Do telomeres adapt to physiological stress? Exploring the effect of exercise on telomere length and telomere-related proteins

Abstract

Aging is associated with a tissue degeneration phenotype marked by a loss of tissue regenerative capacity. Regenerative capacity is dictated by environmental and genetic factors that govern the balance between damage and repair. The age-associated changes in the ability of tissues to replace lost or damaged cells is partly the cause of many age-related diseases such as Alzheimer's disease, cardiovascular disease, type II diabetes, and sarcopenia. A well-established marker of the aging process is the length of the protective cap at the ends of chromosomes, called telomeres. Telomeres shorten with each cell division and with increasing chronological age and short telomeres have been associated with a range of age-related diseases. Several studies have shown that chronic exposure to exercise (i.e., exercise training) is associated with telomere length maintenance; however, recent evidence points out several controversial issues concerning tissue-specific telomere length responses. The goals of the review are to familiarize the reader with the current telomere dogma, review the literature exploring the interactions of exercise with telomere phenotypes, discuss the mechanistic research relating telomere dynamics to exercise stimuli, and finally propose future directions for work related to telomeres and physiological stress.

Figure 1

Common telomere/telomerase dogma across cell types in humans. Telomeres are located on the ends of linear chromosomes. Over time (i.e., with increased numbers of cell divisions), telomeres shorten due to a number of end-processing events; thus, short telomeres are associated with chronological age and a number of age-related diseases. (A) Telomeres function to mask the ends of chromosomes from being recognized by a cell's DNA damage response system. When telomeres reach a certain length, they are no longer masked and the cell recognizes the ends of the chromosome as damaged DNA. When the DNA damage signal is initiated, the cell arrests and enters telomere-induced senescence. This occurs in adult human cells lacking the enzyme telomerase, which maintains and elongates telomeres by using reverse transcriptase activity to add telomere repeats to the ends of chromosomes. (B) During development and in certain adult stem cells, telomerase is expressed and slows telomere shortening in these cells, thus maintaining the pool of cells available in a presenescent state. (C) In 85% of tumor cells, telomerase is dysregulated and allows cancer cells to be immortal and divide indefinitely since they do not undergo telomere-driven senescence.

Figure 2

Telomere-related proteins. Telomere DNA sequences are bound by and interact with several proteins. These proteins and the enzyme telomerase function to regulate telomere length and prevent inappropriate recognition of telomere DNA by the DNA damage response machinery. (A) Telomerase is a ribonucleoprotein consisting of two core components: a catalytically active reverse transcriptase component, TERT and a noncoding RNA template, TERC. Together with several other cofactors such as dyskerin, GAR1, NOP10, and NHP2, telomerase functions to add telomere repeats to the ends of telomeres. (B) A complex of six proteins termed “shelterin” binds to telomere DNA in a tightly regulated stoichiometry and functions to regulate telomere length by preventing inappropriate telomere elongation by telomerase. Telomere repeat binding factors (TRFs) 1 and 2 bind to telomere double-stranded DNA and function to regulate telomere length and T-loop formation. (C) Shelterin also functions to prevent the DNA damage machinery from recognizing telomeres. Both POT1 and TRF2 prevent the telomere from being recognized by DNA damage kinases.