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Article Aging and Atherosclerosis American Heart Association Circula
0703 -
0703 - ..
0704 - Summary/Objective
0705 -
070501 - Follow up ref SDS 3 0000. ref SDS 2 0000.
070502 -
070503 - More research indicates evidence is weak on telomere length signaling
070504 - biological age differences with chronological aging.
070505 -
070506 -
070507 -
070508 -
070509 -
070511 - ..
0706 -
0707 -
0708 - Progress
0709 -
070901 - Article today...
070902 -
070903 - PMC
070904 - US national Library Of Medicine
070905 - National Institutes of Health
070907 - ..
070908 - Journal List > Int J Mol Sci > v.18(12); 2017 Dec > PMC5751176
070909 -
070910 - https://www.ncbi.nlm.nih.gov/pmc/journals/
070911 -
070912 - https://www.ncbi.nlm.nih.gov/pmc/journals/808/
070913 -
070914 - https://www.ncbi.nlm.nih.gov/pmc/issues/303931/
070916 - ..
070917 - International journal of Molecular Sciences (MDPI)
070919 - ..
070920 - Int J Mol Sci. 2017 Dec; 18(12): 2573
070922 - ..
070923 - PMCID: PMC5751176
070924 - PMID: 29186077
070926 - ..
070927 - Published online 2017 Nov 29. doi: [10.3390/ijms18122573]
070928 -
070929 - https://www.mdpi.com/1422-0067/18/12/2573
070930 -
070932 - ..
070933 - Telomeres, Aging and Exercise: Guilty by Association?
070934 -
070935 - Warrick Chilton,1,* Brendan O?Brien,1 and Fadi Charchar1,2,3,*
070936 -
070937 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751176/
070939 - ..
070940 - Author information Article notes Copyright and License
070941 - information Disclaimer
070943 - ..
070944 - Abstract
070946 - ..
070947 - Telomeres are repetitive tandem DNA sequences that cap
070948 - chromosomal ends protecting genomic DNA from enzymatic
070949 - degradation. Telomeres progressively shorten with cellular
070950 - replication and are therefore assumed to correlate with
070951 - biological and chronological age. An expanding body of
070952 - evidence suggests (i) a predictable inverse association between
070953 - telomere length, aging and age-related diseases and (ii) a
070954 - positive association between physical activity and telomere
070955 - length. Both hypotheses have garnered tremendous research
070956 - attention and broad consensus; however, the evidence for each
070957 - proposition is inconsistent and equivocal at best. Telomere
070958 - length does not meet the basic criteria for an aging biomarker
070959 - and at least 50% of key studies fail to find associations with
070960 - physical activity. In this review, we address the evidence in
070961 - support and refutation of the putative associations between
070962 - telomere length, aging and physical activity. We finish with a
070963 - brief review of plausible mechanisms and potential future
070964 - research directions.
070966 - ..
070967 - Keywords: telomeres, aging, physical activity, biomarker,
070968 - association
070969 -
070970 - 1. Introcuction
070971 -
070972 - The global population of persons aged 80 years or older
070973 - will triple by 2050 [1], leading inexorably to a public
070974 - health imperative. Current increases in life expectancy
070975 - exceed concomitant increases in disease free years,
070976 - creating a compression of chronic disease burden in old age
070977 - [2]. Physiological aging is characterized by cumulative
070978 - deleterious changes to biological function [3] and is the
070979 - strongest non-modifiable predictor of most chronic
070980 - diseases. Despite this, significant variability exists in
070981 - the health impact of aging [4].
070983 - ..
070984 - Report that people over 80 will triple by 2050, but that people with
070985 - diseases will increase, places increased burden on health care
070986 - capacity.
070988 - ..
070989 - Article "Telomeres, Aging and Exercise... continues...
070990 -
070991 - The associations between mortality and traditional
070992 - biomarkers such as blood pressure, cholesterol and body
070993 - mass index (BMI) weaken with age [5]. The search for a
070994 - definitive aging biomarker is encumbered by the
070995 - heterogeneity of cellular aging. Post-mitotic cells are
070996 - not subjected to the replicative stresses experienced by
070997 - mitotic cells; therefore, some tissues exhibit greater
070998 - biological aging than others. The highly variable human
070999 - lifespan highlights that the mere passage of chronological
071000 - time is not an effective, isolated measure of aging.
071001 - Biological aging refers to processes that proceed
071002 - independently of chronological aging that reduce organismal
071003 - viability and increase vulnerability. Telomeres are
071004 - regarded by many as the heir apparent of aging biomarkers,
071005 - recording both chronological and biological age [6,7].
071007 - ..
071008 - 2. Telomere Biology -- A Primer
071009 -
071010 - Telomeres are specialized DNA structures that bookend
071011 - nuclear DNA protecting it from degradation [8]. Mitotic
071012 - division imposes a progressive loss of telomeric base
071013 - pairs (bps) due to the inability of DNA polymerases to
071014 - fully replicate the lagging C-strand [9,10]. This
071015 - cumulative loss simultaneously chronicles replicative
071016 - history and imposes a finite replicative limit. Critical
071017 - shortening of telomeres causes eventual disruption of the
071018 - protective protein shelterin complex [11]. Cells requiring
071019 - high replicative capacity express telomerase, a
071020 - specialized ribonucleoprotein complex that synthesizes
071021 - telomeric repeats [12]. Human telomerase consists
071022 - minimally of two core components; a reverse transcriptase
071023 - catalytic subunit (hTERT) and an antisense RNA template
071024 - (hTERC) [12,13]. Telomeres are sensitive to a host of
071025 - stimuli including oxidative stress [14], chronic
071026 - inflammation [15], BMI [16], smoking [17], alcohol intake
071027 - [18], perceived stress [19] and physical activity (PA)
071028 - [20]. A growing body of evidence also indicates that
071029 - telomeres are responsive to habitual PA [20,21].
071031 - ..
071032 - Despite the telomere's popular designation as a mitotic
071033 - clock, the relationship between telomere length and aging
071034 - is inconsistent and does not meet the requisite biomarker
071035 - criteria [22]. Closer examination of the association with
071036 - PA also reveals inconsistencies and methodological
071037 - confounders. The clinical and public interest in the
071038 - PA-telomere association is predicated upon several tacit
071039 - assumptions: (i) mean telomere length is causally
071040 - associated with biological aging and age-related
071041 - pathologies and (ii) PA can lengthen mean telomere length
071042 - and that in doing so; (iii) PA will reduce biological
071043 - aging and disease burden. This review summarizes the
071044 - current evidence for and against telomeres as aging
071045 - biomarkers of aging and potential mediators of
071046 - exercise-induced health gains.
071048 - ..
071049 - 3. Cellular Senesence
071050 -
071051 - Cellular senescence is the progressive and irreversible
071052 - loss of replicative capacity in somatic cells [23].
071053 - Cellular senescence sits astride several paradoxical and
071054 - seemingly incongruent binary functions; namely tissue
071055 - regeneration [24] and tissue dysfunction [25], embryonic
071056 - development [26] and organismal aging [27] and tumor
071057 - promotion [28] and suppression [29]. Senescence is
071058 - triggered when the telomeric terminal restriction fragment
071059 - (TRF) reaches a mean length of 4-7 kb [30]. At this
071060 - critical threshold, the protective shelterin complex is
071061 - disrupted exposing an uncapped double-stranded chromosome
071062 - end. This in turn triggers the ataxia telangiectasia
071063 - mutated (ATM)-p53-p21 axis and subsequent DNA damage
071064 - response (DDR) [31], preventing progression into the
071065 - S-phase of the cell cycle [32,33,34].
071067 - ..
071068 - Replicative senescence refers to proliferative exhaustive
071069 - driven by telomere loss whilst stress-induced senescence
071070 - can be precipitated by oxidative or genotoxic stress,
071071 - regardless of telomere length [35]. Replicative senescence
071072 - is causally implicated in aging and age-related diseases
071073 - such as cardiovascular disease (CVD) [36], diabetes
071074 - [37,38], osteoarthritis [39], glaucoma [40] and cataracts
071075 - [41]. In addition to lost proliferative capacity, cellular
071076 - senescence causes significant changes in gene expression,
071077 - epigenetic factors and cell morphology [42]. Senescent
071078 - cells also acquire a characteristic secretome known as the
071079 - Senescence-Associated Secretory Phenotype (SASP) [43].
071080 - This largely pro-inflammatory phenotype can initiate
071081 - senescence in young cells contributing to tissue
071082 - dysfunction [25], progression of atherosclerosis [36],
071083 - cancer [44] and diabetes [37,38].
071085 - ..
071086 - Replicative exhaustion within the immune system is called
071087 - immunosenescence; a cluster of age-related changes
071088 - resulting in decreased replicative capacity [45,46],
071089 - shortened telomeres [47], increased cytokine production
071090 - [48,49] and increased susceptibility to infectious
071091 - diseases [50]. Given the diverse physiological
071092 - ramifications, senescence may be the causal nexus linking
071093 - the indirect, microscopic causes of aging with the direct,
071094 - macroscopic effects of aging [27].
071096 - ..
071097 - 4. Telomres and Aging
071098 -
071099 - A clear inverse association exists between chronological
071100 - age and telomere length. Support of the causal association
071101 - between telomeres and aging comes from accelerated aging
071102 - conditions such as Dyskeratosis Congenita, Werner?s
071103 - Syndrome and Hutchinson-Gilford Syndrome. Such progeroid
071104 - syndromes are characterized by a sequela of age-associated
071105 - pathologies precipitated by accelerated telomere attrition
071106 - [51,52,53,54,55].
071108 - ..
071109 - The American Federation of Aging Research stipulate that
071110 - any candidate aging biomarker must satisfy the following
071111 - criteria [56,57]:
071112 -
071113 - 1. It must predict the rate of aging and therefore be a
071114 - better predictor of lifespan than chronological age
071115 - 2. It must reflect and monitor the physiological processes
071116 - underlying aging
071117 - 3. It must be a repeatable, unobtrusive and harmless
071118 - measure
071119 - 4. It must be testable in animal models
071121 - ..
071122 - 4.1 Criterion 1?Must Predict the Rate of Aging Better than
071123 - Chronological Age
071125 - ..
071126 - Human telomere length varies by 5000 to 15,000 bps at birth
071127 - [58], a measure that exceeds total average leukocyte
071128 - telomere length (LTL) shortening throughout adult life
071129 - [59]. Genome-wide association studies have identified a
071130 - host of potential candidate loci associated with LTL
071131 - variation [60,61,62,63,64,65]. Estimates of telomeric bp
071132 - loss vary between 30?200 bps per division [66,67].
071133 - Although variable in magnitude, age-related decreases in
071134 - LTL are consistently observed [68]. Three recent studies
071135 - estimated the annual telomere shortening rate at 17.4 [69],
071136 - 15.6 [70] and 48?67 bps per chronological year [71].
071137 - Paternal age at conception of the offspring is associated
071138 - with longer offspring LTL [72,73,74], yet infant LTL is
071139 - positively associated with adult telomere attrition rate
071140 - [75,76]. However, the annual adult attrition rate
071141 - contributes less to population LTL variation than LTL
071142 - variation at birth [77] and attrition rate during the first
071143 - two decades of life [78,79]. Unlike chronological age,
071144 - telomere shortening is not linear; the majority of
071145 - shortening occurs during the rapid somatic expansion from
071146 - birth to puberty [80,81]. Thereafter, adults with either
071147 - longer or shorter than average LTL tend to maintain that
071148 - classification into old age [82,83]. Telomere shortening
071149 - can be heterogeneous within a given cell as longer
071150 - telomeres shorten faster than shorter ones [84,85,86].
071152 - ..
071153 - Paradoxically, telomere lengthening has been observed in
071154 - several longitudinal studies
071155 - [75,76,87,88,89,90,91,92,93,94,95]. When assessed over a
071156 - 2?6 year period, most individuals shorten or maintain
071157 - telomere length; however, 15?44% demonstrate an increase in
071158 - mean LTL [87,89,96]. The assessment time course appears
071159 - important as less lengthening is observed when assessed
071160 - over a 10 year period [97]. Post-intervention increases in
071161 - telomere length may be due to actual telomerase-mediated
071162 - addition of telomeric DNA or an apparent lengthening due to
071163 - redistribution of immune cell subsets [98]; a caveat seldom
071164 - declared in telomeric research.
071166 - ..
071167 - More people are living into old age; however, these people
071168 - eventually die within a very narrow time span as the finite
071169 - biological limit of human lifespan is reached [99]. If
071170 - telomere length reliably scaled with lifespan, individuals
071171 - with shorter telomeres would theoretically die off before
071172 - reaching the limits of human lifespan. This would result
071173 - in an age-associated decrease in telomere length variance
071174 - known as survivor bias; a phenomenon that has been
071175 - demonstrated [100,101] and refuted in the data [102]. Most
071176 - individuals are not living long enough to reach the
071177 - critically shortened telomere threshold referred to as the
071178 - telomeric brink. It is believed that further increases in
071179 - longevity will be limited by telomere length [103]. Given
071180 - an average starting LTL of 10?15 kilobase pairs, even a
071181 - yearly loss of approximately 50 bps should still sustain
071182 - lymphocyte function well beyond 100 years of age. This
071183 - appears to support the theory that the length of the
071184 - shortest telomere, as opposed to the average telomere
071185 - length, triggers cell cycle arrest, genomic instability and
071186 - senescence [85]. Overall, LTL appears to add predictive
071187 - power to health measures but is less effective than
071188 - chronological age [104]. This may be due to high
071189 - variability in LTL at birth and throughout the lifespan.
071190 -
071191 - 4.2 Criterion 2?The Capacity to Reflect Physiological
071192 - Processes
071194 - ..
071195 - Telomeres possess clear biological plausibility as a
071196 - candidate aging biomarker, reflecting oxidative stress,
071197 - inflammation, replicative history and cellular senescence.
071198 - Despite that, associations with age-sensitive functional
071199 - measures are inconsistent. Several studies have failed to
071200 - find associations between LTL and lung function [105], grip
071201 - strength [18], blood pressure [106] and several measures of
071202 - cognitive function [18,101]. However, a more recent
071203 - investigation identified associations with lung function,
071204 - grip strength, pulse pressure, reaction time, general
071205 - mental ability and general health [104]. The Newcastle 85+
071206 - study assessed associations between a panel of 74 candidate
071207 - biomarkers and four health-status measures in a cohort of
071208 - 852 individuals aged 85 years. Leukocyte telomere length
071209 - did not fulfil the criterion of significant association
071210 - with at least two of the health-status measures [107].
071212 - ..
071213 - Boonekamp et al. propose that organisms consist of
071214 - redundancy elements that gradually fail and replace each
071215 - other as they buffer and accumulate damage. Death occurs
071216 - when the last of the elements are exhausted. Boonekamp et
071217 - al. further propose that LTL is better viewed as a
071218 - biomarker of somatic redundancy than biological aging
071219 - [108]. The somatic redundancy model fits with two
071220 - established telomere observations: (i) that longer
071221 - telomeres, possessing more redundancy units, shorten faster
071222 - than short telomeres [84] and (ii) telomere shortening only
071223 - becomes detrimental when a critical threshold is passed
071224 - [109]. The current evidence indicates that LTL likely
071225 - reflects pre-pubertal somatic growth and post-pubertal
071226 - cellular senescence and oxidative stress [58].
071227 -
071228 - 4.3 Criterion 3?A Harmless Repeatable Measure
071230 - ..
071231 - Most studies measure mean telomere length in circulating
071232 - leukocytes as physiological proxy for the target tissue.
071233 - Conclusions from these studies are predicated upon a
071234 - supposed correlation between LTL and target tissue. One
071235 - study correlated LTL with vascular tissue telomere length
071236 - [110] and there is evidence of intra-individual
071237 - correlation in telomere length between different tissues
071238 - [111,112]. A more recent study found correlations with
071239 - only two (intercostal skeletal muscle and liver) out of
071240 - twelve human tissues assessed [113]. Experimental data
071241 - suggests that differences in telomere length between
071242 - tissues are due to tissue-specific attrition rates [114];
071243 - however, these rates appears to regress towards a mean
071244 - value from adulthood to old age [79].
071246 - ..
071247 - Mean LTL represents the average telomere length across a
071248 - heterogeneous cell population. A recent study rank-ordered
071249 - telomeres as longest in B cells, then CD4+ and CD8+CD28+ T
071250 - cells (similar lengths) and shortest in senescent
071251 - CD8+CD28- T cells [115]. Telomerase expression is also
071252 - heterogeneous within the immune system; being highest in B
071253 - cells, followed by CD4+ T cells, CD8+CD28+ T cells and
071254 - lowest in CD8+CD28- T cells [115]. Exercise is known to
071255 - transiently modulate the relative proportions of leukocyte
071256 - subsets in an intensity-dependent fashion [116].
071257 - Therefore, the cellular composition at any given time
071258 - point will determine the mean LTL and telomerase activity
071259 - [115].
071261 - ..
071262 - Considerable variance exists within and between telomere
071263 - measurement techniques. At present, several different
071264 - protocols can be used to measure telomere length [117].
071265 - These range from the original gold standard Southern blot
071266 - analysis of terminal restriction fragment (TRF),
071267 - quantitative polymerase chain reaction-based techniques
071268 - (qPCR), through to single telomere length analysis (STELA),
071269 - flow and quantitative fluorescence in situ hybridization
071270 - (flow FISH and Q-FISH respectively). Each has its own
071271 - strengths, limitations and coefficient of variation (CV),
071272 - making comparisons between studies potentially inaccurate.
071273 - Data from qPCR and Southern blot are weakly correlated (r =
071274 - 0.52) [118]. Comparison between qPCR and flow FISH
071275 - obtained a similarly weak correlation coefficient (r =
071276 - 0.47) [119]. Next generation sequencing (NGS) technology
071277 - has given rise to new methods of telomere length
071278 - measurement. The two key proposed methods both count short
071279 - reads that contain telomeric repeats [120] and are
071280 - appropriate for assessment of mean telomere length in
071281 - genome [121]. However, there is considerable variation
071282 - between NGS methods and qPCR-based measurements at present
071283 - [122]. Differences in DNA extraction protocol also
071284 - significantly influence telomere length [123]. Similarly,
071285 - telomerase can also be assessed using multiple protocols
071286 - and variants thereof, either directly measuring telomerase
071287 - products or signals from telomerase-mediated DNA [124].
071289 - ..
071290 - The likelihood of measurement error in telomere research is
071291 - high. The inter-individual variation in LTL can be 5000 to
071292 - 15,000 bps [58] whilst the yearly shortening rates can vary
071293 - between 30-100 bps [125]. The majority of telomere research
071294 - utilizes qPCR which has a CV of 6.45% compared to TRF which
071295 - has a CV of 1.74% [117]. Such variation is likely to render
071296 - many associations non-significant or questionable at the
071297 - very least.
071299 - ..
071300 - 4.4 Criterion 4--Testable in Animal Models
071302 - ..
071303 - Animal models have significantly furthered the
071304 - understanding of telomere homeostasis and disease;
071305 - however, some inherent limitations affect direct
071306 - inter-species comparisons. The life expectancy of a mouse
071307 - is more than 40 times shorter than that of a human yet
071308 - mouse telomeres are 5 to 10 times longer [126]. The
071309 - telomerase enzyme is functionally active in the majority
071310 - but not all, murine tissues [127]; as distinct from humans
071311 - that lack detectable telomerase levels in many somatic
071312 - cells [128]. The telomerase-negative mTR?/? mouse was
071313 - initially developed to examine the role of telomerase in
071314 - normal and neoplastic growth [129]. It has since made
071315 - valuable contributions to the understanding of telomere
071316 - regulation. However, in addition to exhibiting telomere
071317 - dysfunction and increased end-to-end fusions [129,130],
071318 - late generation mTR?/? mice can also exhibit a host of
071319 - other pathological phenotypes
071320 - [130,131,132,133,134,135,136,137,138,139]. Knock-in of
071321 - telomerase eliminates many of the degenerative phenotypes
071322 - observed in late generation mTR?/? mice [140]. The
071323 - comparatively sterile laboratory conditions mice are
071324 - subjected to remove several negative telomere instigators
071325 - such as variable diets, pollution, ultraviolet light and
071326 - inflammation [141].
071328 - ..
071329 - Whilst rodents are the most widely used animal models,
071330 - zebrafish have also been used extensively in
071331 - telomere/telomerase research. Their short life, relatively
071332 - short generation time and an unlimited capacity to
071333 - regenerate their fins in 7?10 days makes them a convenient
071334 - model [142,143]. Expression levels of zebrafish TERT mRNA
071335 - closely correlate with telomerase activity and in
071336 - accordance with most marine species, they appear to
071337 - maintain telomerase expression in somatic tissues [144]. A
071338 - telomerase-mutant zebrafish strain has been widely used to
071339 - study aging phenotypes; however, it demonstrates aging
071340 - phenotypes that are far more pronounced than wild-type
071341 - animals [145]. Telomere/telomerase has also been
071342 - investigated in avian species [146], primate species
071343 - [147], plants [148,149], nematodes [150,151] and
071344 - Drosophila [152]. Each animal model has made contributions
071345 - to the understanding of telomere homeostasis; however,
071346 - most have physiological discontinuities that challenge
071347 - their representativeness of normal human aging.
071349 - ..
071350 - 5. Telomeres and Age-Related Diseases
071351 -
071352 - Variable associations exist between accelerated telomere
071353 - shortening and age-related diseases such as CVD
071354 - [96,153,154], cancer [155], stroke [156] diabetes
071355 - [157,158,159], dementia [160,161,162], chronic obstructive
071356 - pulmonary disease [163] and skin disorders [164]. Shorter
071357 - LTL was initially associated with coronary artery disease
071358 - (CAD) in 2001 [165]; with similar CVD associations to
071359 - follow [106,153,166,167,168,169,170,171,172,173]. Short
071360 - LTL but not attrition rate, was recently associated with
071361 - carotid atherosclerosis progression [174]. Moreover, short
071362 - telomeres were more strongly associated with early-onset
071363 - than late-onset atherosclerosis. A host of CVD risk
071364 - factors have also been observationally associated with
071365 - shortened LTL including smoking [17], diabetes [158],
071366 - hypercholesterolemia [175], hypertension [176], obesity
071367 - [177], physical inactivity [20], alcohol consumption [178]
071368 - and psychological issues [179]. Several other studies have
071369 - not found associations with blood lipid status [15],
071370 - hypertension [15,153], smoking [101,180] and BMI
071371 - [101,180]. A more recent study found no associations
071372 - between LTL and coronary risk factors including
071373 - cholesterol, triglyceride, HDL-cholesterol,
071374 - LDL-cholesterol, smoking, personal or family history of
071375 - CVD [181].
071377 - ..
071378 - Three key studies have since failed to find any
071379 - association between LTL and early atherosclerosis
071380 - [173,182,183]. Additionally, a recent study associated
071381 - long, as opposed to short LTL with a nearly three-fold
071382 - higher risk of developing myocardial infarction [184].
071383 - Support for a causal link continues to come from genetic
071384 - and observational prospective studies using Mendelian
071385 - randomization to reduce the likelihood of reverse
071386 - causation. A cluster of seven alleles associated with
071387 - shortened LTL are themselves associated with a 21%
071388 - increased CAD risk per standard deviation in LTL
071389 - [185,186,187]. Despite an abundance of conflicting
071390 - evidence, the broader scientific consensus is that
071391 - shortened LTL represents an increased risk of CVD and
071392 - likely reflects accelerated leukocyte turnover due to
071393 - oxidative stress and inflammation.
071395 - ..
071396 - Accumulating evidence indicates an independent
071397 - pro-telomeric effect of statin treatment [188]. Aspirin
071398 - decreases oxidative stress and forestalls endothelial cell
071399 - senescence [189] yet inhibits telomerase activation in
071400 - polymorphonuclear neutrophils from carotid plaques [190].
071401 - Angiotensin-converting enzyme (ACE) inhibitors also
071402 - demonstrate a pro-telomeric effect via upregulation of
071403 - TERT mRNA in endothelial cells [191]. Androgen treatment
071404 - also significantly increased LTL in a cohort with
071405 - telomere-shortening diseases [192].
071407 - ..
071408 - The relationship between LTL and cancer is complex and at
071409 - times paradoxical. A detailed treatment of the role of
071410 - telomeres in malignant transformation is beyond the scope
071411 - of this review. What follows is a brief overview of
071412 - current evidence. Telomere shortening and uncapping (loss
071413 - of shelterin integrity) are believed to play an anticancer
071414 - role [193]. Long LTL is associated with increased risk of
071415 - several cancer types
071416 - [194,195,196,197,198,199,200,201,202,203]. However, in
071417 - some instances shortened telomeres can potentiate cancer
071418 - by fusing with other uncapped telomeres, thereby creating
071419 - genome destabilizing fusion-bridge-breakage cycles [193].
071420 - Telomerase activity is a critical component in malignant
071421 - transformation with 85?90% of all malignant tumors being
071422 - telomerase positive [128,204]. It is estimated that ~15%
071423 - of human cancers maintain telomere length through one or
071424 - more mechanisms referred to as Alternative Lengthening of
071425 - Telomeres (ALT) [205]. A cluster of seven alleles
071426 - associated with LTL homeostasis, TERC, TERT,
071427 - oligonucleotide/oligosaccharide-binding fold containing
071428 - one gene (OBFC1), zinc finger protein 208 (ZNF208),
071429 - regulator of telomere elongation helicase 1 (RTEL1),
071430 - acylphosphatase 2 (ACYP2) and nuclear assembly factor 1
071431 - ribonucleoprotein (NAF1) are simultaneously associated
071432 - with CAD [185] and cancer [195,198]. If the alleles result
071433 - in comparatively long telomeres, the cancer risk is
071434 - elevated and the CAD risk is reduced; the reverse is also
071435 - true. It has been proposed that the cancer protection
071436 - conferred by short telomeres represents an evolutionary
071437 - trade-off resulting in decreased proliferative and
071438 - regenerative capacity [206]. Non-linear U-shaped
071439 - relationships have been observed between telomere length
071440 - and several cancer risk profiles [207]. This may in part
071441 - be explained by the destabilizing and potentially
071442 - oncogenic effects of shortened telomeres [208] and the
071443 - increased replicative capacity and potential accumulation
071444 - of abnormalities associated with longer telomere length
071445 - [209].
071447 - ..
071448 - One proposed explanation for the discrepant associations
071449 - is that telomere uncapping has an anti-cancer effect in
071450 - the young but a potentially pro-cancer effect in the
071451 - elderly [210]. Hypothetically, the more robust telomere
071452 - dysfunction-based mechanism of the young would prevent
071453 - tumorigenesis whilst the shortened, uncapped and depleted
071454 - telomeres of the elderly may allow bypass of aberrant
071455 - cells [210].
071457 - ..
071458 - 6. Telomres, Longevity and Mortality
071459 -
071460 - The association with overall longevity is similarly
071461 - inconsistent. Whilst several studies support an
071462 - association with longevity [211,212,213,214], just as many
071463 - refute it [101,180,215,216]. However, the observation that
071464 - LTL is longer in women may be linked to the greater
071465 - longevity observed in women [217]. Additionally, in twin
071466 - studies, the individual with longer LTL exhibits enhanced
071467 - longevity compared to the other twin [218].
071469 - ..
071470 - A range of studies have identified age-adjusted inverse
071471 - associations between mean LTL and all-cause mortality
071472 - [69,88,160,162,211,212,219,220,221,222,223,224,225,
071473 - 226,227]. However, other studies were unable to replicate
071474 - the association in similar cohorts [18,91,96,101,153,
071475 - 180,215,216,228,229,230]. Analysis of cohorts from Costa
071476 - Rica, Taiwan and United States of America found that after
071477 - adjustment for gender and age, LTL ranked between 15th and
071478 - 17th out of 20 established predictors and biomarkers of
071479 - all-cause mortality [231]. A cohort of 4576 healthy
071480 - individuals had LTL measured twice within a 10-year
071481 - interval and were then monitored for morbidity and
071482 - mortality for another 10 years. Change in LTL and risk of
071483 - all-cause mortality were not significantly associated [95].
071484 - Despite abundant associations between telomere length and
071485 - age-associated mortality, the association diminishes with
071486 - age [108]; failing to predict mortality in cohorts of the
071487 - very old [101,180]. Paradoxically, telomere length in
071488 - early childhood most accurately predicts life expectancy
071489 - [108,232].
071491 - ..
071492 - 7. Physical Activity and Telomere Length
071493 -
071494 - The widely touted relationship between PA and LTL is
071495 - replete with inconsistencies. Support for a positive
071496 - association has come from a range of
071497 - observational/cross-sectional studies [20,179,223,233,
071498 - 234,235,236,237,238,239,240,241,242,243,244,245,246,
071499 - 247,248]. A summary of human studies that significantly
071500 - associated PA with telomere length is contained in Table 1.
071501 - Telomere length has been assessed in skeletal muscle cells
071502 - and white blood cells (WBCs) in response to aerobic
071503 - training, resistance training and self-reported PA. The
071504 - observed associations appear hormetic, with low and
071505 - excessive levels of activity associated with shorter
071506 - telomeres [241,244] and moderate levels more commonly
071507 - associated with longer LTL [223].
071508 -
071510 - ..
071511 - Table 1
071513 - ..
071514 - Terminology...
071516 - ..
071517 - CHD: coronary heart disease. CVD: cardiovascular disease.
071518 - FlowFISH: fluorescence in situ hybridization combined with
071519 - flow cytometry. TL: telomere length. LTL: leukocyte
071520 - telomere length. PA: physical activity. PBMCs: Peripheral
071521 - blood mononuclear cells. TRF: terminal restriction
071522 - fragment analysis. TRFL: terminal restriction fragment
071523 - length. T/S qPCR: the ratio of telomere PCR value to
071524 - single-copy gene value derived from quantitative PCR. SD:
071525 - standard deviation. SES: socio-economic status. VO2max:
071526 - maximal volume of oxygen uptake.
071527 -
071529 - ..
071530 - Ref Subjects (n) Tissue Measurement Key Findings
071531 -
071532 - Sedentary: one unit increase in the
071533 - 63 healthy post-menopausal Leukocytes T/S qPCR Perceived Stess Scale = 15-fold
071534 - 19 women; sedentary group, increase in odds of having short
071535 - active group telomeres (p < 0.05).
071536 -
071537 -
071538 - Leisure time PA positively associated
071539 - 20 White twins 2401: 2152 with LTL (p < 0.001) LTLs of the most
071540 - females, 249 males Leukocytes Southern blot active subjects were 200 nucleotides
071541 - TRF longer than least active (p = 0.006)
071542 -
071543 -
071544 - <elative PA (p < 0.0002) and absolute
071545 - PA (P = 0.0052) associated with longer
071546 - 5823 adult participants; LTL after adjustment for demographic
071547 - 70 males (n = 2766), females Leukocytes T/S qPCR variables.
071548 - (n=3057) Prevalence of short telomeres
071549 - associated with relative PA
071550 - <p < 0.0001)
071551 -
071552 -
071553 -
071554 -
071555 - PA positively associated with
071556 - <RFI (p < 0.005)
071557 - 1552 Caucasian female twins Overall decreasing trend in
071558 - 749 monozygotic twins. Leukocytes Southern blot TRFI with lower SES (p < 0.024)
071559 - 179 Distributed into six TRF Significant difference in TRFI
071560 - socioeconomic status (SES) between non-nanual and manual
071561 - groups workers (p < 0.01)
071562 -
071563 -
071564 -
071565 -
071566 -
071567 - 44 healthy post-menopausal Leukocytes T/S qPCR LTL significantly higher in habitual
071568 - 223 women, divided into habitual exercise group compared to sedentary
071569 - and sedentary grups group (p < 0.01)
071570 -
071571 -
071572 - LTL is positively associated
071573 - with self-reported physical
071574 - 274 pairs same sex twins Leukocytes Southern blot ability in all pairs combined
071575 - 233 (153 dizygotic pairs, 121 TRF (p = 0.006).
071576 - monozygotic pairs) Positive association between
071577 - PA and LTL in all pairs
071578 - (p = 0.034).
071579 -
071580 -
071581 -
071582 -
071583 - 67 male ultra-marathon LTL 11% longer in ultra-marathon
071584 - 234 runners, 63 age and Leukocytes T/S qPCR runners compared to controls
071585 - sex-matched controls (p < 0.001).
071586 -
071587 -
071588 -
071589 - Moderately or highly active women
071590 - had 0.07 SD increase in LTL
071591 - 235 Nurse's health study--7813 compared to least active
071592 - females Leukocytes T/S qPCR (p = 0.02). Greater moderate
071593 - or vigorous activity associated
071594 - with longer LTL (p = 0.02).
071595 -
071596 -
071597 -
071598 -
071599 - 392 post-menopausal women Southern blot No PA significantly associated
071600 - 236 with State I-III breast PBMCs TRF with shorter LTL (p = 0.03).
071601 - cancer
071602 -
071603 -
071604 -
071605 - Low frequency PA an independent
071606 - 237 895 participants: 476 Leukocytes T/S qPCR predictor of short LTL
071607 - females, 419 males (p < 0.001).
071608 -
071609 -
071610 -
071611 -
071612 -
071613 -
071614 - LTL significantly longer in
071615 - 944 participants with stable subjects with high exercise
071616 - CHD, distributed into three capacity compared to low
071617 - 238 exercise capacity groups: Leukocytes T/S qPCR (p < 0.001). Association
071618 - low (n = 299), moderate: remained after adjustment
071619 - n = 334, high: n = 381 for CVD severity and
071620 - physical inactivity
071621 - (p = 0.005)
071622 -
071623 -
071624 -
071625 - LTL of older exercising subjects
071626 - 57 participants stratified significantly longer than
071627 - into four groups: young Southern blot age-matched sedentary controls
071628 - 239 sedentary (n = 15), young Leukocytes TRF (p < 0.001). LTL of older
071629 - exercising (n = 10), older exercisers not significantly
071630 - sedentary (n = 15), older different from young exercisers
071631 - exercising (n = 17) (p = 0.12). LTL positively
071632 - associated with VO/2max
071633 - <p < 0.01).
071634 -
071635 -
071636 - 1764 adults: 51% males, 49% LTL longer in upper tertile
071637 - females, 73% non-Hispanic (p = 0.04) and middle tertile
071638 - 240 whites; distributed into Leukocytes T/S qPCR (p = 0.02) compared to
071639 - cardiorespiratory fitness lowest tertile.
071640 - tertiles
071641 -
071642 -
071643 - 69 healthy participants: Significantly longer telomeres
071644 - 34 males, 35 females; PMBCs T/S qPCR in second exercise energy
071645 - 241 distributed into four expenditure quartile compared
071646 - exercise energy expenditure to first (p = 0.001) and
071647 - quartiles fourth (p = 0.04) quartiles.
071648 -
071649 -
071650 -
071651 - Longer telomeres in older athletes
071652 - 20 male participants: 5 compared to older non-athletes
071653 - young athletes, 5 young Skeletal T/S qPCR (p = 0.04). Young athletes not
071654 - 242 non-athletes, 5 older muscle different to young non-athletes
071655 - athletes, 5 older (p = 0.12). Strong correlation
071656 - non-athletes between VO/2max and T/S ratio
071657 - in athletes (p = 0.02).
071658 -
071659 -
071660 - One SD below mean PA levels,
071661 - major life stressors were
071662 - associated with LTL shortening
071663 - 243 239 post-menopausal women Leukocytes T/S qPCR (p = 0.008). One SD above
071664 - mean PA level, major life
071665 - stressors were not associated
071666 - with LTL shortening (p = 0.48).
071667 -
071668 -
071669 -
071670 - Inverted ?U? response. Moderate
071671 - PA positively associated with
071672 - 782 males: three PA groups Southern blot longest LTL (p = 0.03).
071673 - 244 low (n = 148), moderate (n Leukocytes TRF LTL the same in low and high PA
071674 - = 398), high (n = 236) groups. Moderate PA group had
071675 - lowest proportion of short
071676 - LTL (p = 0.02).
071677 -
071678 -
071679 -
071680 - 46 participants distributed T cell TL longer in moderately
071681 - into three PA groups: trained and intensively trained
071682 - 245 never trained (n = 15), PMBCs Flow-FISH compared to never trained
071683 - moderately trained (n = 16), (p < 0.05). Significantly longer
071684 - intensively trained (n = 15) telomeres in CD8+ T cells in IT
071685 - <roup (p < 0.05).
071686 -
071687 -
071688 -
071689 - 36 healthy participants Mean TL from leg muscle of
071690 - 246 distributed into three Skeletal T/S qPCR the old immobile group was
071691 - groups: young (n = 12), muscle significantly shorter than
071692 - old mobile (n = 12), old old mobile group (p < 0.05),
071693 - immobile (n = 12) young group (p < 0.05), arm
071694 - <uscle (p < 0.05).
071695 -
071696 -
071697 -
071699 - ..
071700 - Young sedentary controls Older sedentary controls had shorter
071701 - (n = 26), young athletes Flow-FISH mononuclear cell telomeres than all
071702 - 247 (n = 32), middle-aged Leukocytes and other groups (p < 0.001). Age-dependent
071703 - sedentary (n = 21), T/S qPCR telomere loss attenuated in lymphocytes
071704 - middle-aged athletes (p < 0.001) and granulocytes (p < 0.001)
071705 - (n = 25) of older athletes.
071706 -
071707 -
071708 -
071709 - 667 healthy adolescents: Vigorous PA positively associated
071710 - 248 169 white males, 179 white Leukocytes T/S qPCR with telomere length (p = 0.009)
071711 - females, 155 black males,
071712 - 164 black females
071713 -
071714 -
071715 - 249 6474 participants: 49.6% Leukocytes T/S qPCR LTL positively associated
071716 - males, 50.4% females with running (p = 0.03)
071717 -
071718 -
071719 -
071720 - Baseline TL better preserved in
071721 - endurance athletes (p = 0.003).
071722 - 20 endurance athletes, 42 Buccal T/S qPCR Intermediate TL reduced in
071723 - 268 age- and gender-matched cells endurance athletes compared
071724 - controls to baseline (p = 0.002).
071725 - Final time point TL reduced
071726 - in endurance athletes
071727 - compared to baseline (p
071728 - = 0.0006).
071729 -
071730 -
071731 -
071732 -
071733 - 269 477 healthy males and Leukocytes T/S qPCR Vigorous PA positively associated
071734 - females with LTL (p < 0.01).
071735 -
071736 -
071737 -
071738 - LTL longer in participants: currently
071739 - exercising compared to inactive
071740 - 270 814 participants: 397 Leukocytes T/S qPCR (p = 0.013), engaged in intensive
071741 - males, 417 females activity (p = 0.011), participating
071742 - in sport for 10 years prior to
071743 - assessment (p = 0.017).
071744 -
071745 -
071746 - Highest self-reported PA associated
071747 - with longer LTL compared to lowest
071748 - 271 1476 older aged white and Southern blot PA (p = 0.02). Higher levels of
071749 - African American women Leukocytes TRF moderate-to-vigorous PA (p = 0.04)
071750 - and faster walking speed (p = 0.03)
071751 - associated with longer LTL.
071752 -
071753 -
071754 - Greater walking distance (p = 0.007)
071755 - and better chair test performance
071756 - Southern blot (p = 0.04) associated with longer
071757 - 272 582 older adults Leukocytes TRF LTL cross-sectionally. Change in
071758 - chair test performance associated
071759 - with less LTL shortening
071760 - longitudinally (p = 0.04).
071761 -
071762 -
071763 -
071765 - ..
071766 - A 2016 study of 6474 males and females positively
071767 - associated running with LTL yet found no associations with
071768 - other PA domains including aerobics, basketball,
071769 - bicycling, dancing, running, stair climbing, swimming,
071770 - walking and weight-lifting [249]. The authors speculate
071771 - that the sustained weight-bearing status of running may
071772 - preferentially activate signaling pathways, citing other
071773 - studies that demonstrated associations in ultra-endurance
071774 - runners [234]. One can only speculate that insufficient
071775 - statistical power explains the lack of association found
071776 - in other studies employing running as the independent
071777 - variable [250,251]. Self-reported PA was positively
071778 - associated with LTL in a cohort of 5823 men and women from
071779 - the National Health and Nutrition Examination Survey
071780 - (NHANES) [70]. Objectively measured maximal
071781 - cardiorespiratory fitness (VO2max) has also been
071782 - positively associated with LTL in a cohort of obese women
071783 - [252] and older exercise-trained participants [239].
071785 - ..
071786 - The positive associations have been refuted by several
071787 - observational and interventional studies [15,89,97,250,
071788 - 251,252,253,254,255,256,257,258,259,260,261,262,263,
071789 - 264,265,266]. A summary of human studies that found no
071790 - significant association between PA and telomere length is
071791 - contained in Table 2. A rigorous 2015 systematic review and
071792 - meta-analysis concluded that insufficient quality evidence
071793 - exists to conclusively associate PA with LTL [267].
071794 - Approximately 54% of studies reviewed found no relationship
071795 - between PA and LTL; 41% found a positive association and 5%
071796 - identified a curvilinear relationship [267]. Most of the
071797 - positive associations were weak to moderate with only two
071798 - studies reporting strong associations [223,234]. The
071799 - analysis cited methodological issues such as weak
071800 - correlations, assessment of varied tissue types, arbitrary
071801 - cuff-off points, inadequate blinding of researchers,
071802 - selective inclusion of other potentially confounding
071803 - lifestyle factors and discrepant measurement techniques as
071804 - possible confounders [267]. Discrepant modes of PA and the
071805 - wide-spread use of self-reported PA with its inherent
071806 - biases may also explain the lack of association in several
071807 - of the studies. A similar review conducted in 2013 assessed
071808 - the effect of exercise in animals and humans and identified
071809 - three general association types: positive association,
071810 - inverted ?U? response and no association [21].
071812 - ..
071813 - Table 2
071815 - ..
071816 - A summary of studies showing no association between
071817 - physical activity and telomere length.
071819 - ..
071820 - CAD: coronary artery disease. LTL: leukocyte telomere
071821 - length. PA: physical activity. PBMCs: peripheral blood
071822 - mononuclear cells. TRF: terminal restriction fragment
071823 - analysis. T/S qPCR: the ratio of telomere PCR value to
071824 - single-copy gene value derived from quantitative PCR.
071825 - VO2max: maximal volume of oxygen uptake.
071827 - ..
071828 - Ref Subjects (n) Tissue Measurement Key Findings
071829 -
071830 -
071831 - 2509 participants: males Southern blot Self-reported PA not associated
071832 - 15 (n = 1218), females (n = Leukocytes TRF with LTL (p = 0.806).
071833 - 1291)
071834 -
071835 -
071836 -
071837 - 89 608 individuals with stable Leukocytes T/S qPCR PA did not independently
071838 - CAD: 244 males, 364 females modulate LTL (p = 0.59).
071839 -
071840 -
071841 -
071842 - 95 4576 male and female Leukocytes T/S qPCR Change in LTL over 10 years not
071843 - Danish participants associated with PA (p = 0.85)
071844 -
071845 -
071846 -
071847 - No significant association between
071848 - 612 advanced prostate cancer PA and LTL in all subjects combined
071849 - 273 cases 1049 age-matched Leukocytes T/S qPCR (p = 0.262).
071850 - controls LTL positively associated with
071851 - healthy lifestyle factors (e.g.,
071852 - diet, PA, smoking) (p = 0.004).
071853 -
071854 -
071855 -
071856 - 17 marathon runners 15 age- Lymphocytes No significant difference between
071857 - 250 and sex-matched sedentary and T/S qPCR marathon runner lymphocyte TL
071858 - controls granulocytes (p = 0.6) and granulocyte
071859 - (p = 0.9) compared to controls.
071860 -
071861 -
071862 - No significant difference in minimum
071863 - TRF between runners and sedentary
071864 - 251 18 experienced runners, Skeletal Southern blot (p = 0.805). Minimum TRF within
071865 - 19 sedentary individuals muscle TRF runners inversely related to years
071866 - of running (p = 0.007) and hours
071867 - spent training (p = 0.035).
071868 -
071869 -
071870 - 439 overweight and obese
071871 - women Randomized into: No significant difference in LTL
071872 - dietary weight loss in exercise group (p = 0.51),
071873 - 252 (n = 118), aerobic Leukocytes T/S qPCR diet and exercise group (p = 0.14).
071874 - exercise (n = 117), Baseline LTL positively associated
071875 - diet and exercise (n = with VO/2max (p = 0.03).
071876 - 117), control (n = 87)
071877 -
071878 -
071879 - 253 2284 women (Nurses? Leukocytes T/S qPCR No association between LTL
071880 - Health Study) and PA (p = 0.69).
071881 -
071882 -
071883 - 255 981 individuals: 467 males, Leukocytes T/S qPCR Work related PA not associated
071884 - 514 females with LTL (p = 0.933)
071885 -
071886 -
071887 -
071888 -
071889 - 521 obese individuals Self-reported PA not associated
071890 - 256 randomized into: 2 Leukocytes T/S qPCR with telomere length (p = 0.186).
071891 - Mediterranean diet groups,
071892 - 1 low-fat control group
071893 -
071894 - No significant difference in LTL
071895 - 190 subjects with impaired Leukocytes T/S qPCR following multi-faceted lifestyle
071896 - 257 glucose tolerance, 188 intervention at 4.5 years follow
071897 - controls up (p = 0.76).
071898 -
071899 -
071900 - 14 individuals, 7 Skeletal Southern blot TL not significantly associated
071901 - 258 powerlifters, 7 muscle TRF with 8 ± 3 years of powerlifting
071902 - healthy controls experience (p = 0.07).
071903 -
071904 -
071905 -
071906 - 599 healthy males: No association between
071907 - 259 392 former athletes, 207 Leukocytes T/S qPCR self-reported volume of
071908 - controls leisure time PA and LTL
071909 - in later life (p = 0.845).
071910 -
071911 -
071912 -
071913 - 42 participants: 10 young Skeletal Southern blot Tibialis anterior telomere
071914 - 261 males, 6 young females, 13 muscle TRF length not significantly
071915 - old males, 13 old females influenced by self-reported
071916 - PA (p value not available).
071917 -
071918 -
071919 -
071920 - 16 obese middle-aged women No significant change in LTL after
071921 - 262 randomized into: exercise Leukocytes T/S qPCR 6 months of aerobic training.
071922 - group, control group
071923 -
071924 -
071925 -
071926 - 263 136 participants: 50 Lymphocytes T/S qPCR Self-reported PA not associated
071927 - males, 86 females with longer TL (p = 0.4570).
071928 -
071929 -
071930 - No association between PA and
071931 - LTL. Presence of five low-risk
071932 - 264 5862 women Leukocytes T/S qPCR healthy lifestyle factors
071933 - associated with longer LTL
071934 - (p = 0.015).
071935 -
071936 -
071937 - PA not significantly associated
071938 - 265 1942 male and female Leukocytes T/S qPCR with LTL in males or females
071939 - participants (p-value not available)
071940 -
071941 -
071942 -
071943 - 2006 Chinese participants: No significant difference in TL
071944 - 266 male (n = 976), female Leukocytes T/S qPCR across quartiles of self-reported
071945 - (n = 1030) PA (p = 0.32)
071946 -
071947 -
071948 - 84 Caucasian individuals No significant difference in
071949 - distributed into two groups: PBMC telomere length between
071950 - 274 exercise trained (n = 44), PBMCs T/S qPCR exercising group and controls
071951 - recreationally active (p = 0.72).
071952 - controls (n = 40)
071953 -
071954 -
071955 -
071956 - 203 healthy participants;
071957 - 275 African (n = 96), Caucasian Leukocytes T/S qPCR Habitual PA not associated with LTL.
071958 - (n = 107)
071959 -
071961 - ..
071962 - Whilst some studies identify beneficial chronic effects of
071963 - exercise on telomere length, acute telomere shortening has
071964 - also been observed within the same cohort [268]. A study
071965 - of 2006 Chinese participants found no significant
071966 - difference in LTL across quartiles of PA [266]. Crucially,
071967 - the author cited possible decreased role of PA in the
071968 - seventh decade given potential selection bias of recruiting
071969 - healthy elderly participants. A common criticism of
071970 - studies failing to find associations with PA is the lack of
071971 - statistical power; however, a range of studies with sample
071972 - sizes ranging from 1942?5862 participants have failed to
071973 - find an association between PA and LTL
071974 - [15,95,253,264,265,266]. In a cohort of 4576 Danish men
071975 - and women, PA was not associated with LTL change over 10
071976 - years [95]. A study by Sun et al. (2012) did not
071977 - demonstrate an association between PA and LTL in a cohort
071978 - of 5862 middle-aged women [264]; however, the addition of
071979 - five low-risk factors (smoking status, PA, adiposity,
071980 - alcohol use and diet) to the analysis established a
071981 - significant association.
071982 -
071984 - ..
071985 - 8. Proposed Mechanisms
071986 -
071987 - Despite the positive associations between habitual PA and
071988 - LTL, a clear mechanistic understanding of telomeric
071989 - adaptation is lacking. Following is a summary of the more
071990 - widely held mechanistic theories and some candidate
071991 - mechanisms still subject to further investigation. For a
071992 - detailed review of other candidate molecules and signaling
071993 - pathways, readers should seek out the relevant reviews
071994 - [21].
071996 - ..
071997 - 9. Telomerase and Physical Activity
071998 -
071999 - Longer telomeres are often inferred by increased
072000 - telomerase activity; however, levels do not reliably
072001 - correlate with telomere length [276]. In a study of 124
072002 - health individuals, telomerase activity progressively
072003 - decreased in concert with telomere length from ages 4 to
072004 - 39 years. However, 65% of individuals aged 40 years or
072005 - older exhibited low yet stable telomerase expression
072006 - despite continued telomere shortening [277].
072008 - ..
072009 - Mouse models have demonstrated exercise-induced telomerase
072010 - increases [247,278,279,280]; however, human results are
072011 - conflicting. In one study, there was no difference in
072012 - peripheral blood mononuclear cell (PBMC) telomerase
072013 - expression between physical fitness categories [241]. Yet
072014 - in another study, endurance-trained athletes demonstrated
072015 - increased leukocyte telomerase compared to controls [247].
072016 - A 3 month multifaceted intervention consisting of diet,
072017 - exercise and stress management techniques increased PBMC
072018 - telomerase expression; however, direct causation cannot be
072019 - assigned to one specific modality [281]. Whilst some
072020 - interventional studies using acute and intensive exercise
072021 - interventions failed to increase leukocyte telomerase
072022 - expression [260], a recent study elicited increased PBMC
072023 - telomerase expression after a single bout of treadmill
072024 - running [282]. Exercise-induced increases in hTERT mRNA
072025 - have been observed; however, a correlation with telomerase
072026 - enzyme activity can only be inferred [283].
072028 - ..
072029 - Telomerase preferentially targets short telomeres [284],
072030 - therefore acute increases in telomerase may be an attempt
072031 - to stabilize critically shortened telomeres [285]. This
072032 - may explain the increased telomerase activity and
072033 - shortened telomeres that accompany subclinical coronary
072034 - atherosclerosis [286].
072036 - ..
072037 - 10. Oxidative Stress
072038 -
072039 - The accumulation of oxidative stress-induced DNA damage is
072040 - a key factor in cellular dysfunction and organismal aging
072041 - [287], neurodegeneration [288,289], atherosclerosis,
072042 - diabetes [290] and carcinogenesis [291]. Telomeric DNA is
072043 - particularly susceptible to oxidative damage due to the
072044 - telomeric G triplet [14,292,293,294]. Chronic oxidative
072045 - stress decreases telomeric DNA repair mechanisms [295],
072046 - resulting in cumulative and irreparable damage [35]. In
072047 - doing so, telomeres chronicle chronic exposure to
072048 - oxidative stress [296].
072050 - ..
072051 - Paradoxically, mild exposure to oxidative stress serves a
072052 - telomere protective function by increasing anti-oxidant
072053 - defense systems [262,297,298,299,300,301] and enhancing
072054 - oxidative damage repair systems [302]. Cellular
072055 - antioxidant capacity is correlated with cellular
072056 - proliferative capacity and telomere attrition rate [303].
072057 - Overexpression of superoxide dismutase reduces telomere
072058 - shortening in human fibroblasts [304]. Additionally, under
072059 - conditions of oxidative stress, telomerase translocates to
072060 - the mitochondria where it appears to play a protective
072061 - function [305,306]. The association between habitual
072062 - moderate intensity exercise and longer telomeres [223,273]
072063 - may be mediated by an exercise-induced increase in
072064 - antioxidant defenses. However, a study of obese
072065 - middle-aged women demonstrated increases in antioxidant
072066 - enzymes without concomitant changes in LTL [262].
072067 -
072069 - ..
072070 - 11. Inflammation
072071 -
072072 - The PA-mediated attenuation of chronic inflammation likely
072073 - underpins the protective effect of PA on LTL. Chronic
072074 - inflammation causes hematopoietic stem cell activation and
072075 - subsequent WBC turnover resulting in telomere attrition
072076 - [307]. Shortened LTL have been associated with elevated
072077 - concentrations of pro-inflammatory cytokines interleukin
072078 - (IL)-6 and tumor necrosis factor (TNF)-? [308]. Chronic
072079 - inflammation can also elicit replicative senescence,
072080 - oxidative stress and modulation of telomerase activity
072081 - [309,310,311,312,313]. Shorter mean LTL may reflect an
072082 - increased burden of senescent cells which are known to
072083 - create a pro-inflammatory phenotype [314,315]. Despite the
072084 - association, chronic inflammation levels but not LTL
072085 - predicted successful aging in a cohort of 1554
072086 - centenarian, supercentenarians and very old individuals
072087 - [228].
072089 - ..
072090 - What does "chornic inflammation" mean - how is it achieved,
072091 - maintained in a way that predicts "...successful aging in
072092 - centenarian, supercentenarians and very old..." people"?
072094 - ..
072095 - Article continues...
072096 -
072097 - A consistent inverse association is seen between habitual
072098 - PA and chronic inflammation [316,317]. The inverted ?U?
072099 - response of telomere homeostasis identified in some
072100 - studies may be partially explained by the hormetic
072101 - inflammatory and oxidative stress response to exercise
072102 - [318,319]. Whether PA decreases inflammation and
072103 - subsequent telomere attrition or decreases telomere
072104 - attrition, therefore forestalling the onset of
072105 - senescence-mediated inflammation, remains an open
072106 - question.
072108 - ..
072109 - 12. The Shelterin Complex
072110 -
072111 - Mouse models have demonstrated exercise-induced plasticity
072112 - of shelterin components including Trf2 mRNA [279] and
072113 - skeletal muscle Trf1 mRNA [320]. Human studies, mostly
072114 - observational, have identified increased TRF2 mRNA and
072115 - protein in young and middle-aged athletes compared to
072116 - controls [247]. Increased mRNA expression of leukocyte
072117 - adrenocortical dysplasia homolog (TPP1) and hTERT mRNA was
072118 - also observed in athletes compared to controls [254].
072119 - Athletes who performed seven marathons in one week
072120 - demonstrated upregulated DNA damage repair enzymes Ku70
072121 - and Ku80 in addition to increased TRF1, TRF2 and Pot-1
072122 - mRNA expression. This occurred without concomitant changes
072123 - in telomere length or telomerase activity [260]. A single
072124 - 30 min bout of treadmill running upregulated WBC hTERT and
072125 - telomeric repeat binding factor 2 (TERF2IP) mRNA
072126 - expression in healthy males [283]. Whilst highly plausible
072127 - mechanisms, these observations do not infer causation.
072129 - ..
072130 - 13. Epigenetics and Telomere Homeostasis
072131 -
072132 - Telomere length is influenced by a host of epigenetic
072133 - factors including methylation of sub telomeric DNA
072134 - [321,322,323], histone modification [324,325],
072135 - posttranslational modifications of shelterin components
072136 - [326,327] and non-coding RNAs [328]. An in-depth review of
072137 - all proposed epigenetic pathways is beyond the scope of
072138 - this review. What follows is a brief overview of the
072139 - current evidence.
072141 - ..
072142 - MicroRNAs (miRNAs) play critical roles in modulating gene
072143 - expression via translational repression or total
072144 - degradation of the target mRNA [329]. MiRNAs mediate
072145 - several exercise adaptations [330,331,332,333,334] and
072146 - demonstrate exercise-induced expression profiles in
072147 - leukocyte subsets [335,336,337,338,339]. Exercise-induced
072148 - increases in WBC miR-186 and miR-96 expression were
072149 - observed after a 30-min exercise bout [283]. In silico
072150 - analysis identified TERF2IP as a potential regulatory
072151 - target of miR-186 and miR-96. Telomeric repeat factor 1 is
072152 - translationally repressed by miR-155 resulting in
072153 - chromosome alterations and telomere fragility [328].
072154 - Animal models indicate that miR-155 expression decreases
072155 - in response to exercise [340]. Expression of TERT mRNA is
072156 - regulated by miR-498 [341]; however, little is known about
072157 - the exercise responsiveness of miR-498.
072159 - ..
072160 - A clear understanding of the role of miRNA-mediated
072161 - telomere homeostasis is still in its infancy. The
072162 - direction of the miRNA-telomere interaction is currently
072163 - unclear; telomere shortening may actually cause
072164 - differential miRNA expression [342]. Most of the
072165 - established miRNA-telomere associations have been observed
072166 - in cancer cell lines, wherein dysregulated telomere
072167 - maintenance mechanisms may have corrupted the observed
072168 - associations. To gain a causal understanding of the role
072169 - of miRNAs in telomere homeostasis, gain/loss of function
072170 - experiments must be conducted in cell lines and animal
072171 - models.
072173 - ..
072174 - Accumulating evidence indicates that global DNA
072175 - methylation may regulate telomere length variability in
072176 - adults [343,344]. Associations between DNA methylation and
072177 - telomere length were initially established in mice [345];
072178 - subsequent human studies identified a positive association
072179 - between global DNA methylation at proximal sub telomeric
072180 - regions and telomerase activity [346]. Little is currently
072181 - known about exercise-induced methylation changes within
072182 - telomeres.
072184 - ..
072185 - Human telomeres have long been considered
072186 - transcriptionally silent; however, recent evidence
072187 - indicates they are transcribed by RNA polymerase II,
072188 - producing a class of long noncoding RNA (lncRNA)
072189 - containing telomeric repeats called TERRA [347,348]. TERRA
072190 - molecules are displaced from telomeres and recruited to
072191 - chromosomal ends through interaction with the telomeric
072192 - structure, including shelterin components TRF1 and TRF2
072193 - [349]. TERRA also interacts with telomeres via the
072194 - formation of RNA:DNA hybrid structures known as R-loops
072195 - [350,351,352,353], which are involved with gene expression
072196 - regulation [354] and transcription termination [355]. In
072197 - shortened or damaged telomeres, TERRA is observed in
072198 - increased levels [356,357,358]. Upregulation of TERRA is
072199 - also observed in instances of DNA damage or loss of TRF2
072200 - [358]. With so much still to learn about lncRNAs such as
072201 - TERRA, a full understanding of their potential
072202 - telomere-regulatory role is several years away.
072204 - ..
072205 - 14. Conclusions
072206 -
072207 - The proposed associations with aging and exercise are
072208 - biologically plausible. Telomere length holds tantalizing
072209 - promise as a biomarker; however, a host of evidential
072210 - inconsistencies and paradoxes must be addressed. Leukocyte
072211 - telomere length is highly variable at birth, a metric
072212 - influenced by genetic inheritance and paternal age at
072213 - conception. It reflects lifelong exposure to oxidative and
072214 - inflammatory burden yet childhood LTL has more predictive
072215 - fidelity than LTL in adulthood or old age. Oscillating
072216 - throughout the lifespan, even inexplicably lengthening
072217 - despite advancing age, mean LTL differs between genders.
072218 - Attrition rates also differ between genders and appear
072219 - dependent upon initial telomere length. Shortening
072220 - trajectories can be further influenced by variable
072221 - exposure to a wide range of environmental stimuli. The
072222 - association between PA is more questionable with 50% of
072223 - studies failing to find a significant association.
072225 - ..
072226 - Investigations into plausible mechanisms have returned
072227 - promising yet inconsistent findings. The prevailing
072228 - consensus is that exercise-induced reductions in
072229 - oxidative stress and inflammation likely mediate the
072230 - effect. The possibility that LTL is a physiological
072231 - epiphenomenon cannot be excluded. Changes in LTL may
072232 - simply be coincidental processes that reflect, without
072233 - directly influencing, the primary mechanism. It is likely
072234 - that telomere length per se is significant only in so much
072235 - as it reflects the resultant phenotype via pathways such
072236 - as senescence-associated inflammation.
072238 - ..
072239 - It has been proposed that evolutionary pressures have
072240 - fine-tuned telomere length to reduce the risk of short and
072241 - long telomere pathologies, namely atherosclerosis and
072242 - cancer [359,360,361]. The long-term consequences of
072243 - manipulating telomere length are not well understood and
072244 - should therefore be approached with equal measures of
072245 - enthusiasm and evidence.
072247 - ..
072248 - 15. Conclusions
072249 -
072250 - The proposed associations with aging and exercise are
072251 - biologically plausible. Telomere length holds tantalizing
072252 - promise as a biomarker; however, a host of evidential
072253 - inconsistencies and paradoxes must be addressed. Leukocyte
072254 - telomere length is highly variable at birth, a metric
072255 - influenced by genetic inheritance and paternal age at
072256 - conception. It reflects lifelong exposure to oxidative and
072257 - inflammatory burden yet childhood LTL has more predictive
072258 - fidelity than LTL in adulthood or old age. Oscillating
072259 - throughout the lifespan, even inexplicably lengthening
072260 - despite advancing age, mean LTL differs between genders.
072261 - Attrition rates also differ between genders and appear
072262 - dependent upon initial telomere length. Shortening
072263 - trajectories can be further influenced by variable
072264 - exposure to a wide range of environmental stimuli. The
072265 - association between PA is more questionable with 50% of
072266 - studies failing to find a significant association.
072268 - ..
072269 - Investigations into plausible mechanisms have returned
072270 - promising yet inconsistent findings. The prevailing
072271 - consensus is that exercise-induced reductions in oxidative
072272 - stress and inflammation likely mediate the effect. The
072273 - possibility that LTL is a physiological epiphenomenon
072274 - cannot be excluded. Changes in LTL may simply be
072275 - coincidental processes that reflect, without directly
072276 - influencing, the primary mechanism. It is likely that
072277 - telomere length per se is significant only in so much as it
072278 - reflects the resultant phenotype via pathways such as
072279 - senescence-associated inflammation.
072281 - ..
072282 - It has been proposed that evolutionary pressures have
072283 - fine-tuned telomere length to reduce the risk of short and
072284 - long telomere pathologies, namely atherosclerosis and
072285 - cancer [359,360,361]. The long-term consequences of
072286 - manipulating telomere length are not well understood and
072287 - should therefore be approached with equal measures of
072288 - enthusiasm and evidence.
072290 - ..
072291 - 16. Future Directions
072292 -
072293 - Telomere and telomerase research is on the brink of truly
072294 - significant contributions to human health and disease
072295 - management. Exciting associations and plausible putative
072296 - mechanisms seem to promise therapeutic targets for the
072297 - future. The extensive associations strongly imply causal
072298 - involvement and warrant closer, more detailed analysis. We
072299 - propose four general areas of future research direction.
072301 - ..
072302 - First, evidence of actual telomere lengthening is lacking.
072303 - Whether an individual can move from the lowest to the
072304 - highest quartile of LTL through lifestyle interventions,
072305 - presumably with an enhanced phenotype, remains an open and
072306 - essential question. Given the propensity for LTL to track
072307 - through the lifespan [82], the capacity of PA to modulate a
072308 - seemingly centrally-driven measure must be addressed. If
072309 - actual telomere lengthening is identified, it must then be
072310 - determined whether such lengthening lies within the
072311 - considerable natural ebb and flow of telomere length
072312 - dynamics over time.
072314 - ..
072315 - The second future direction regards selection of the most
072316 - relevant telomeric metric. Evidence suggests that the
072317 - proportion of short telomeres may be more consequential
072318 - than mean LTL given the ability of very long telomeres
072319 - within a cell to skew the mean [362,363]. Studies reporting
072320 - longer LTL in the physically active should also report the
072321 - relative proportion of the shortest telomeres.
072323 - ..
072324 - The third future direction regards the use of mediation
072325 - analysis to quantify positive and negative telomere
072326 - instigators. Mediation analysis models a hypothesized
072327 - causal chain in which a variable of interest influences an
072328 - intervening mediator variable which in turn mediates the
072329 - outcome variable. This allows the effect of exposure to the
072330 - mediator on the outcome variable. Mediation analysis
072331 - quantifies the exposure of likely mediating factors such as
072332 - oxidative stress, inflammation and age. Analysis of this
072333 - sort would also reveal whether changes in telomere length
072334 - can occur independently of factors like oxidative stress
072335 - and inflammation. As an example, a recent study found that
072336 - fasting insulin partially mediates the association between
072337 - genetically determined LTL and CHD risk [364].
072339 - ..
072340 - The final proposed direction is the development of a
072341 - regularly updated international consensus document on
072342 - telomere research methodology. Developed by an
072343 - international consortium of leading telomere researchers,
072344 - this document could outline: (i) preferred measurement
072345 - techniques; (ii) acceptable coefficients of variation;
072346 - (iii) universally accepted definitions and criteria for
072347 - long and short telomeres and (iv) rigorous methods of data
072348 - interpretation. In time, publishing in accordance with such
072349 - guidelines would become the standard expectation with
072350 - reputational costs incurred for discrepant methodologies.
072352 - ..
072353 - Many exciting discoveries are undoubtedly yet to come from
072354 - the field; however, many of these may be lost to
072355 - unacceptably large measurement variations and inconsistent
072356 - methodologies. The irresistible logicality of the reported
072357 - telomeric associations risks the premature inference of
072358 - causation. The final quantum leap to be made will be the
072359 - translation of benchtop findings into clinically relevant
072360 - interventions. Only then will the ends have justified the
072361 - means.
072362 -
072364 - ..
072365 - Author Contributions
072367 - ..
072368 - Warrick Chilton conceived and composed this manuscript.
072369 - Fadi Charchar and Brendan O?Brien edited and commented upon
072370 - the final draft. All authors reviewed the manuscript.
072372 - ..
072373 - Conflicts of Interest
072375 - ..
072376 - The authors declare no conflict of interest.
072377 -
072379 - ..
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