Cell Physiologic Stresses and Telomere-Based Cell Senescence

2003 senior Scholar Award in aging

The biological processes that cause human aging are complex and remain poorly understood. Two general mechanisms have been proposed to explain the aging of human tissue. The first postulates that aging is caused by the accumulated damage that cells within our tissues sustain due to various stresses that they encounter during a human lifetime. An alternative explanation of aging involves internal biological clocks, which dictate the onset of age-associated changes in the body, doing so through the release of specific signals such as hormones and other cues.

Both mechanisms assume that the aging of human tissues can be attributed largely or totally to the progressive deterioration of the individual cells composing our tissues. Consequently, an excellent experimental system for understanding aging involves the study of cells that are propagated in culture, e.g., in Petri dishes. When normal cells are extracted from human tissues and propagated under such conditions, they are able to grow and divide for an extended period of time. However, after a certain time span, such cells will invariably enter a state termed ësenescence. These cells will no longer be capable of dividing, will undergo drastic changes in their shape and function, and yet will remain viable for extended periods of time. Past research has shown that that this process, as observed with cultured cells, reflects changes that occur in cells in the human body during the aging process. Moreover, it is possible to induce cells to divide indefinitely and avoid senescence by activating or inactivating specific genes in these cells. Strikingly, the same genes that can ìimmortalizeî cells in culture are also genes that enable normal human cells to become cancer cells. Thus, from the viewpoint of a cell, the avoidance of senescence/aging leads to uncontrolled cell division and to the acquisition of the ability to form a tumor.

My laboratory studies the genes that control the aging and senescence of cells following prolonged cycles of growth and division, and the molecular changes that occur in these cells during this extended propagation. By understanding the function of these genes and the precise nature of the molecular events occurring in cells during aging, we hope to understand which changes in cells throughout the human body contribute to the aging process.

In recent years we have focused our attention on entities within cells called ìtelomeresî. Telomeres are specialized structures found at the ends of all chromosomes. They are composed of specific DNA and protein components, and their normal role is to serve as caps or shieldsî that protect the chromosome ends from fusing to one another and from other forms of damage. Some years ago, it was discovered that telomeres play an important role in aging: as cell populations proceed through repeated cycles of growth and division, their telomeres shorten progressively. The interpretation of this finding was that telomeres, through their length, ìcountî the number of times a lineage of cells has divided, and instruct these cells to enter in senescence after an appropriate, pre-determined number of divisions. Research performed in my laboratory and by others has shown that activation of a certain gene in such cells can prevent the shortening of telomeres, and that this also prevents the aging of cells ñ as manifested by their entrance into senescence. Such immortalized cells are then poised, following additional alterations, to become cancer cells.

Recent discoveries made in my lab have shed new light on these mechanisms. We have recently found that in addition to such progressive shortening, telomeres undergo dramatic changes in their structure during senescence ñ changes that affect several specific DNA and protein components of telomeres. These changes in telomere structure (rather than telomere length) also occur when cells are exposed to various biological and biochemical stresses. Such stresses cause cells to undergo accelerated or even immediate senescence ñ in effect, a type of trauma-induced aging. One type of stress that appears to be especially important is that caused by oxygen radicals.

Our findings indicate that telomeres operate as a type of stress-response mechanism. Thus, a cell suffers from stress caused by various external sources or by the products of cellular metabolism. In response to this cumulative stress, the structure of telomeres undergoes dramatic changes, acting as a switch to activate the aging program in the cell.

In our planned research, we will study the role played by telomeres during aging and senescence. We aim to discover how cells translate different stresses to which they are exposed into an internal biochemical signal, and how this signal causes changes in the structure of telomeres. We will also study the manner by which resulting changes in the telomeres act as a switch to activate the senescence/aging program within a cell. In addition, we will study whether in the aging human body similar changes in telomere structure occur, and whether in diseases involving cellular stress a similar role for telomeres is observed. Elucidation of the mechanism by which the aging program is activated in individual cells in the body is a crucial for understanding the aging process in general.

Robert A. Weinberg Ph.D.
Whitehead Institute for Biomedical Research