance of this effort is underscored by the world’s changing demographics. By the year 2025, the world population will include 1.2 billion individuals over the age of 60, an age beyond which major diseases such as cancer, diabetes, heart disease and Alzheimer’s disease doubles every 5 years. In the United States, there is an anticipated 45% increase in cancer by the year 2030 due to the fact that advancing age is the most important risk factor for cancer. Similarly, the 45% chance of developing Alzheimer’s disease by age 85 will result in a four-fold increase in expenditures from today’s $250 billion dollars. This disease burden is unsustainable. Given that the aging process itself is a major driver of these diseases, we are working towards an understanding of the molecular circuitry of aging that could be used to prevent age-associated diseases.
Our laboratory has been dissecting the molecular pathways governing the aging process and how these pathways are linked to the diseases of aging such as cancer, Alzheimer’s, diabetes, or cardiomyopathy. A number of studies have indicated that the intimate link between advancing age and age-related diseases relates in part to core pathways of aging being commandeered to drive the pathogenesis of those major diseases.
Our principal experimental approach to understanding the aging process has been through the study of telomeres,
the ‘caps’ at the ends of chromosomes which function to maintain chromosomal integrity. With advancing age, telomeres become progressively damaged, resulting in the eventual activation of the aging process. Telomere integrity can be restored by a telomere synthesizing enzyme called telomerase, however this enzyme is low in adult cells leading to eventual activation of aging signals.
In early studies, we engineered knockout mice that lacked telomerase and showed that this deficiency resulted in premature aging. Building on these early studies, our laboratory engineered a second strain of mice in which
telomerase expression could be turned on or off. In the telomerase “off” state, the mice aged prematurely. They were very feeble physiologically and their lifespans were shortened significantly. When we reactived telomerase activity in the animal, telomeres were restored and aging signals in the mice were extinguished. We saw a dramatic reversal of aging signs and symptoms, including restoration of fertility, increased physical activity, improved cognitive function and increased brain size, among other widespread tissue changes. In addition, lifespan was restored significantly towards normal levels.
These findings convey the fundamental point that tissues, even those in a very severe state of degeneration, retain a remarkable capacity to renew themselves. It is tempting to speculate that a detailed understanding of the circuitry of aging could provide a framework for pharmacologic manipulation of the aging process.
While aging statistics are daunting, I am optimistic that science will deliver a dramatically increased health span of humans. I believe that, when history views our generation, we will be recognized as the first to understand the genetic basis of life and disease and to harness such knowledge to change the human experience. With these advances will come important political, societal and moral issues that will challenge future generations as the world population continues to age and expand. The scientific quest will continue as there is nothing more central than our desire to exist and exist in a healthy state.