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Association between genetically predicted telomere length and facial skin aging in the UK Biobank: a Mendelian randomization study

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Are shorter telomeres causal risk factors for facial aging on a large population level? To examine if longer, genetically predicted telomeres were causally associated with less facial aging using Mendelian randomization analysis. Two-sample Mendelian randomization methods were applied to the summary statistics of a genome-wide association study (GWAS) for self-reported facial aging from 417, 772 participants of the UK Biobank data. Twenty single-nucleotide polymorphisms (SNPs) that were of genome-wide significance were selected as instrumental variables for leukocyte telomere length. The main analyses were performed primarily using the random-effects inverse-variance weighted method and were complemented with the MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was used to assess horizontal pleiotropy. Longer genetically predicted telomeres were associated with a lower likelihood of facial aging (β = - 0.02, 95% confidence interval: - 0.04, - 0.002). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was close to zero (0.002) that was not suggestive of horizontal pleiotropy. Our findings provided evidence to support a potential causal relationship between longer genetically predicted telomeres and less facial aging.
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SHORT COMMUNICATION
Association between genetically predicted telomere length
and facial skin aging in the UK Biobank: a Mendelian
randomization study
Yiqiang Zhan &Sara Hägg
Received: 10 August 2020 /Accepted: 28 September 2020
#The Author(s) 2020
Abstract Are shorter telomeres causal risk factors for
facial aging on a large population level? To examine if
longer, genetically predicted telomeres were causally
associated with less facial aging using Mendelian ran-
domization analysis. Two-sample Mendelian randomi-
zation methods were applied tothe summary statistics of
a genome-wide association study (GWAS) for self-
reported facial aging from 417, 772 participants of the
UK Biobank data. Twenty single-nucleotide polymor-
phisms (SNPs) that were of genome-wide significance
were selected as instrumental variables for leukocyte
telomere length. The main analyses were performed
primarily using the random-effects inverse-variance
weighted method and were complemented with the
MR-Egger regression, weighted median, and weighted
mode approaches. The intercept of MR-Egger regres-
sion was used to assess horizontal pleiotropy. Longer
genetically predicted telomeres were associated with a
lower likelihood of facial aging (β=0.02, 95% confi-
dence interval: 0.04, 0.002). Comparable results
were obtained using MR-Egger regression, weighted
median, and weighted mode approaches. The intercept
of MR-Egger regression was close to zero (0.002) that
was not suggestive of horizontal pleiotropy. Our find-
ings provided evidence to support a potential causal
relationship between longer genetically predicted telo-
meres and less facial aging.
Keywords Telomeres .Aging .Facialaging .Mendelian
randomization .Genetics .Skin aging
Introduction
Telomeres are comprised of hexanucleotide DNA re-
peats and a complex structure of surrounding proteins at
the end of chromosomes, protecting genetic information
by maintaining the stability of chromosomes during
cellular divisions [1]. Each time a cell divides, a small
amount of telomeric DNA is lost because of the inability
of the polymerase to fully elongate the ends of DNA.
Consequently, telomeres are shorten with each cell di-
vision and are therefore recognized as a potential bio-
logical marker for cellular aging [2]. Telomere attrition
over time results in critically short telomere lengths and
leads to cellular senescence and apoptosis in normal
cells. Skin cells, whose turnover cycle could be driven
in part by telomeres replenishment, have a proliferative
capacity that varies from a few days in newborns to a
few weeks in adults [3,4]. And facial skin cells are of
particular interest. Maintaining a fast renewal of skin
cells could slow down facial aging and make people
look younger.
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https://doi.org/10.1007/s11357-020-00283-0
Y. Zhan
German Center for Neurodegenerative Diseases, Ulm, Germany
Y. Zhan (*)
Institute of Environmental Medicine, Karolinska Institutet,
Stockholm, Sweden
e-mail: yiqiang.zhan@ki.se
S. Hägg
Department of Medical Epidemiology and Biostatistics,
Karolinska Institutet, Stockholm, Sweden
Different molecular mechanisms have been sug-
gested to explain facial aging, where telomeres as a
marker for biological aging have recently been gaining
momentum [5]. For example, an in vitro experiment
showed that skin cells with telomeres lengthened by a
procedure that delivered a modified mRNA encoding
TERT to cells were able to divide more times than
untreated cells [6]. However, studies like this one need
to be further investigated in large population-based
analyses.
Therefore, in this study, we aimed to examine the
potential causal association between leukocyte telomere
length (TL), which was correlated with TL in skin cells
(correlation coefficient r=0.83) [7], and facial aging
using a Mendelian randomization (MR) approach [8]
in data collected from 417,772 participants of the UK
Biobank [9].
Materials and methods
Instrumental variable selection
The European Network for Genetic and Genomic Epi-
demiology (ENGAGE) conducted a genome-wide asso-
ciation study (GWAS) for leukocyte TL in 78,592 indi-
viduals of European ancestry [10]. Mean leukocyte TL
was measured in a mixed population of leukocytes, and
measurements were conducted using an established
quantitative polymerase chain reaction technique which
Table 1 SNPs selected as instrumental variables and their associations with leukocyte TL in ENGAGE consortium
SNP Chromosome Position (hg37) Gene Effect allele Other allele βse(β)
rs2695242
proxy of rs3219104
r
2
=1
1 226594038 RARP1 GT0.039 0.006
rs55749605 3 101232093 SENP7 AC0.037 0.007
rs7643115
proxy of rs10936600
r
2
=1
3 169512241 TERC AG0.086 0.006
rs2320615
proxy of rs4691895
r
2
=1
4 164069949 NAF1 G A 0.055 0.006
rs13137667 4 71774347 MOB1B C T 0.077 0.014
rs2853677 5 1287194 TERT AG0.064 0.005
rs7705526 5 1285974 TERT A C 0.082 0.006
rs805297
proxy of rs2736176
r
2
=1
6 31622606 PRRC2A A C 0.034 0.006
rs34991172 6 25480328 CARMIL1 GT0.061 0.010
rs59294613 7 124554267 POT1 AC0.041 0.005
rs9419958 10 105675946 STN1 (OBFC1) CT0.064 0.007
rs228595 11 108105593 ATM AG0.028 0.005
rs76891117
proxy of rs2302588
r
2
=1
14 73399837 DCAF4 G A 0.048 0.008
rs7194734 16 82199980 MPHOSPH6 TC0.037 0.006
rs62053580 16 74680074 RFWD3 GA0.039 0.007
rs3785074 16 69406986 TERF2 G A 0.035 0.006
rs8105767 19 22215441 ZNF208 G A 0.039 0.005
rs71325459
proxy of rs34978822
r
2
=1
20 62268341 RTEL1 TC0.122 0.022
rs73624724 20 62436398 RTEL1/ZBTB46 C T 0.051 0.007
rs75691080 20 62269750 RTEL1/STMN3 TC0.067 0.009
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expressed TL as a ratio of the telomere repeat number
(T) to a single-copy gene (S) [11]. Leukocyte TL mea-
surements were standardized either by using a calibrator
sample or by quantifying against a standard curve. In
total, 20 single-nucleotide polymorphisms (SNPs) at 17
genomic loci were independently associated with leu-
kocyte TL at a level of genome-wide statistical signifi-
cance (P<5×10
8
). In our study,we use these 20 SNPs
as instrumental variables, and included proxy SNPs
through LDlink if SNPs found to be palindromic
(Table 1).
Facial aging GWAS
In the UK Biobank, the facial aging domain was mea-
sured by the question (field code 1757)Do people say
that you look younger than you are, older than you are,
about your age, do not know, and prefer not to answer?
Analyses of this variable were performed in 417,772
British participants using a mixed linear model-based
tool (fastGWA) that has treated facial aging as an ordinal
categorical variable while controls for population strat-
ification by principal components and for relatedness by
a sparse genetic relationship matrix as well as age and
sex [9]. These data were analyzed and made publicly
available by the Complex Trait Genomics lab
(http://fastgwa.info).
Statistical analysis
The data on the instrumental variables and the facial
aging GWAS were harmonized by the respective chro-
mosomes and positions (human genome build 37). The
random-effects inverse-variance weighted (IVW) meth-
od was used as the primary estimator for the MR analysis
[12]. This method has a higher statistical power with the
assumption that all SNPs are valid instrumental vari-
ables. The weighted median approach [13], MR-Egger
regression [14], and weighted mode method [15] were
used as complementary analysis. The weighted median
approach yields consistent estimates when at least 50%
of the weights in the analysis are from valid instrumental
variables. The MR-Egger regression can adjust for di-
rectional pleiotropy but is of low power. The intercept of
MR-Egger regression is used as a test for horizontal
pleiotropy. The weighted mode approach is consistent
when the largest number of similar individual-instrument
causal effect estimates comes from valid instruments,
even if most instruments are invalid. To examine if there
was a reverse causation between TL and facial aging, we
conducted an additional MR analysis as bi-directional
MR analysis using 98 SNPs of genome-wide signifi-
cance for facial aging as instrumental variables in
UKB. Then, we harmonized their respective effect sizes
and standard errors for these SNPs in ENGAGE TL
GWAS. All statistical analyses were conducted in R
3.6 and TwoSampleMR package [16].
Thepresentstudyonlyusedpubliclyavailable
summary-level statistics. No individual-level data was
analyzed. Ethical approval is therefore not required.
Results
Table 1describes 20 genetic variants as instrumental
variables and their associations with leukocyte TL. Six
palindromic SNPs were replaced by their corresponding
proxy SNPs (r
2
= 1). The scatter plot for the effects of
these SNPs on leukocyte TL and facial aging is shown
in Fig. 1.
The MR analysis shows that longer genetically pre-
dicted leukocyte TL was associated with a lower likeli-
hood of facial aging (β=0.02, 95% confidence interval
Fig. 1 Facial skin aging. Scatter plot for the effects of SNPs on
leukocyte telomere Length and facial aging. IVW, inverse-
variance weighted; MR, Mendelian randomization. The horizontal
axis represents the effects of each genetic variant on leukocyte
telomere length, and the vertical axis denotes the effects of each
genetic variant on facial aging. The orange lines around the solid
black points are the corresponding confidence intervals for the
effects. The slopes of solid lines represent the estimates from IVW,
weighted median, weighted mode, and MR-Egger regression
analyses
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[CI]: 0.04, 0.002) using the IVW method (Table 2).
Similar results were obtained through MR-Egger
regression (β=0.06, 95% CI: 0.12, 0.002), weight-
ed median (β=0.03, 95% CI: 0.05, 0.007), and
weighted mode approaches (β=0.03, 95% CI: 0.05,
0.007). These estimates were also plotted in Fig. 1.
We additionally performed a leave-one-out analysis,
which yielded comparable results and did not find no-
ticeable effects of any single SNP that could dominate
the results (Fig. 2). The funnel plot did not imply that
there were heterogeneousSNPs (Fig. 3). We did not find
evidence for directional pleiotropy from the MR-Egger
regression (intercept: 0.002, P=0.16).
Additional bi-directional MR analysis was performed
by using 98 SNPs that were of genome-wide
Table 2 Association between telomere length and facial aging in
the UK Biobank
Methods β95% CI
Inverse variance weighted 0.02 0.04, 0.0002
MR-Egger regression 0.06 0.12, 0.002
Weighted median 0.03 0.05, 0.007
Weighted mode 0.03 0.05, 0.007
MR Mendelian randomization
Fig. 2 Facial skin aging. Leave-one-out analysis for the estimates for leukocyte telomere length on facial aging. IVW, inverse-variance
weighted
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significance for facial aging as instrumental variables.
We did not find a significant effect of genetically pre-
dicted facial aging on leukocyte TL (β=0.08, 95%
CI: 0.22, 0.05).
Discussion
In the present study, for the first time, we examined the
association of genetically predicted leukocyte TL and
facial aging in a large population-based cohort, the UK
Biobank, using the MR method. By leveraging several
MR estimation approaches, we found that longer genet-
ically predicted leukocyte TL was associated with a
lower likelihood of facial aging. Our study, corroborat-
ing previous experimental studies of skin cells, provides
further evidence to support a causal role of leukocyte TL
in facial aging.
To the best of our knowledge, no studies have been
published to investigate the role of TL in facial aging
using population-based cohorts until now. A previous
study examined TL in cells of the sun-protected and
sun-exposed skins [17]. Further studies employed
ultraviolet-exposed skin cells to study the roles of TL
in photoaging [1821]. These studies, taken together,
were suggestive of the functions of TL in skin aging at
the cellular level [5,22]. Further evidence at the popu-
lation level, however, is lacking. The limited number of
studies on this topic at the population level is partly due
to the difficulties in facial aging measurements. For
example, although the three-dimensional human facial
morphology assessment instruments [23], among others
[24], can offer objective and comprehensive features for
facial aging, they have not been widely available for
aging researchers because of infeasibility and high cost.
To overcome the challenges in facial aging mea-
surement and to make the best use of questionnaire-
based instruments, a subjective assessment of facial
aging could be valuable in this regard measurement
[2527]. In this study, we examined the role of TL
by taking advantage of questionnaire-based mea-
surement for facial aging in the UK Biobank. An
advantage of this type of data is that the large
sample size in the UK Biobank could outweigh the
concerns in measurement error for questionnaire-
based facial aging assessment. Indeed, we obtained
consistent and significant estimates by using various
MR approaches in this study. Further studies are
warranted to explore the biological mechanisms of
TL in facial aging.
Despite the advantages of the large sample size, our
study is prone to several limitations. First, the MR
assumptions, particularly the no-pleiotropy assumption,
must be satisfied in order to yield a valid estimate. The
intercept of MR-Egger regression analysis approaches
zero suggesting no strong evidence for directional plei-
otropy. Second, the MR methods used in this study also
assume a linear relationship between TL and facial
aging. We cannot examine further if there was a non-
linear relationship. Third, as facial aging GWAS was
analyzed using mixed linear models, the effect sizes
cannot be interpreted using a more intuitive way. The
results could rather be used for testing purposes. Fourth,
as alluded above, the facial aging was measured using a
single question in the UK Biobank, which could lead to
measurement error. Future studies are encouraged in
order to develop a more detailed questionnaire-based
instrument to measure diverse dimensions of facial ag-
ing. Fifth, in this study, facial aging was assessed only
using qualitative data and not objectively assessed using
skin turgor [28] or facial wrinkles per area of skin [29].
Lastly, TL was measured in leukocyte rather than skin
cells. However, a previous study demonstrated that the
correlation of TL in leukocyte and skin cells was high
(correlation coefficient r=0.83)[7], and a recent study
found that TL varies by tissue type but is generally
correlated among tissue types [30].
In summary, our study provided novel evidence to
support a causal role of genetically predicted leukocyte
Fig. 3 Facial skin aging. Funnel plot for the SNPs. IV, instru-
mental variable
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TL in facial aging. Further studies are warranted to
explore the biological mechanisms of TL in facial aging.
Acknowledgments The authors thank ENGAGE telomere con-
sortium for sharing GWAS summary statistics.
Authorscontributions YZ and SH contributed to study de-
sign, data analysis, manuscript writing, and results interpretation.
Funding Open Access funding enabled and organized by
Projekt DEAL. This is study was supported by a Junior Group
Leader Startup Grants at DZNE. SH is supported by grants from
the Swedish Research Council (2019-01272, 2015-03255), the
Strategic Research Program in Epidemiology at Karolinska
Institutet, and King Gustaf V:s and Queen Victorias Freemason
Foundation.
Data availability The data are publicly available.
Compliance with ethical standards
Conflict of interest The authors declare that they have no con-
flicts of interest.
Ethical approval The present study only used summary statis-
tics rather than individual-level data. IRB is exempted according to
the rules at Karolinska Institutet, Sweden.
Consent to participate Not applicable.
Consent for publication Not applicable.
Code availability The codes are from TwoSampleMR package.
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distributionand reproduction in any medium or format,
as long as you give appropriate credit to the original author(s) and
the source, provide a link to the Creative Commons licence, and
indicate if changes were made. The images or other third party
material in this article are included in the article's Creative Com-
mons licence, unless indicated otherwise in a credit line to the
material. If material is not included in the article's Creative Com-
mons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of
this licence, visit http://creativecommons.org/licenses/by/4.0/.
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Recent evidence suggests that shorter telomere length (TL) is associated with neuro degenerative diseases and aging related outcomes. The causal association between TL and brain characteristics represented by image derived phenotypes (IDPs) from different magnetic resonance imaging (MRI) modalities remains unclear. Here, we use two-sample Mendelian randomization (MR) to systematically assess the causal relationships between TL and 3,935 brain IDPs. Overall, the MR results suggested that TL was causally associated with 193 IDPs with majority representing diffusion metrics in white matter tracts. 68 IDPs were negatively associated with TL indicating that longer TL causes decreasing in these IDPs, while the other 125 were associated positively (longer TL leads to increased IDPs measures). Among them, ten IDPs have been previously reported as informative biomarkers to estimate brain age. However, the effect direction between TL and IDPs did not reflect the observed direction between aging and IDPs: longer TL was associated with decreases in fractional anisotropy and increases in axial, radial and mean diffusivity. For instance, TL was positively associated with radial diffusivity in the left perihippocampal cingulum tract and with mean diffusivity in right perihippocampal cingulum tract. Our results revealed a causal role of TL on white matter integrity which makes it a valuable factor to be considered when brain age is estimated and investigated.
... Facial ageing has been measured by UKB on a questionnaire (field code 1757) answered by the participants (22). The question asked "Do people say that you look:" with five available answers of "Younger than you are, " "Older than you are, " "About your age, " "Do not know" and "Prefer not to answer." ...
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Background While increased age is an established risk factor for COVID-19, there is great heterogeneity in outcomes within age groups. This is because chronological age does not reflect health, unlike biological age. We intend to investigate the association between accelerated ageing and COVID-19 outcomes through the lens of three measures, namely phenotypic age acceleration (PhenoAgeAccel), telomere length (Adjusted T/S Ratio) and facial ageing, and to examine whether there are differences across ethnic groups. Methods Taking participants from the UK Biobank, we associated accelerated ageing with severe COVID-19 outcomes, defined as COVID-related hospitalisation or death. Separate logistic regressions models were created for age and the three accelerated ageing-related variables, adjusting for a variety of covariates in each model. Multivariable logistic regression models were also created within White, Black, Asian and Other ethnic groups to assess for potential differing associations. Forward likelihood ratio logistic regression models were created to evaluate importance of the variables and to assess for patterns of association across the total population and ethnic groups. Results After adjusting for all covariates, the odds ratio (OR) and 95% confidence interval (95% CI) of COVID-19 severe outcomes for age was 1.080 (1.074–1.086). After further adjusting age for the accelerated ageing variables, the ORs were 1.029 (1.020–1.039) for PhenoAgeAccel and 0.847 (0.772–0.929) for Facial Ageing's “Younger Than You Are” while Adjusted T/S ratio and “Older Than You Are” were statistically insignificant. The OR for age remained similar across ethnic groups. Both PhenoAgeAccel and younger facial ages in the White population and PhenoAgeAccel in the Black population had ORs of 1.031 (1.021–1.042), 0.853 (0.774–0.939), and 1.049 (1.001–1.100), respectively. Both Adjusted T/S Ratio and older facial ages showed statistical insignificance in all ethnicities. In forward logistic regression, age and PhenoAgeAccel were the age-related variables selected most frequently in all models. Interpretation Accelerated ageing is associated with increased COVID-19 severity. The mechanisms at work here are likely immunosenescence and inflamaging. This association indicates that anti-ageing treatment may improve COVID-19 outcome. The results within ethnic groups and that of telomere length were inconclusive, but point to a need for future, more focused research on the topic.
... Maintaining fast renewal of skin cells could slow down facial aging and make people look younger. Recent experimental studies have supported a potential causal relationship between longer genetically predicted telomeres and less facial aging [5]. ...
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Telomere length, a hallmark of cellular senescence, decreases with age and is associated with age-related diseases. Environmental factors, including dietary and lifestyle factors, can affect the rate at which telomeres shorten, and telomere protection prevents this from happening. The protection of telomeres by natural molecules has been proposed as an antiaging strategy that may play a role in treating age-related diseases. This study investigated the effect of a cycloartane-type triterpene glycoside (astragaloside IV). Astragaloside IV is one of the primary compounds from the aqueous extract of Astragalus membranaceus, and it provides telomere protection both in vitro and in vivo. In a study cohort with 13 participants, telomere length in human skin samples was analyzed after daily treatment for 4 weeks. A comparison of the average median telomere length between the treatment and control groups (5342 bp vs. 4616 bp p = 0.0168) showed significant results. In the second clinical cohort with 20 participants, skin parameters at baseline and after 4 and 8 weeks were measured in vivo. The results show that the product improved hydration by 95%, the skin appeared brighter by 90%, and wrinkle visibility was reduced by 70%. The combination of biologically active compounds in the cream possesses telomere-protecting properties and notable antioxidant activity in vitro and in vivo.
... Therefore, there might be distinct causal pathways from variation to outcomes and this could violate the IV3 assumption [36]. Vertical pleiotropy will occur if a variant shows direct correlations to exposure on the same biological pathway as well as another phenotype, which cannot result in a violation of the IV assumption and can provide a unique causal pathway from genetic variation to outcomes through exposure [37]. Horizontal pleiotropy can produce bias when SNPs ...
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Objective: Evidence suggests that omega-3 fatty acid intake exerts a protective effect on lung cancer, but its causal association with risk of lung cancer remains uncertain. This study attempts to clarify the causal effect of omega-3 fatty acids on lung cancer utilizing genome-wide association study (GWAS) data with Mendelian randomization (MR) approach. Methods: This study acquired omega-3 fatty acid data from the UK Biobank and data of lung cancer patients from the Consortium and International Lung Cancer Consortium (ILCCO). Single-nucleotide polymorphisms (SNPs) associated with omega-3 fatty acids were screened as instrumental variables (IVs) in line with the criteria of p < 5E - 8, linkage disequilibrium R 2 > 0.001 and distance < 10000 kb. Through inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode, causal association between omega-3 fatty acids and risk of lung cancer was evaluated. Cochran's Q test was applied for a heterogeneity test. The pleiotropy and horizontal pleiotropy among IVs were evaluated via MR-Egger regression intercept analysis. Results: Totally, 42 SNPs associated with omega-3 fatty acids were identified as IVs. According to the results of IVW (OR (95% CI): 0.899 (0.817, 0.990), p = 0.03), MR-Egger (OR (95% CI): 0.856 (0.750, 0.977), p = 0.026), weighted median (OR (95% CI): 0.899 (0.817, 0.990), p = 0.001), simple mode (OR (95% CI): 0.901 (-0.678, 1.199), p = 0.478), and weighted mode (OR (95% CI): 0.859 (0.782, 0.944), p = 0.003), omega-3 fatty acids showed a causal association with low risk of lung cancer. No genetic pleiotropy or horizontal pleiotropy was found according to MR-Egger regression intercept analysis. Conclusion: Our findings provide sufficient evidence that omega-3 fatty acids are causal protective factors of lung cancer. Despite this, further work is required for elucidating the potential mechanisms.
... TL has therefore been acknowledged as a putative predictive biomarker for biological aging [1]. TL shortens as people become older and has been reported to be a risk factor for metabolic disorders like diabetes [2,3], cardiocerebrovascular disease, and metabolic syndrome [4][5][6][7], among others like dementia and cancer [8][9][10][11][12][13][14]. Its association with immunological functions and virus infection has, however, rarely been investigated [15]. ...
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Background: Telomeres undergo shortening with each cell division, which could be accelerated by infection. The association between virus infection and telomere length is poorly understood. In the present study, we investigated the putative associations between leukocyte telomere length (TL), cytomegalovirus (CMV) infection, and C-reactive protein (CRP) in a national representative sample of noninstitutionalized population. Methods: We analyzed data that was collected in a cross-sectional setting, where 3,987 participants were enrolled with available data on telomere length. The association between telomere length with previous CMV infection and CRP was analyzed using multivariable linear regression models. We further tested if obesity, measured by body mass index (BMI), and smoking could modify this relationship. Results: In total, around 46% percent of the study population were men and 54% were women. Average ages were 35.1 years for men and 35.0 years for women. One unit increase of CMV antibody IgG titer was associated with -0.07 (95% confidence interval: -0.12, -0.01) unit decrease of leukocyte TL when sex was adjusted for. After additionally adjusting for BMI and smoking status, the magnitude of the association was only slightly decreased to -0.06 (95% confidence interval: -0.11, -0.01). The effect sizes were comparable after additionally adjusting for CRP. These analyses imply that previous CMV infection affects leukocyte TL through pathways other than CRP. Conclusions: Previous CMV infection was associated with shorter leukocyte TL. This association was independent of CRP.
Chapter
The progression of age triggers a vast number of diseases including cardiovascular, cancer, and neurodegenerative disorders. Regardless of our plentiful knowledge about age-related diseases, little is understood about molecular pathways that associate the ageing process with various diseases. Several cellular events like senescence, telomere dysfunction, alterations in protein processing, and regulation of gene expression are common between ageing and associated diseases. Accumulating information on the role of microRNAs (miRNAs) suggests targeting miRNAs can aid our understanding of the interplay between ageing and associated diseases. In the present chapter, we have attempted to explore the information available on the role of miRNAs in ageing of various tissues/organs and diseases and understand the molecular mechanism of ageing.
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Are shorter telomeres causal risk factors for Alzheimer’s disease (AD)? This study aimed to examine if shorter telomeres were causally associated with a higher risk of AD using Mendelian randomization (MR) analysis. Two-sample MR methods were applied to the summary effect sizes and standard errors from a genome-wide association study for AD. Twenty single nucleotide polymorphisms of genome-wide significance were selected as instrumental variables for leukocyte telomere length. The main analyses were performed primarily using the random-effects inverse-variance weighted method and complemented with the other three methods: weighted median approaches, MR-Egger regression, and weighted mode approach. The intercept of MR-Egger regression was used to assess horizontal pleiotropy. We found that longer telomeres were associated with lower risks of AD (odds ratio = 0.79, 95% confidence interval: 0.67, 0.93, P = 0.004). Comparable results were obtained using weighted median approaches, MR-Egger regression, and weighted mode approaches. The intercept of the MR-Egger regression was close to zero. This may show that there was not suggestive of horizontal pleiotropy. Our findings provided additional evidence regarding the putative causal association between shorter telomere length and the higher risk of AD.
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Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
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The genome-wide association study (GWAS) has been widely used as an experimental design to detect associations between genetic variants and a phenotype. Two major confounding factors, population stratification and relatedness, could potentially lead to inflated GWAS test statistics and hence to spurious associations. Mixed linear model (MLM)-based approaches can be used to account for sample structure. However, genome-wide association (GWA) analyses in biobank samples such as the UK Biobank (UKB) often exceed the capability of most existing MLM-based tools especially if the number of traits is large. Here, we develop an MLM-based tool (fastGWA) that controls for population stratification by principal components and for relatedness by a sparse genetic relationship matrix for GWA analyses of biobank-scale data. We demonstrate by extensive simulations that fastGWA is reliable, robust and highly resource-efficient. We then apply fastGWA to 2,173 traits on array-genotyped and imputed samples from 456,422 individuals and to 2,048 traits on whole-exome-sequenced samples from 46,191 individuals in the UKB. fastGWA is a mixed linear model–based approach for performing genome-wide association analyses at biobank scale, while controlling for population stratification and relatedness.
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Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in non-blood, disease-relevant tissue types. Here we characterize variability in TL measurements for 6,391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) Project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation impacts TL in multiple tissue types, and that TL can mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health. ONE SENTENCE SUMMARY Telomere length varies by tissue type but is generally correlated among tissue types (positively) and with age (negatively).
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Objectives Despite variation in lifestyle and environment, first signs of human facial aging show between the ages of 20–30 years. It is a cumulative process of changes in the skin, soft tissue, and skeleton of the face. As quantifications of facial aging in living humans are still scarce, we set out to study age‐related changes in three‐dimensional facial shape using geometric morphometrics. Materials and methods We collected surface scans of 88 human faces (aged 26–90 years) from the coastal town Split (Croatia) and neighboring islands. Based on a geometric morphometric analysis of 585 measurement points (landmarks and semilandmarks), we modeled sex‐specific trajectories of average facial aging. Results Age‐related facial shape change was similar in both sexes until around age 50, at which time the female aging trajectory turned sharply. The overall magnitude of facial shape change (aging rate) was higher in women than men, especially in early postmenopause. Aging was generally associated with a flatter face, sagged soft tissue (“broken” jawline), deeper nasolabial folds, smaller visible areas of the eyes, thinner lips, and longer nose and ears. In postmenopausal women, facial aging was best predicted by the years since last menstruation and mainly attributable to bone resorption in the mandible. Discussion With high spatial and temporal resolution, we were able to extract a shared facial aging pattern in women and men, and its divergence after menopause. This fully quantitative three‐dimensional analysis of human facial aging may not only find applications in forensic and ancient human facial reconstructions, but shall include lifestyle and endocrinological measures, and also reach out to studies of social perception.
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Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base ( http://www.mrbase.org ): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies.
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As the most voluminous organ of the body that is exposed to the outer environment, the skin suffers from both intrinsic and extrinsic aging factors. Skin aging is characterized by features such as wrinkling, loss of elasticity, laxity, and rough-textured appearance. This aging process is accompanied with phenotypic changes in cutaneous cells as well as structural and functional changes in extracellular matrix components such as collagens and elastin. In this review, we summarize these changes in skin aging, research advances of the molecular mechanisms leading to these changes, and the treatment strategies aimed at preventing or reversing skin aging.
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Background: Mendelian randomization (MR) is being increasingly used to strengthen causal inference in observational studies. Availability of summary data of genetic associations for a variety of phenotypes from large genome-wide association studies (GWAS) allows straightforward application of MR using summary data methods, typically in a two-sample design. In addition to the conventional inverse variance weighting (IVW) method, recently developed summary data MR methods, such as the MR-Egger and weighted median approaches, allow a relaxation of the instrumental variable assumptions. Methods: Here, a new method - the mode-based estimate (MBE) - is proposed to obtain a single causal effect estimate from multiple genetic instruments. The MBE is consistent when the largest number of similar (identical in infinite samples) individual-instrument causal effect estimates comes from valid instruments, even if the majority of instruments are invalid. We evaluate the performance of the method in simulations designed to mimic the two-sample summary data setting, and demonstrate its use by investigating the causal effect of plasma lipid fractions and urate levels on coronary heart disease risk. Results: The MBE presented less bias and lower type-I error rates than other methods under the null in many situations. Its power to detect a causal effect was smaller compared with the IVW and weighted median methods, but was larger than that of MR-Egger regression, with sample size requirements typically smaller than those available from GWAS consortia. Conclusions: The MBE relaxes the instrumental variable assumptions, and should be used in combination with other approaches in sensitivity analyses.
Article
Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.
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The search for reliable indicators of biological age, rather than chronological age, has been ongoing for over three decades, and until recently, largely without success. Advances in the fields of molecular biology have increased the variety of potential candidate biomarkers that may be considered as biological age predictors. In this review, we summarize current state-of-the-art findings considering six potential types of biological age predictors: epigenetic clocks, telomere length, transcriptomic predictors, proteomic predictors, metabolomics-based predictors, and composite biomarker predictors. Promising developments consider multiple combinations of these various types of predictors, which may shed light on the aging process and provide further understanding of what contributes to healthy aging. Thus far, the most promising, new biological age predictor is the epigenetic clock; however its true value as a biomarker of aging requires longitudinal confirmation.
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Facial wrinkling is one of the most notable signs of skin aging. Men and women show different wrinkling patterns yet the lifestyle and physiological factors underlying these sex-specific patterns are relatively unknown. Here, we investigated sex-specific determinants for facial wrinkles. Wrinkle area was quantified digitally using facial photographs of 3,831 north-western Europeans (51-98 years, 58% female). Effect estimates from multivariable linear regressions are presented as the percentage difference in the mean value of wrinkle area per unit increase of a determinant (%Δ). Wrinkle area was higher in men (median 4.5%, [interquartile range (IQR):2.9-6.3]) than in women (3.6%, [IQR:2.2-5.6]). Age was the strongest determinant, and current smoking (men:15.5%Δ; women:30.9%Δ) and lower body mass index (men:1.7%Δ; women:1.8%Δ) were also statistically significantly associated with increased wrinkling. Pale skin color showed a protective effect (men: -21.0%Δ; women: -28.5%Δ) and, in men, sunburn tendency was associated with less wrinkling. In women, low educational levels and alcohol use were associated with more wrinkling, while female pattern hair loss and a higher free androgen index were associated with less wrinkling. In summary, we validated known and identified additional determinants for wrinkling. Skin aging reducing strategies should incorporate the sex differences found in this study.