Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives

Abstract

Telomere shortening is a well-known hallmark of both cellular senescence and organismal aging. An accelerated rate of telomere attrition is also a common feature of age-related diseases. Therefore, telomere length (TL) has been recognized for a long time as one of the best biomarkers of aging. Recent research findings, however, indicate that TL per se can only allow a rough estimate of aging rate and can hardly be regarded as a clinically important risk marker for age-related pathologies and mortality. Evidence is obtained that other indicators such as certain immune parameters, indices of epigenetic age, etc., could be stronger predictors of the health status and the risk of chronic disease. However, despite these issues and limitations, TL remains to be very informative marker in accessing the biological age when used along with other markers such as indices of homeostatic dysregulation, frailty index, epigenetic clock, etc. This review article is aimed at describing the current state of the art in the field and at discussing recent research findings and divergent viewpoints regarding the usefulness of leukocyte TL for estimating the human biological age.

Keywords: age-related telomere shortening; aging-related disease; biomarker of biological age; leukocyte telomere length; mortality; telomerase.

Figure 1

Telomere attrition, telomere length and telomerase. Chromosomes have repeated base segments called telomeres that shorten with each replication cycle (cell division). The enzyme telomerase has the capability to extend the telomere ends, thus prolonging cell life and potentially inducing immortality (which is a cancer cell hallmark). The figure and its legend are reproduced from the article by Aunan et al. (2016) with permission from John Wiley and Sons (License Number 4938770663443). Copyright © 2016 BJS Society Ltd Published by John Wiley & Sons Ltd.

Figure 2

Schematic of telomere length reprogramming in mammalian embryonic development. The greatest telomere lengthening takes place during the earliest stages of preimplantation development, the cleavage-stage embryo, which may coincide with zygote genome activation. Recombination-mediated telomere lengthening (ALT) is also purportedly responsible for reprogramming in pluripotent stem cells, including ESCs, ntESCs, and iPSCs. Later, in development and adult life, telomerase becomes the dominant telomere maintenance mechanism for the inner cell mass and in tissue-specific telomere replenishment in stem cell niches. The figure and its legend are reproduced from the article by Kalmbach et al. (2014) distributed under the terms of the Creative Commons Attribution License. Copyright: © 2014 Keri Kalmbach et al.

Figure 3

Scatter plots and density plots of LTL as a function of age for males and females residing in different countries. Measurements of LTL were performed in the same laboratory on DNA donated by participants in different studies in different countries. The horizontal dashed lines in the top panels and vertical dashed lines in the bottom panels indicate LTL values of 5 kb. The bottom plots are smoothed histograms obtained by kernel density estimation. The figure and its legend are reproduced from the article by Steenstrup et al. (2017) distributed under the terms of the Creative Commons Attribution License (CC BY 3.0). Copyright © 2017 Steenstrup et al.

Figure 4

Telomere length in study participants up to 115 years of age. Leukocyte telomere length vs. age is shown for males (blue or cyan) and females (green or red). Centenarians, (semi)supercentenarians, and centenarian offspring are shown in blue (males) or red (females), respectively. Unrelated participants younger than 100 years are indicated in cyan (males) or green (females). Regression lines belonging to these groups are indicated by the same color. The figure and its legend are reproduced from the article by Arai et al. (2015) distributed under the terms of the Creative Commons CC-BY license. Copyright © 2015, Elsevier.

Figure 5

Correlations of BAs in 288 individuals (612 complete measurements). A total of 612 complete measurements assessed from 288 individuals were included to estimate the correlations of BAs. BAs were broadly categorized into four groups according to the main biological structural levels where the BA measurements were implemented (A). We estimated the repeated-measure correlation coefficients between BAs and between BA residuals and illustrated the correlation coefficients in heat maps (B,C). Red and blue tiles represented positive and negative correlations, respectively; color density indicated the magnitude of correlation coefficients. All BAs were correlated to varying degrees (B). After regressing out CA from BAs, most of the original correlations were attenuated (C). BA, biological age; DNAmAge, DNA methylation age estimator; FAI, functional aging index; FI, frailty index; CA, chronological age. The figure and its legend are reproduced from the article by Li et al. (2020) distributed under the terms of the Creative Commons Attribution License. Copyright © 2020, Li et al.

Figure 6

Survival analyses of baseline BAs with the risk of all-cause mortality in subgroups classified by sex, baseline smoking status, and baseline age (one-BA models). A total of 845 individuals were included to estimate the mortality associations of BAs in subgroups. We used Cox regression models to estimate the change in mortality risk associated with a one-SD increment of the respective BA at baseline assessment (one-BA models). All models controlled for sex, educational attainment, smoking status, and BMI, stratified by participants' birth year, and accounted for left truncation and right censoring. Attained age was used as the time-scale and thus age was inherently adjusted for. BA-mortality associations were illustrated in the forest plot (A–C), in which points and horizontal lines denoted HRs (95% CIs) and point shapes and colors represented subgroups. The associations of BAs with mortality risk were generally stronger in women (except for Horvath DNAmAge and physiological age), more pronounced in the younger individuals (except for Horvath DNAmAge, physiological age and cognitive function), and a bit stronger in current or ex-smokers (for Horvath DNAmAge and DNAmGrimAge). BA, biological age; DNAmAge, DNA methylation age estimator; FAI, functional aging index; FI, frailty index; CA, chronological age; HRs (95%CIs), hazard Ratio (95% Confidence Interval). The figure and its legend are reproduced from the article by Li et al. (2020) distributed under the terms of the Creative Commons Attribution License. Copyright © 2020, Li et al.

Figure 7

Correlation between skeletal muscle TL (MTL) and LTL. The figure and its legend are reproduced from the article by Hiam et al. (2020) distributed under the terms of the Creative Commons Attribution License (CC BY 3.0). Copyright © 2020 Hiam et al.

Figure 8

TL in human tissues. Using a Luminex-based assay, TL was measured in DNA samples from >25 different human tissue types from 952 deceased donors in the GTEx project. TL within tissue types is determined by numerous factors, including zygotic TL, age, and exposures. TL differs across tissues and correlates among tissue types. TL in most tissues declines with age. The figure and its legend are reproduced from the article by Demanelis et al. (2020) with permission from AAAS (License Number 4910920603987). Copyright © 2020 The Authors.

Figure 9

Decline in telomere length with age differs between lymphocytes and granulocytes. The median telomere length in nucleated blood cells from 835 healthy individuals ranging from birth (umbilical cord blood) to 102 years of age were measured by flow FISH. The results were used to calculate the telomere attrition over time using linear regression in three age segments. (A) Median telomere length in lymphocytes (black dots). (B) Median telomere length in granulocytes (gray dots). Breakpoints in the piece-wise linear regression lines are marked by rectangles and the three age groups are marked by dotted vertical gray lines at 1 and 18 years. On average 8 individuals were tested per age-year. (C) At any given age, a wide range of telomere length was observed and the decline in telomere length with age in lymphocytes was more pronounced than in granulocytes. The shaded area represents the estimated length of subtelomeric DNA. Note that in older individuals, on average only 1–2 kb of telomere repeats were present in lymphocytes. The figure and its legend are reproduced from the article by Aubert et al. (2012a) distributed under the terms of the Creative Commons Attribution License. Copyright: © 2012 Aubert et al.