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Aging, The Molecular Concepts

3. TELOMERES AND TELOMERASE IN THE REGULATION OF HUMAN CELLULAR AGING

There is substantial experimental evidence that cellular aging is dependent on cell division, and the number of population doublings or cell generations measures the total cellular lifespan, not by chronological time (1). This means there is an intrinsic process occurring during cell growth, which culminates in the cessation of cell division. If a genetically determined counting program, which controls the number of cell divisions, regulates cellular age, then it is important to determine and understand what this mechanism is in molecular terms (2). During the past few years, there has been mounting evidence that the progressive loss of the telomeric ends of chromosomes may be an important timing mechanism in the aging process both in cell culture and in vivo (Table 3.I) (3-6). It is thought that the loss of telomeres eventually induces antiproliferative signals that result in cellular senescence (7-9). A hypothesis gaining prominence (Table 3.II) is that activation of telomerase, a special ribonucleoprotein reverse transcriptase important in maintaining telomere length stability, is necessary for the sustained growth of most tumors (10, 11).

3.1. FUNCTIONS OF TELOMERES

Telomeres are repeated TTAGGG DNA sequences (22) that stop natural chromosome ends from behaving as random breaks, which might activate DNA-damage, induced cell cycle arrest. Telomeres also provide the structural basis for solving the end replication problem (23. 24) (the inability of DNA polymerase to completely replicate the end of a DNA duplex).

Telomeric sequences shorten each time the DNA replicates. When at least some of the telomeres reach a critically short length, cells show signs of genomic instability and eventually stop dividing, which may cause or contribute to age-related diseases. In cancer, telomerase (25, 26) is almost always upregulated or reactivated and maintains the length of telomeres, allowing tumor cells to continue to proliferate.

TABLE 3.I
Evidence in support of the telomere hypothesis of aging
• Telomeres are shorter in most somatic tissues from older individuals compared to younger individuals (4. 5).
• Telomeres are shorter in somatic cells than in germline cells (6).
• Children born with progeria (early aging syndrome) have shortened telomeres compared with age-matched controls (12).
• Telomeres in normal cells from young individuals progressively shorten when grown in cell culture (3).
• Experimental elongation of telomeres extends proliferative capacity of cultured cells (13, 14).

TABLE 3.II
Telomere/telomerase model of aging and cancer
• Cellular senescence occurs when telomeres are short. Although the mechanism for this phenomenon has not been elucidated, tumor suppressor genes and cell cycle checkpoint control genes (p53 and RB-pl6) may be involved (15-17).
• Cells usually require 4-6 mutations to become malignant (18, 19). After becoming mutant in one allele, it generally requires 20-30 divisions to both eliminate the remaining wild-type allele and achieve a population size large enough for a second mutation to occur.
• Pre-cancerous cells thus usually become senescent before they can accumulate 4-6 mutations (20).
• Mutation(s) can occur in the telomerase repression pathway, which causes the enzyme to up regulate or reactivate (2, 8, 10).
• Telomerase activity in cancer cells correlates with the stabilization of telomere length and cellular immortalization (11, 21).
• Telomerase activity or a mechanism to maintain telomere stability is necessary for the continued proliferation of cells and is a critical, perhaps rate-limiting, step in cancer progression.

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