Role of Telomeres and Telomerase in Aging and Cancer

Abstract

Telomeres progressively shorten throughout life. A hallmark of advanced malignancies is the ability for continuous cell divisions that almost universally correlates with the stabilization of telomere length by the reactivation of telomerase. The repression of telomerase and shorter telomeres in humans may have evolved, in part, as an anticancer protection mechanism. Although there is still much we do not understand about the regulation of telomerase, it remains a very attractive and novel target for cancer therapeutics. This review focuses on the current state of advances in the telomerase area, identifies outstanding questions, and addresses areas and methods that need refinement.

Significance: Despite many recent advances, telomerase remains a challenging target for cancer therapy. There are few telomerase-directed therapies, and many of the assays used to measure telomeres and telomerase have serious limitations. This review provides an overview of the current state of the field and how recent advances could affect future research and treatment approaches. Cancer Discov; 6(6); 584-93. ©2016 AACR.

Figure 1

All somatic normal human cells display progressive telomere shortening with increased cell divisions. In the absence of a mechanism to maintain telomeres, cells eventually undergo replicative senescence (aging). Ectopically expressing just the catalytic subunit (TERT) of the telomerase holoenzyme complex is sufficient to maintain telomere length and immortalize normal cells. While normal cells with or without telomerase activity are not transformed, in the background of additional oncogenic changes, normal cells not only upregulate or reactivate telomerase but can become fully malignant.

Figure 2

With increasing cell divisions, telomeres progressively shorten. Even stem cell s that self-renew, there is a gradual shorterning of telomeres. After a finite number of cell doublings, eventually the cells have sufficient short telomeres that they undergo a growth arrest called senescence or the Mortality Stage I (M1). This has also been termed the Hayflick limit. Premalignant cells that have obtained a number of oncogenic changes can bypass M1 and enter into an extended lifespan period. This has been termed the extended lifespan period but vventually these cells also slow down in proliferation and enter a period called crisis. In crisis there is a balance between cell growth and apoptosis and the vast majority of the cell population dies. A rare cell can upregulate telomerase or the much rarer ALT pathway and continue to growth. The hallmark of cells escaping crisis is almost universally, stable but short telomere lengths and telomerase activity.

Figure 3

If one assume spontaneous mutations can occur approximately each 20 cell divisions (about 1 million cells), and assuming that mutations provide a premalignant cell with a slight growth advantage, then after 60–100 doubling (at least in cell culture conditions) the cells would contain some very short telomeres that are uncapped and initiate DNA damage signaling. This is a potential potent initial anti-cancer senescence “brick wall” that protect large long-lived species such as humans from the early onset on cancer. It is now believed that it requires 8–15 key oncogenic changes for a normal cell to become a cancer cell, so senescence could have evolved in humans to prevent most cancer until later in life. Eventually, however, senescence can be bypassed and this can lead to telomerase activation and cancer progression.

Figure 4

Recent evidence suggests telomere length can regulate genes over long distances. There are genes several megabases from a telomere that are silenced in young cells, expressed in old cells and repressed again when TERT is introduced into old cells. Using 3D FISH with a subtelomeric probe and a distal gene of interest, one can observe adjacent probe signals in young cells and separated signals in old cells with short telomeres. This model provide an explanation for how gene expression changes can occur during aging without initiating a DNA damage signal. As an example, the model (right side) shows a schematic of how telomeres when long could repress the expression of a specific gene over long distances and when telomeres shorten as part of normal aging, expression of that specific gene could change. Genes (X and Y in the illustration) although closer to the telomere are not regulated by this mechanism (TPE-OLD). Previously it has been shown that ISG15, desmoplaskin, C1S, and SORBS2 are regulated by this mechanism (62, 63).