Telomeres, Telomerase and Aging

Speaker: Chantal Autexier, Ph.D., Lady Davis Institute for Medical Research, Jewish General Hospital, and Bloomfield Center for Research in Aging; Departments of Anatomy and Cell Biology, and Medicine, McGill University, Montreal QC.

Dr. Chantal Autexier discussed the role of telomeres in the maintenance of genetic and cellular integrity, and how telomere disruption is involved in cellular senescence and the aging process.

Telomeres and Their Role in Cellular Integrity
Telomeres are noncoding repetitive DNA sequences (TTAGGG) that protect the ends of linear eukaryotic chromosomes. In humans, a shelterin complex of 6 main proteins binds telomeres.¹ Both the structure and the length of telomeres are important for cellular integrity (Figure 1).

The telomeres are thought to prevent the cell’s damage response mechanisms from recognizing the ends of linear chromosomes as double-stranded DNA breaks, including those arising when chromosomes are damaged by stresses such as ionizing radiation. Interfering with telomere structure or length can lead to end-to-end fusions between chromosomes, chromosome instability and abnormalities, and cell division problems (cell senescence, cell death, or cells becoming cancerous).

In the body, most cells are unable to maintain telomere length from one division to the next, as the DNA replication machinery is unable to fully replicate the ends of chromosomes, leading to telomere shortening every time cells divide. Once a critical point—the Hayflick limit—is reached, most cells exit the cell cycle and undergo cell senescence. However, a small proportion of cells are able to re-enter the cell cycle, and this is usually associated with the lengthening of telomeres and the expression of telomerase, an enzyme directly involved in telomere formation and maintenance. Bodnar et al. have shown that forced expression of telomerase prevents telomere loss and growth arrest of normal human fibroblasts in culture and is sufficient for telomere lengthening and cell immortalization (extended lifespan).²

While most cells do not express telomerase, some cells do, such as stem cells, cells of the germ line, and 85% of cancer cells. Such cells are therefore able to maintain telomere length and structure through a large number of cell division cycles.

Telomere Shortening, Cell Senescence, and Tissue Aging
The process by which a cell exits the cell cycle is called replicative senescence. This can be triggered by various stresses, such as radiation damage and oxidative stress.^3,4 In many cases, senescence is caused by, or associated with, loss of telomere integrity.

The cell cycle is controlled by multiple checkpoint mechanisms that sense DNA damage, activate repair mechanisms, and trigger cell death when damage cannot be repaired. Tumour suppressors are important cell cycle regulators that regulate cell senescence and death, ensuring that a cell with extensive damage dies or stops dividing. When these checkpoint proteins are absent or malfunctioning, damaged cells continue to grow. Although tumour suppressors protect an organism from the accumulation of damaged cells, they also contribute to tissue aging. As damaged and senescent cells are eliminated through cell death, cell pools responsible for tissue renewal and the maintenance of tissue function are depleted.

In humans and other organisms, tissues that undergo rapid self-renewal—lining of the gut, skin, hair follicles, and bone marrow—are the ones most affected by telomere shortening, cell senescence and cell death. Many age-related pathologies affect these tissues.

According to Dr. Autexier, many studies have shown a correlation between telomere shortening and replicative senescence, cell death and aging, and between telomere length maintenance, the presence of telomerase activity and cellular immortalization, longevity or cancer formation.