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Physical Activity, a Modulator of Aging Through Effects on Telomere Biology

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Physical Activity, a Modulator of Aging Through Effects on Telomere Biology www.aging-us.com AGING 2020, Vol. 12, No. 13 Review Physical activity, a modulator of aging through effects on telomere biology Maria Donatella Semeraro1, Cassandra Smith2,3, Melanie Kaiser1, Itamar Levinger2,3, Gustavo Duque3,4, Hans-Juergen Gruber1, Markus Herrmann1 1Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria 2Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia 3Australian Institute for Musculoskeletal Science (AIMSS), University of Melbourne and Western Health, St Albans, VIC, Australia 4Department of Medicine-Western Health, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia Correspondence to: Markus Herrmann; email: [email protected] Keywords: telomeres, telomerase, physical activity, exercise, aging Received: March 5, 2020 Accepted: June 4, 2020 Published: June 23, 2020 Copyright: Semeraro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Aging is a complex process that is not well understood but involves finite changes at the genetic and epigenetic level. Physical activity is a well-documented modulator of the physiological process of aging. It has been suggested that the beneficial health effects of regular exercise are at least partly mediated through its effects on telomeres and associated regulatory pathways. Telomeres, the region of repetitive nucleotide sequences functioning as a “cap” at the chromosomal ends, play an important role to protect genomic DNA from degradation. Telomeres of dividing cells progressively shorten with age. Leucocyte telomere length (TL) has been associated with age-related diseases. Epidemiologic evidence indicates a strong relationship between physical activity and TL. In addition, TL has also been shown to predict all-cause and cardiovascular mortality. Experimental studies support a functional link between aerobic exercise and telomere preservation through activation of telomerase, an enzyme that adds nucleotides to the telomeric ends. However, unresolved questions regarding exercise modalities, pathomechanistic aspects and analytical issues limit the interpretability of available data. This review provides an overview about the current knowledge in the area of telomere biology, aging and physical activity. Finally, the capabilities and limitations of available analytical methods are addressed. INTRODUCTION conditions [6, 7]. Today, cardiovascular disease (CVD), cancer and respiratory disease are the most common Over the last 200 years average life expectancy in causes of death worldwide [8, 9]. Other lifestyle and developed countries has more than doubled and is now age-related conditions such as musculoskeletal disease, above 80 years [1]. In numerous studies this linear diabetes and dementia are also increasing rapidly and increase is suggested to rise to an average life span of thus impact the number of disability-adjusted life years 100 years or more [2–4]. This dramatic increase in life (DALYs), calculated in a population as the sum of the expectancy was largely driven by changes in lifestyle, Years of Life Lost (YLL) due to premature mortality sanitation and a continuous improvement of health care and the Years Lost due to Disability (YLD) [10, 11]. [5]. As a result, the major causes of death have shifted Therefore, strategies to promote healthy aging have from infectious disease to chronic age-related gained great interest in developed societies. www.aging-us.com 13803 AGING The process of aging remains incompletely understood. protein 1 (RAP1). TRF1 and TRF2 interact with the A better understanding of the complex and interrelated double-stranded telomeric DNA, whereas POT1 biological mechanisms of aging would help to develop associates with single-stranded telomeric DNA [19]. interventions that delay the aging process. Through interactions with the shelterin proteins the Environmental and lifestyle factors, such as physical terminal telomere section flips backwards resulting in activity, nutrition, stress and smoking, are major the formation of a looped structure (t-loop). determinants of the aging process [12]. In particular, Furthermore, the shelterin proteins aid in displacing a regular exercise is a safe and cost-effective way to short section of double-stranded telomeric DNA so that reduce morbidity and premature mortality [13]. the single stranded G-rich overhang at the 3´end can be However, the molecular mechanisms that mediate the interposed. This structure is referred to as “D-loop” and beneficial effects of exercise are incompletely protects the free end of the DNA strand from understood and remain an area of active research. In recognition as a strand break, which would induce numerous observational and intervention studies the inappropriate repair processes. preservation of telomeres, the protective end-caps of all chromosomes, has been proposed as an appealing The interaction between the shelterin protein subunits is putative mechanism that contributes partially to the complex and has been investigated using mouse beneficial health effects of physical activity [14]. This conditional knock-out cells for TRF1, TRF2, POT1, review aims to provide an overview on the current TPP1. It has been shown in several studies that knowledge in the area of telomere biology, aging and shelterins prevent DNA damage response (DDR) physical activity. In addition, the capabilities and activity at telomeres, chromosomal rearrangements and limitations of available analytical methods will be cell cycle arrest, thus demonstrating a role in addressed. maintaining telomere function and preserving genomic stability [17, 18, 29]. Through the binding of TRF1 and Structure and function of telomeres TRF2 to double-stranded telomeric TTAGGGn repeats RAP1, TIN2, TPP1 and POT1 can be recruited. TIN2 The genetic information of eukaryotes is encoded in the can bridge TRF1 and TRF2/RAP1 complexes by deoxyribonucleic acid (DNA), which is packed in the binding to both proteins simultaneously. Furthermore, chromosomes. With every division of mitotic cells a TIN2 associates with the TPP1/POT1 heterodimer, small fragment of DNA at the ends of every which is typically bound to single-stranded TTAGGG chromosome remains unreplicated due to a repeats [19, 24]. These intimate interactions result in the physiological phenomenon named the end-replication formation of a “capped” loop [20, 30, 31]. problem [15]. In order to prevent the loss of coding genetic information thousands of identical, non-coding Telomere length (TL) varies greatly between species oligonucleotides are attached to the ends of all [32]. At birth, every human individual has a specific TL chromosomes. These terminal non-coding DNA-regions that ranges between 5 to 15 kb [33]. Throughout life are called telomeres. Human telomeres contain telomeres shorten continuously with a rate between 20- approximately 2,500 tandem copies of a simple 50 bp due to the end-replication phenomenon, oxidative hexanucleotide with the sequence 5'-TTAGGGn-3' [16]. stress and other modulating factors [15, 33]. However, For most of its length, telomeric DNA is double telomere shortening rates and consequently also average stranded. However, the last portion of 30–100 base pairs TL vary amongst different tissue types, which is at least (bp) at the 3’-end of the G-rich strand is single-stranded. partly explained by tissue-specific proliferation rates This G-rich overhang at the 3’-end is essential for [34, 35]. In dividing cells, the end replication problem is telomere maintenance and capping [17, 18]. Telomeres an important driver of telomere shortening that can be give rise to a complex three-dimensional structure modified by other factors, such as oxidative stress or limiting the access of telomerase and DNA damage inflammation [33]. In postmitotic cells instead, repair (DDR) enzymes to the free ends of each DNA- oxidative stress can directly damage telomeric DNA strand. This three-dimensional structure is achieved and drive cells into senescence [36, 37]. The TL of through the binding of a highly abundant protein peripheral blood leucocytes (LTL) has gained complex, named shelterin, to the telomeric substantial interest as a potential marker of biological hexanucleotide sequence 5’-TTAGGGn-3‘. The age [17]. Mean LTL in adults is approximately 11 kb shelterin complex is composed of the following six- and declines with an annual rate of 30-35 bp. Telomere subunits (see Table 1): telomeric repeat binding factor 1 attrition is most pronounced during the first two years (TRF1), telomeric repeat binding factor 2 (TRF2), of life, which are characterized by rapid somatic growth TRF1-interacting nuclear protein 2 (TIN2), telomeric [34, 35, 38, 39]. The shortening of telomeres is not a overhang binding protein 1 (POT1), TIN2 and POT1 unidirectional process since the reverse-transcriptase interacting protein 1 (TPP1), and repressor-activator telomerase is capable of adding new hexanucleotides to www.aging-us.com 13804 AGING Table 1. Shelterin complex, subunits and functions. Shelterin subunits Function References Telomeric repeat binding factor 1 Determines the structure of telomeric ends, it is de Lange [20] (TRF1)- binds to the canonical TTAGGG implicated in the generation of t-loops, and it double-stranded telomeric
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