Telomeres and aging
Review of research articles published in 2009 that have made or will make a significant contribution to the study of aging – Part 1.
Article by Mikhail V. Blagosklonny et al. Impact papers on aging in 2009 published in Aging magazine, March 2010, volume 2, No. 3.
Translated by Evgenia Ryabtseva
Resume
The Editorial Board of the journal Aging provides an overview of research articles published in 2009 that, according to the members of the board, have made or will make a significant contribution to the study of aging. In addition to many other topics, these articles discuss genes that accelerate aging or, conversely, increase the lifespan of model organisms; reactions to DNA and telomere damage; molecular mechanisms for increasing life expectancy with a low-calorie diet and pharmacological interventions in the aging process. According to the hypothesis, the formation of which began in 2009, the aging process is controlled not by a random set of factors, but by a genetically regulated system and it can be slowed down both with the help of genetic and pharmacological approaches.
Telomeres and aging
In 2009, the Nobel Prize in Physiology or Medicine was awarded to Elizabeth Blackburn, Carol Greider and Jack Szostak for their contribution to the study of mechanisms for maintaining a constant length of the end sections of chromosomes of eukaryotic organisms – telomeres – carried out by a specialized reverse transcriptase – telomerase. To date, this prize is the closest in time to the Nobel Prize related to the study of aging. Of course, this work is more important for the study of fundamental issues of cell biology and cancer than for the study of aging processes. Indeed, although telomere shortening explains replicative aging – the Hayflick limit characteristic of human cells, it cannot explain the difference in mouse and human lifespan. However, there may be other relationships between telomeres and aging.
The results of several papers published by Epel and Blackburn and co-authors in 2009 indicate the existence of a previously unknown relationship between telomere length and age-related diseases. According to the data published in the first issue of the journal Aging, the rate of telomere shortening in peripheral blood leukocytes of elderly men is a prognostic factor of mortality from diseases of the cardiovascular system [1]. Even more intriguing is the revealed relationship between pessimism, short leukocyte telomeres and elevated levels of interleukin-6 (IL-6) in postmenopausal women [2]. The causal relationship between telomere length and these physiological indicators is unclear, but in this regard, several non-mutually exclusive assumptions can be made. Rapid shortening of telomeres may indicate hyperactivation of cells, their excessive proliferation and/or the formation of a hypersecretory phenotype, which is often associated with physiological aging of cells, depletion of the stem cell population and the development of senile diseases.
These assumptions are not contradicted by the established fact that telomere length regulates the expression of the interferon-stimulated gene-15 (ISG15). Short telomeres activate an ISG15-mediated signaling mechanism independent of DNA damage. These data demonstrated for the first time that the activity of a human endogenous gene can be regulated by telomere length until signs of telomere dysfunction and DNA damage appear. It has been suggested that stimulation of the ISG15 gene by shortening telomeres may contribute to the development of chronic inflammation associated with aging [3]. The data also obtained in 2009 do not contradict this idea, according to which the secretion of inflammatory cytokines, such as IL-6 and IL-8, by cells in the phase of physiological aging, regardless of the cause that caused their aging (telomere dysfunction or DNA damage), is suppressed by two microRNAs (miRNA-146a and miRNA-146b) [4]. It is possible that these miRNAs modulate inflammatory responses by influencing the mechanisms of signal transduction that contribute to the formation of a hypersecretory phenotype associated with physiological aging. It would be interesting to know whether miRNA-146a/b and ISG15 expression are suppressed, and whether this effect depends on the status of telomeres.
It was found out that violations of the functioning of the telomere-binding protein are sufficient for the development of severe telomere damage, not accompanied by their shortening, but leading to premature tissue degeneration and the formation of neoplasia foci [5]. A new vision has been formed of the mechanisms of maintaining telomere length, as well as the processes of repairing DNA damage occurring in telomeres. For example, it turned out that the so–called "defenders of the genome" - RecQ helicase enzymes - are actively involved in this process [6].
It also turned out that damaged telomeres are the main factor causing a high degree of variability in the level of activity of mechanisms signaling DNA damage in tumor line cells. These data can help determine the relative contributions made by double-stranded breaks of non-telomeric DNA and damaged telomeres to the level of genome instability [7].
Continuation: Reaction to DNA damage and aging.
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