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The paternal age at conception effect on offspring telomere length: Mechanistic, comparative and adaptive perspectives

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Abstract

Telomeres are repeating DNA found at the ends of chromosomes that, in the absence of restorative processes, shorten with cell replications and are implicated as a cause of senescence. It appears that sperm telomere length (TL) increases with age in humans, and as a result offspring of older fathers inherit longer telomeres. We review possible mechanisms underlying this paternal age at conception (PAC) effect on TL, including sperm telomere extension due to telomerase activity, age-dependent changes in the spermatogonial stem cell population (possibly driven by ‘selfish’ spermatogonia) and non-causal confounding. In contrast to the lengthening of TL with PAC, higher maternal age at conception appears to predict shorter offspring TL in humans. We review evidence for heterogeneity across species in the PAC effect on TL, which could relate to differences in statistical power, sperm production rates or testicular telomerase activity. Finally, we review the hypothesis that the PAC effect on TL may allow a gradual multi-generational adaptive calibration of maintenance effort, and reproductive lifespan, to local demographic conditions: descendants of males who reproduced at a later age are likely to find themselves in an environment where increased maintenance effort, allowing later reproduction, represents a fitness improving resource allocation. This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
rstb.royalsocietypublishing.org
Review
Cite this article: Eisenberg DTA, Kuzawa CW.
2018 The paternal age at conception effect on
offspring telomere length: mechanistic,
comparative and adaptive perspectives.
Phil. Trans. R. Soc. B 373: 20160442.
http://dx.doi.org/10.1098/rstb.2016.0442
Accepted: 6 October 2017
One contribution of 19 to a theme issue
‘Understanding diversity in telomere
dynamics’.
Subject Areas:
evolution, genetics, health and disease and
epidemiology
Keywords:
intergenerational inertia, predictive adaptive
response, senescence, disposable soma,
evolutionary biology, plasticity
Author for correspondence:
Dan T. A. Eisenberg
e-mail: dtae@dtae.net
Electronic supplementary material is available
online at https://dx.doi.org/10.6084/m9.
figshare.c.3945181.
The paternal age at conception effect on
offspring telomere length: mechanistic,
comparative and adaptive perspectives
Dan T. A. Eisenberg1and Christopher W. Kuzawa2
1
Department of Anthropology, Center for Studies in Demography and Ecology, University of Washington,
Seattle, WA, USA
2
Department of Anthropology, Institute for Policy Research, Northwestern University, Evanston, IL, USA
DTAE, 0000-0003-0812-1862
Telomeres are repeating DNA found at the ends of chromosomes that, in the
absence of restorative processes, shorten with cell replications and are impli-
cated as a cause of senescence. It appears that sperm telomere length (TL)
increases with age in humans, and as a result offspring of older fathers inherit
longer telomeres. We review possible mechanisms underlying this paternal age
at conception (PAC) effect on TL, including sperm telomere extension due to
telomerase activity, age-dependent changes in the spermatogonial stem cell
population (possibly driven by ‘selfish’ spermatogonia) and non-causal con-
founding. In contrast to the lengthening of TL with PAC, higher maternal
age at conception appears to predict shorter offspring TL in humans.
We review evidence for heterogeneity across species in the PAC effect on TL,
which could relate to differences in statistical power, sperm production rates
or testicular telomerase activity. Finally, we review the hypothesis that the
PAC effect on TL may allow a gradual multi-generational adaptive calibration
of maintenance effort, and reproductive lifespan, to local demographic con-
ditions: descendants of males who reproduced at a later age are likely to find
themselves in an environment where increased maintenance effort, allowing
later reproduction, represents a fitness improving resource allocation.
This article is part of the theme issue ‘Understanding diversity in
telomere dynamics’.
1. Introduction
Telomeres are repeating nucleotide sequences found at the ends of chromosomes
that shorten in dividing cells as they proceed through the cell cycle [1,2]. As a
result, telomeres decrease in length with age in most human tissues [3] and
frequently in somatic tissues of metazoans [4].This shortening can eventually
place limits on further cell replication. Environmental factors, like smoking,
inflammation and infection shorten telomere length (TL), but also have
TL-independent effects on biology. Thus, correlations between TL and health
outcomes should not be assumed to be directly causal. Still, converging
evidence from molecular biology, and experimental and epidemiological studies
strongly suggest that shorter TL can directly influence health, particularly by
impairing immune and cardiovascular function [5– 8].
In contrast to the tendency for TL to decrease in length with age in most
human tissues, sperm TL shows a positive correlation with age [7,9]. In accord-
ance with the fact that DNA carried in sperm contribute half of each offspring’s
autosomal genome, offspring of older fathers have longerTLs [7,10]. This putative
paternal age at conception (PAC) effect on TL is intriguing because it appears to be
a rare case of intergenerational genetic plasticity in which the DNA passed on to
offspring is systematically changed based upon the age at reproduction of one’s
father. This finding, combined with evidence that the PAC effect accumulates
across at least two generations of recent ancestors, has led us to hypothesize
that the PAC effect on TL represents an example of adaptive intergenerational
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plasticity whereby an offspring’s investment in telomere-
dependent maintenance effort (e.g. immunity) might be
adjusted based on the average ages of reproduction of recent
male ancestors [7,11,12].
In this review, we explore the mechanistic, comparative and
evolutionary dimensions of the PAC effect on TL. To this end,
we first examine the biology of sperm formation which may
underlie the PAC effect. We then briefly consider evidence
that PAC associations with TL are caused by sperm TL increas-
ing with paternal age and whether a maternal age at
conception (MAC) effect on TL exists in humans. We proceed
to examine what is known about the PAC effect on TL across
species. Because telomeres are a general feature of eukaryotic
nuclear chromosomes [13], cross-species variability can
provide insights into the evolutionary bases and possible func-
tion of TL, including the PAC effect on TL. We conclude our
review by considering whether the PAC effect on TL could
represent an adaptation allowing relatively rapid intergenera-
tional adjustment of somatic maintenance effort—and
perhaps even female reproductive lifespan—based upon
predicted environmental and demographic conditions.
2. Mechanisms leading to PAC effect on TL
in humans
Evidence that telomeres lengthen with age in human sperm,
a finding that runs counter to their behaviour in most cell
lines and tissues, has led to a search to explain these findings.
Explanations fall into two broad and not mutually exclusive
categories. First, there is some evidence that especially high
levels of telomerase in testes could lead to a progressive
lengthening of TL with age in sperm. Second, there may be
selective loss of spermatogonial stem cells with shorter TL
and gains of spermatogonial stem cells with longer TL.
Below, we discuss the logic and empirical evidence for each
of these scenarios to help set the stage for a broader discus-
sion of telomeres from the perspectives of comparative and
evolutionary biology.
(a) Telomerase
Since males need to produce a constant supply of sperm via cell
division, mechanisms must be in place to allow this production
despite the shortening of TL which occurs with each round of
DNA replication. Telomerase, a reverse-transcriptase enzyme
that carries an RNA template molecule coding for the telomere
DNA sequence, is a chief mechanism via which telomeres
are lengthened. Telomerase is generally inactive in postnatal
human somatic tissues, but is active across adult life at high
levels in men’s testes [14], and appears to be critical for contin-
ued sperm production. Spermatogonia are the diploid stem
cells that give rise to a series of daughter cells, including pri-
mary spermatocytes (diploid) and secondary spermatocytes
(haploid) which eventually result in terminally differentiated
spermatozoa (sperm).The RNA component of telomerase is
expressed at high levels in human spermatogonia [15], con-
sistent with TLs being actively maintained via lengthening in
the relevant stem cell population. The telomerase RNA tem-
plate component is also highly expressed in primary and
secondary spermatocytes [15] suggesting that sperm TL exten-
sion with age could be at least partially due to extension of TL
not in the spermatogonia, but in differentiated spermatogonia
descendant cells. In humans, TLs increase between the
spermatogonia and primary spermatocyte stage and then
decrease with further differentiation towards spermatozoa
[16]. However, older men show similar or slightly greater
rates of TL decline between spermatogonia and differentiated
spermatozoa, suggesting that the PAC effect on sperm TL is
probably due to changes in spermatogonial stem cell TL [16].
If spermatogonial telomerase activity is sufficiently high it
could not only maintain TL in spite of continued sperm
production, but also progressively lengthen telomeres with
age [14,15,17– 21].
(b) Selective changes in spermatogonia
Selective survival and/or replication of spermatogonia with
long telomeres is another potentially compelling explanation
for the PAC effect on TL in humans—although one not
necessarily mutually exclusive with that of testicular telomer-
ase activity [22,23]. Evidence for such an effect comes from a
study documenting shifts in the distribution of spermatogo-
nial TL with age. As Kimura et al. [22] pointed out, if
spermatogonia TLs were extended at a uniform rate within
individuals (e.g. via telomerase) this leads to the expectation
that the distribution of sperm TL will shift to the right with
age while maintaining the same shape of the distribution
(figure 1a—Scenario A). Instead, these authors found that
older men not only have longer average sperm TL than
younger men, but that they have relatively fewer short and
more long telomeres in their sperm (figure 1b, consistent
with figure 1a—Scenario B) [22]. One possible explanation
for this change in distribution of sperm TL with age is selec-
tive changes wherein spermatogonia with shorter TL are less
likely to survive or replicate to form daughter spermatogonia
than spermatogonia with longer TL.
Furtherclues to the biology of the PACeffect may come from
examinations of not just the changes in the mean TL of sperm
and offspring with age, but also the changes in TL variance.
While analysis suggests that sperm TL variances increase as a
man ages [22,24], a twin study deploying a novel analysis
suggest that the range of sperm TL transmitted to the next gen-
eration decreases with paternal age (i.e. by comparing the
similarity in TLs between dizygotic twins with different aged
fathers). This apparent contradiction between sperm TL and
the TLs passed on by fathers to their offspring via sperm is unre-
solved. One possible explanation is that the increasing variance
in sperm TL with age is driven by greater within-sperm
(i.e. across chromosome end) variation in sperm TL, even as
between sperm mean TL variation decreases with age. Alterna-
tively, it is possible that there is a selective bias such that only a
subset of the sperm with a lower variance in TL in older men are
capable of fertilizing and producing viable offspring. Indeed,
there is some evidence that sperm functionality varies with TL
[25– 29]. Regardless, future studies should be attentive not just
to changes in mean TL in sperm and offspring with increasing
age, but also to changes in variances and distributions of TL
across chromosomes, sperm cells and offspring.
(c) Is the PAC effect on TL due to selfish
spermatogonial selection?
Related to the selection scenarios outlined above, de novo
germ line mutations that drive a recently described phenom-
enon called selfish spermatogonial selection (SSS) [30,31] could
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theoretically also contribute to a progressive lengthening of
average sperm TL with age. SSS is a phenomenon wherein
some spermatogonial stem cells acquire mutations that affect
the phenotype of the spermatogonia in a way that increases
their rate of division to form daughter spermatogonia.
Mutations which cause SSS seem to be in pathways regulating
self-renewal and differentiation of spermatogonial stem cells
[30] and have shared signatures with preneoplastic somatic
mutations [31,32]. SSS explains some autosomal-dominant
disorders that increase in prevalence with PAC [31,32].
Spermatogonial stem cells which are capable of expanding
in a pattern consistent with SSS seem to gain their selective
advantage via signalling pathways including PI3 K (phospha-
tidylinositol-3 kinase)/AKT, and STAT3 (signal transducer and
activator of transcription 3) [33,34]. These same pathways also
play a role in regulating telomerase activity [35– 37], hinting at
the potential for shared biology between SSS and the PAC on
TL—and possibly even that de novo mutations that drive SSS
could increase telomerase activity. Because these highly prolif-
erative cell lines become numerically dominant with time, any
tendency for these cells to express telomerase at higher levels,
and increase sperm TL, could cause average sperm TL to
increase with age.
Despite these shared molecular pathways between SSS and
the PACeffect on TL, it is presently unclear if SSS contribute to
the PAC effect on TL. Available data provide mixed support for
such a role. On the one hand, and as noted above, age-related
shifts in the distribution of sperm TL suggest that the PAC
effect on TL is at least partially driven by selective losses of
spermatogonia with shorter TL and gains in spermatogonia
with longer TL. These findings are potentially consistent with
the selective expansion of long TL spermatogonia described
in the SSS model. However, the SSS model also leads to the
expectation that SSS mutations increase exponentially in fre-
quency with age (see [38]). In contrast, this expectation is not
confirmed for the PAC effect on TL. Instead in humans both
sperm and offspring TL appear to increase linearly, not expo-
nentially, with advancing PAC. In contrast to the nonlinear
changes in SSS, telomerase activity extends telomeres during
the DNA replicative phase (S phase) of the cell cycle in
humans [39], such that a slight but persistent overshooting of
expression of testicular telomerase is expected to lead to a
linear increase in sperm TL with age, which is consistent
with the character of the PAC– TL association as documented
thus far in humans.
This line of investigation suggests multiple areas for future
research. First, while the PAC effect on TL has been observed to
be linear, large and well-powered studies should continue to
examine whether exponential models are a better fit for the
influence of male age on sperm and offspring TL, which
would be consistent with a role for SSS. Second, important evi-
dence for SSS has been demonstrated via examination of the
clustering of mutations within the testes [40]. SSS leads to the
expectation that spermatogonia with SSS mutations will tend
to cluster together as some spermatogonia symmetrically
divide and take over a region of testes [30]. If SSS is driving
the PAC effect on TL we should find that long TL in spermato-
gonia also tends to cluster together. Since mutations which
cause SSS are in pathways which also regulate telomerase
activity, it is possible that these SSS mutations tend to cause
increased telomerase activity and thereby longer telomeres. If
de novo mutations that drive SSS also cause higher telomerase
activity and longer TL then clusters of spermatogonia with
these mutations should also tend to have higher telomerase
activity and longer TL.
3. Is the PAC association with TL causal in
humans?
Despite the plausibility of the above scenarios linking advan-
cing paternal age with sperm telomere lengthening, it remains
possible that the PAC association with TL in humans is not
causal. The most obvious non-causal scenario is one in which
men who inherited longer TLs at birth tend to live healthier
and/or longer lives. Even if sperm TL did not change at all
with male age, we might then see that healthier men with
longer TL are more likely to reproduce at later ages and more
likely to volunteer to donate sperm (used in telomere studies)
at later ages. Because mortality is low in early adulthood and
high in late adulthood, this non-causal scenario leads to the
expectation that the PAC effect should be most apparent, or
A
B
12
young
old
frequency (%/kb)
03020
MW (kb)
MW (kb) 10
2
4
6
8
10
(a)(b)
Figure 1. Hypothetical and empirical changes in distributions of sperm TL with age. (a) Two hypothetical scenarios for shifts in TL distributions in sperm from young
and older donors. Scenario A depicts a uniform shift in the TL distribution towards longer telomeres in sperm of older men (interrupted blue line) from that of
younger men (red line). Scenario B depicts a reconfiguration of the distribution, so that shorter telomeres are disproportionably ‘under-represented’, while longer
telomeres are ‘over-represented’. (b) Frequency distributions of TLs in sperm from eight young (18– 19 years; red triangles) and eight older donors (50 –59 years;
blue circles) based on averaging the within-ejaculate variation in TL from southern blot telomere restriction fragment length analysis across individuals. Adapted
from Kimura et al. [22]. (Online version in colour.)
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perhaps only apparent, among offspring born to fathers of
advanced age. Contrary to this expectation, past studies point
to a PAC effect on sperm and offspring TL that is linear and
apparent even when fathers are young [22,41]. If men with
longer TL were more likely to donate sperm samples with
advancing age, than we would expect these donors to not
only have longer sperm TL, but also longer blood TL. Contrary
to this, within the same men, sperm TL shows a cross-sectional
increase with age while blood TL shows a cross-sectional
decrease [42]. Thus, although selection of men with longer TL
is a theoretically possible explanation for the PAC effect on
TL, multiple lines of evidence argue against this explanation.
Factors such as birth order or socio-economic status (SES)
might also be correlated with PAC but affect offspring TL via
pathways independent of changes in sperm TL with paternal
age. For example, older fathers could have higher SES and
being raised in a higher SES household could promote
increased TL in their offspring. If the PAC– TL association
were due to factors such as health, SES, or birth order we
would expect the PAC effect to be attenuated after statistical
adjustment for these factors, and to change across ecological
and cultural contexts where these factors and their inter-
correlations vary. Contrary to this, the PAC association with
offspring TL is reported in all human populations studied,
including in the US, Canada, UK, Denmark and the Philippines
[10,22,41,43]. The PAC effect has been found to not be attenu-
ated appreciably by adjustment for SES, birth order or other
factors [41,44]. Similarly, there is no evidence that the human
PAC effect varies with offspring age [10,22,41,43,45,46] (elec-
tronic supplementary material, table S1) [41], as might be
expected if age-related changes in paternal provisioning ability
led to variable rates of postnatal TL attrition across indivi-
duals born to fathers varying in age (see evidence for this in
European shag: [47]). Finally, our closest living relatives, chim-
panzees, show a similar PACTL association despite having
very different mating, rearing (e.g. no paternal care) and
social systems than humans [48]. Collectively, these findings
suggest that these other sources of confounding are unlikely
to account for the PAC– TL association.
4. Is there a maternal age effect on TL in
humans?
Because oocytes are all produced prenatally, while sperm are
continually produced throughout life, it is thought that there
is more potential for TL plasticity with age in sperm than in
oocytes. Nonetheless, studies in humans tend to show a positive
correlation between MAC and offspring TL. One challenge in
assessing a MAC effect on offspring TL comes from the typi-
cally strong age correlation between reproductive partners in
humans. That is, offspring of older mothers may have longer
TL simply because the offspring’s fathers are also older.
Supporting the hypothesis that PAC is of primary impor-
tance in determining offspring TL in humans, controlling for
MAC in regression models tends to lead to a larger PAC
effect than when not controlling for MAC (figure 2a—most
values greater than 1). Comparing the PAC and MAC effects
included together in the same regression model, most human
studies show evidence for a negative association between
MAC and offspring TL (figure 2b—most values less than 0).
Both of these patterns are particularly apparent in larger
studies (farther to the right in both figures), which due to
their greater statistical power are likely to have more reliable
estimates. The Eisenberg et al. [41] study of 295 Filipino
women stands out as an outlier among the studies investi-
gated. Of note, that study focused on a small subset of the
sample (16% of a larger sample) for which data on PAC and
MAC were opportunistically available. In contrast, another
cohort from the same population (the offspring of these
women) with more complete MAC and PAC data (Eisenberg
et al. [41], N¼1711) shows results more consistent with other
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Kimura et al. [22]
Unryn et al. [10]
Kimura et al. [22]
Eisenberg et al. [41]
Arbeev et al. [50]
Arbeev et al. [50]
Eisenberg et al. [41]
Kimura et al. [22]
Broer et al. [46]
44 111 235 295 995 1182 1711 1954 5127
PAC b with MAC in model/PAC b without
MAC in model
N
(a)
–1.0
–0.5
0
0.5
1.0
1.5
Kimura et al. [22]
Unryn et al. [10]
Kimura et al. [22]
Eisenberg et al. [41]
Arbeev et al. [50]
Arbeev et al. [50]
Eisenberg et al. [41]
Kimura et al. [22]
Broer et al. [46]
44 111 235 295 995 1182 1711 1954 5127
MAC b/PAC b (both together in same model)
N
(b)
Figure 2. Comparing the relative strength of the PAC and MAC effects on offspring TL in human studies: (a) assesses how the PAC effect on offspring TL changes
after controlling for the MAC effect. Calculated by examining PAC effect in a regression model including MAC and one not including MAC and then dividing PAC effect
in first model by PAC effect in second. Values greater than 1 indicate that PAC effect increases when controlling for MAC, suggesting that PAC effect is not driven by
MAC. (b) Assesses direction and relative magnitude of MAC effect compared to PAC effect (the ratio of MAC effect/PAC effect). Values greater than 1 indicate a greater
positive MAC effect than PAC effect. Values less than zero indicate MAC effects in opposite direction of PAC effects (i.e. shorter offspring TL with older MAC). Statistics
from Eisenberg et al. [41] has been updated from the original publication based on measurement improvements in the same dataset [49]. Studies with multiple
entries include separate estimates for independent cohorts. (Online version in colour.)
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studies. We speculate that biases introduced by opportunistic
sampling might account for the outlier results among the
older cohort in this study.
The tendency towards a negative association between
MAC and offspring TL (figure 2b) might be explained if
oocytes that had fewer mitotic divisions tend to be ovulated
earlier in the lifecycle than those ovulated later—although it
is not clear if this occurs in humans [51]. In cows, it has been
shown that TLs in immature oocytes are shorter in older
cows than in younger ones, providing some support for this
notion [52]. However, in cows TLs elongate during embryo
development up until the blastocyst stage and TL has not
been shown to differ between young and old cows at the blas-
tocyst stage [52], suggestingthat initial differences in oocyte TL
may be obscured or eliminated through TL changes over the
course of development. Because telomere and telomerase
biology vary markedly across species [53,54], it may be that
more of the initial oocyte differences in TL with MAC are
retained with age in humans compared to other species.
Together, available evidence suggests that, at least in
humans, older PAC probably acts to extend offspring TL
while older MAC may slightly decrease offspring TL. This
apparent negative MAC effect on TL could result if oocytes
formed after more mitotic divisions, which will tend to
decrease TL, tend to be ovulated later in life. Evidence in
other species, among which parental ages are less strongly
correlated and can be experimentally manipulated, may
provide more definitive answers.
5. Cross-species evidence
Because telomeres are general features of eukaryotic nuclear
chromosomes [13], additional insights into their function, and
the extent of variability and possible function of the PAC
effect on TL, may be gained by looking at these processes
across species differing in life-history and reproductive strat-
egies. Non-human studies also sometimes have the advantage
of allowing the use of experimental approaches (e.g. selecting
the age of mating), low correlations between parental ages,
and more invasive and precise tissue sampling. High testicular
telomerase levels are probably a general feature of mammals;
indeed, high telomerase activity has been found in testes in
all mammalian species in which it has been examined, includ-
ing 15 rodent species spanning from the small, short-lived
mouse to the long-lived naked mole-rat and large capybara
[54], cats, dogs [55], long-tailed macaques [21] and humans [14].
As summarized in table 1, the PAC effect on TL has only
been studied in eight species. Findings are highly variable
across species, hinting at rapid evolution of telomere/sperm
production biology. Only half of the studied species show stat-
istically significant associations between PAC and offspring/
sperm TL—two of these associations are negative and two are
positive. Although the remaining null findings could reflect
the true nature of the biology of these species, it is important
to also consider the effect of statistical power as a limitation.
All else equal, the greater the range of variation in PAC, the
greater the statistical power to detect relationships. As illus-
trated in supplementary figure 1, assuming the yearly PAC
effect size observed in humans, PAC effects in species with
limited variation of PAC require large sample sizes to detect
an association. For example, samples greater than 1000 and
4000, respectively, would be needed to reliably detect a PAC
of human magnitude in European shagsand Soay sheep. Incon-
trast, assuming the much greater PAC effect found in
chimpanzees, the more manageable sample sizes of 80 and
346 would be sufficient. Conversely, the significant negative
PAC effects found in mice and sand lizards, despite limited
power, imply a very large magnitude effect on TL in order to
be detected in these species (table 1). The negative PAC effects
on TL in mice shows that even high testicular telomerase
activity, as has been documented in this species [54], may not
be sufficient to increase sperm TL with age, or that testicular tel-
omeraseactivity is by itself insufficient to explain the PAC effect.
Building on the idea that the continual need for production
of sperm is a key driver of the PAC effect on TL, Eisenberg et al.
[48] predicted that the PAC effect should be larger in species
with greater sperm production rates. This prediction gains
only limited support in the sparse available data. The chimpan-
zeehuman comparison is particularly informative given
the close phylogenetic relationship between the two species.
Chimpanzees experience sperm competition secondary to
Table 1. Paternal age effect on offspring TL across species. Bold values indicate p,0.05.
genus species common name N
PAC s.d.
(years) r
a
p
relative
testis size
b
refs
Lacerta agilis sand lizard 12 1.38
c
20.59 0.041 [56]
Phalacrocorax aristotelis European shag 204 4.38 þ0.43 [47]
Acrocephalus arundinaceus great reed warbler 154 þ0.7 [57]
Mus musculus mouse 12
c
0.39 2
0.05 0.5 [58]
Ovis aries Soay sheep 318 2.17 0.066 0.238 4.9/1.2
d
[59]
c
Macaca fascicularis
e
long-tailed macaque 9 7.8 þNS 2.3 [21]
Homo sapiens Human 144 8.2 0.15 0.03 0.5 [48]
Pan troglodytes chimpanzee 40 6.4 0.42 0.009 1.5 [48]
a
Correlation values if reported, otherwise ‘þ’ indicates positive association and ‘2 negative association.
b
Ratio of observed mass of testis to that predicted by body mass from [60].
c
Personal communication.
d
Breeding season/non-breeding season calculated from [61].
f
Testicular TL instead of offspring TL.
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their promiscuous mating system, which has led to a higher
rate of sperm production compared to humans [62,63]. Consist-
ent with an effect of sperm production rate on the magnitude of
the PAC effect on TL, chimpanzees show increases in TL with
each year of delayed paternal conception that are an estimated
six-fold greater than in humans ( p¼0.026) [48]. In contrast,
Soay sheep, which have a much larger relative testes size
(and probably, sperm productive rates) even than chimpan-
zees, lack a discernible PAC effect on TL (table 1). Possibly
explaining this, Soay sheep are seasonal breeders whose rela-
tive testes size reduces considerably in the off season
(table 1), which probably reflects an attenuated sperm pro-
duction rate [64]. Additionally, as noted above, statistical
power to detect a PAC effect on TL may be low in this species.
In sum, while all 19 measured mammalian species show
evidence for high testicular telomerase activity, evidence of
PAC associations with offspring TL show little consistency
across species. Depending on the species, PAC has been
shown to relate to offspring TL in positive or negative direc-
tions, while in others there is no evidence for an association.
Some of the null findings might be a result of low statistical
power. The most consistent pattern is a tendency for catarrhine
primates to have positive PAC effects—as evident from signifi-
cant positive relationships between PAC and offspring TL in
humans and chimpanzees and suggestive evidence for a
similar relationship in a small sample of long-tailed macaques.
6. Does the PAC effect on TL allow adaptive
transmission of plasticity-generated genetic
information across generations?
Thus, evidence for relationships between PAC and offspring
TL are most consistently observed in humans and their close
primate kin. Although it is presently uncertain if there is a
direct causal relationship between PAC and offspring TL in
humans, such an effect is a likely explanation in our view, in
light of the converging evidence reviewed above (§3). Irrespec-
tive of the specific underlying mechanisms, an effect of PAC on
offspring TL would represent an unusual form of intergenera-
tional genetic plasticity in which the DNA passed on to
offspring varies systematically based on the father’s age at
reproduction. Age at reproduction is an event that is of funda-
mental importance from an evolutionary perspective.
Organisms have limited energy and other substrate that can
be devoted to growth, reproduction, maintenance, activity
or storage [65]. According to some models of aging [66], the
optimal allocation of resources varies primarily based on una-
voidable mortality and other environmental circumstances.
When the likelihood of living and reproducing into the
future are high, intensive investment in maintenance effort at
the expense of reduced immediate reproductive expenditure
can be a good fitness strategy. Conversely, when extrinsic mor-
tality risks are high, optimism about the future is reduced,
shifting the balance in favour of current reproductive expendi-
ture and at a cost to maintenance functions. This evolutionary
life-history perspective has lead us to suggest that the PAC
effect on TL may represent an adaptation whereby TLs
passed on to offspring are systematically altered to improve
the fit to the environmental and demographic setting he or
she is likely to encounter across the life course [7]. That is,
males with the ability to adjust the TL of their offspring in
response to their own age of reproduction may have had off-
spring with higher average fitness—thus selecting for this
capability to adjust sperm TL with age.
One obvious limitation to the utility of the PAC effect on TL
as a reliable signal of the expected age at reproduction is the
noise introduced by stochastic processes, such as the effect of
birth order. A father may sire multiple children at different
ages, thus potentially sending different age signals to offspring
facing the same environment. This problem led Eisenberg [7] to
suggest that TL might not only reflect the father’s age at con-
ception, but could, by virtue of the high fidelity of DNA
replication, also reflect the conception ages of multiple gener-
ations of paternal ancestors going back in time. In this
scenario, the TL that an individual receives would reflect not
just one’s own father’s age, but also that of the grandfather
and other more distant male ancestors, thereby providing a
rolling average age of recent reproductive timing in the lineage
(for a related example, see [67]). Consistent with this pre-
diction, a subsequent study showed that the paternal
grandfather’s age at conception of the father predicted the
grandchild’s TL, independent of and additive to, the effect of
the father’s age at conception [41]. Studies of socio-economic
status across many generations show high levels of continuity
within families across multiple countries around the world
[68], suggesting a level of consistency that could make the
PAC effect on TL a good adaptive signal of local conditions.
We also recognize, however, that this same stability in socio-
economic status may complicate efforts to distinguish a direct
PAC effect on offspring TL from other processes like niche
construction, genetic, epigenetic and cultural transmission.
It is important to note that, older fathers transmitting longer
telomeres to their offspring than younger fathers do not imply
that TLs increase with each generation. The testes are formed
from the intermediate mesoderm early in pre-natal develop-
ment [69]. Sperm production in the testis begins at puberty,
but adult-like sperm concentration, morphology and motility
are not evident until some years later [69,70]. This developmen-
tal sequence involves many cell divisions, which probably
allow opportunities for TL shortening due to cell replication
and DNA damage, prior to the onset of any mechanisms that
cause lengthening of TL in spermatogonia with age. It is pre-
sently not clear at what age (if any) a man would need to
reproduce in order to transmit longer telomeresto his offspring
than he himself received. However, all else equal, intergenera-
tional lengthening of sperm TL is made more likely as
the conception ages of one’s father, and his recent paternal
ancestors, is delayed.
(a) What are the potential benefits of inheriting long
telomeres from late-reproducing male ancestors?
If the PAC effect on TL does provide a reliable cue of local
demographic conditions, as we hypothesize, it is of interest
to consider the biological changes that might be calibrated in
response to this information, and the trade-offs probably
involved. As alluded to above, because TL provides a limit
on how many times a cell can replicate, longer TL is expected
to enhance cell proliferation-dependent functions. Because
mounting an immune response often involves cell prolifer-
ation-dependent processes, this leads to the expectation that
longer TL should manifest as more robust cell-proliferation-
dependent components of immunity, and possibly a slowing
of the pace of immune senescence with advancing age.
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Indeed, experimental and longitudinal observational evidence
in vitro, in mice, and in humans suggests that longer TL pro-
motes resistance to infection, and that these effects are
evident in young adulthood and possibly infancy [7,71– 74].
Longer TL are also likely to reduce the likelihood of athero-
sclerosis by improving vascular maintenance and reducing
the build-up of senescent cells in atherosclerotic plaques
[75,76]. Additionally long TLs probably improve wound
healing, which also relies upon cellular proliferation [77].
Another biological function that depends upon cell prolifer-
ation is gamete formation. As discussed above, in females the
pool of oocytes is established in its entirety during fetal life,
and menopause occurs when the pool of follicles is depleted.
It has been hypothesized that TL could influence the pace of
female reproductive senescence, including late-life fecundity,
by influencing the pool of initial oocytes formed, and their via-
bility as a woman ages [78,79]. There is evidence that TL
measured in blood cells is shorter in women who experience
menopause at an earlier age—although this finding has not
been replicated across all ethnic groups [78– 80]. While links
between TL and female reproduction await additional vali-
dation in humans, they add to the list of candidate cell
replication-dependent processes in offspring that might benefit
as a result of inheriting longer TL from older fathers.
(b) The potential costs of inheriting long telomeres
Given that longer telomeres very probably improve functions
that require cell proliferation, it also seems likely that long tel-
omeres will carry costs. Otherwise we would expect the rapid
evolution and fixation of inherited (i.e. germ line) long telo-
meres to avoid any functional constraints imposed by short
telomeres, and thus no association between TL and fitness
relevant phenotypes in the general population. The most com-
monly cited fitness cost associated with inheriting long TL is an
increased risk of cancer. The theoretical reasons to expect a link
between longer telomeres and cancer risk are clear: because
accumulation of oncogenic mutations is dependent on cell
replication, a cell lineage with shorter TL is less likely to gain
the necessary mutations for cancer development before cell
proliferation stops due to critically short TL [76]. However,
there are also pathways via which longer TL could promote
cancer protection. Short TLs are known to cause chromosomal
instability and fusions which can promote cancer, although it
has been argued that this only occurs in rare pathological con-
ditions and is of limited relevance to the general population
[76]. Longer TL also promotes improved immune function
[7,71– 73], which plays a key role in combating cancer-inducing
pathogens and parasites (e.g. human papillomavirus and
Helicobacter pylori), as well as fighting off cancers once they
begin to develop [7,81].
Empirical results have not yet given a clear resolution to the
TL-cancer question. Although telomerase shows high activity
in the vast majority of cancers and the activation of telomere
maintenance pathways in somatic tissues is likely to be critical
for cancer development, it is less clear what role inheriting
longer telomeres—germ line TL—plays in cancer risk [7].
Results from prospective human studies tend to show that
longer somatic TL is associated with decreased cancer risk or
has no association with cancer at all [8285]. In contrast, gen-
etic polymorphisms associated with longer TL tend to
predict increased cancer risk—particularly for rarer cancers
[6,84,86,87]. These contrasting results could be due to the fact
that measured somatic TL are confounded by environmental
variables that shorten TLs and increase cancer risks via other
pathways (e.g. smoking), or pleiotropic effects of TL-associated
genetic polymorphisms that increase cancer risk via germ line
TL-independent pathways [84,88,89].
Another factor that reduces the likelihood that cancer has
been a key factor shaping within-species variation in TL in
humans is the fact that in human cancer mortality is very
rare until middle age and mostly occurs in the elderly [7].
Additionally, human cancer is thought to have been much
less prevalent before recent changes coincident with the demo-
graphic transition and industrialization [7]. While humans
engage in extensive intergenerational transfers of resources
that allow us to continue to contribute to inclusive fitness late
in life, the force of selection still declines with age in
humans—such that late-life traits are less shaped by natural
selection than those earlier in life [7]. The presence of a PAC
effect on TL in chimpanzees, among whom many of these fac-
tors do not apply, suggests that the PAC effect on TL that is
documented in human populations very probably predates
the human– chimpanzee split. Given this, other TL-influenced
(i.e. cell proliferation dependent) phenotypes which influence
health earlier in life, such as immunity and wound healing
ability, may be more likely to shape optimal TL.
In the absence of clear costs to longer telomeres, or of
benefits of having shorter TL, Eisenberg proposed the thrifty
telomere hypothesis [7]. The thrifty telomere hypothesis suggests
that longer telomeres promote increased maintenance effort
and thereby health and longevity—but that this comes at ener-
getic costs. Increased investments in long-term maintenance
mean less energy available for current reproductive invest-
ments, a strategy that could reduce fitness in environments
with high extrinsic mortality risks. By the reasoning of this
model then, in low mortality environments, offspring inherit
longer telomeres from multiple recent generations of male
ancestors, who reproduced on average at later ages. This
signal of late-life survival and reproduction in turn facilitates
a shift in resource allocation away from immediate repro-
duction and in favour of enhanced maintenance effort and
lifespan extension—via boosted immunity, wound repair,
and perhaps even oocyte number and longevity. This model
leads to several testable predictions, including that individuals
who inherit longer TL will exhibit evidence for greater main-
tenance expenditures at an expense to reproduction, and that,
controlling for potential confounders, secular trends in PAC
will predict improved immune function in progeny.
7. Conclusion
The putative PAC effect on TL represents a novel type of inter-
generational plasticity. We are not aware of any other such
systematic alteration to DNA sequences that are transmitted
to offspring. As we have reviewed, there is convergent evi-
dence that this PAC effect on TL is due to progressive
lengthening of sperm TL as human males age (as we note, it
is at present less clear how widespread this phenomena is in
other species). The biological mechanisms underlying these
increases in sperm TL are less certain, but could include
some combination of high testicular telomerase activity, selec-
tive loss of spermatogonia with short TL and/or increased
proliferation of spermatogonia with long TL. We also reviewed
parallels between selfish spermatogonial selection and the PAC
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7
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effect on TL which might reflect shared biology. Unlike the
plasticity created by continued sperm production with age,
oocytes are produced prenatally and correspondingly there is
limited evidence for a MAC effect on offspring TL. If a MAC
effect exists, it is likely to be negative rather than positive.
The PAC effect on TL has only been studied across eight
species and shows considerable variation, with chimpanzees
showing a positive six-fold greater PAC effect than humans,
other species showing negative PAC effects and several show-
ing no associations at all. We note that statistical power to
detect PAC effects will be limited by a combination of variation
in PAC within a species and study sample size, and that some
past studies are thus underpowered to detect human-sized
PAC effects. In the future, appropriately powered comparative
studies will help clarify the extent, and possible function, of
PACTL associations across a wider range of species.
We have suggested that the PAC effect on TL could rep-
resent an adaptive intergenerational signalling mechanism.
Specifically, age at reproduction is a key factor shaping life-
history strategies and having had multiple generations of
recent male ancestors who reproduced at later ages may
indicate that similar demographic conditions are likely to be
experienced in the near future. Longer TLs are postulated
to promote increased maintenance effort, particularly via
improved immune function and wound healing. Maintenance
effort is energetically costly and has a greater fitness payoff in
contexts of lower extrinsic mortality and delayed reproduction.
In addition, there is emerging evidence that inheriting longer
telomeres could also allow increased proliferation of follicles
in female offspring, which might delay the timing of meno-
pause and cessation of reproductive senescence when recent
male ancestors have delayed reproduction themselves.
Other similar adaptive intergenerational signalling mech-
anisms have been suggested [12] but it remains unclear how
common or adaptive such phenomena are [90– 92]. The PAC
effect on TL is noteworthy, and distinct from many examples
of maternal-offspring signalling, for being multi-generational
[41] which may allow for the communication of an integrated
signal reflecting average age at conception among multiple
recent generations of paternal ancestors [12]. Further, the
PAC effect on TL is based in changes to DNA sequences
and thus provides an intergenerational signalling pathway
that is mechanistically well-established and of high fidelity.
Data accessibility. This article has no additional data.
Authors’ contributions. D.T.A.E. led the researching, writing and design of
the article. C.W.K. contributed to refining the ideas, writingand revising.
Competing interests. We have no competing interests.
Funding. We received no funding for this study.
Acknowledgements. Thanks to Neil Metcalfe, Tiffany Pan, Rebecca Ortega,
Robert Tennyson, Peter Rej and an anonymous reviewer for feedback
on an earlier draft of this manuscript; Abraham Aviv, Anne Goriely,
Alexander Hill, and ‘Understanding Diversity in Telomere Dynamics’
conference attendees and organizers, for valuable discussions; Mats
Olsson, Pablo Bermejo-A
´lvarez, Dan Nussey and Hannah Froy for
sharing data for table 1; and Karl Riabowol for sharing data used to
test whether PAC varies by own age in this manuscript.
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... Previous studies have also reported an increase in sperm TL (TL plasticity increases with age and is higher in sperms than in oocytes), which may be a potential reason for the newborn to inherit longer telomeres in older fathers. The increase in sperm TL and its underlying biological mechanisms are less known; however, selective loss of spermatogonia with short TL due to apoptosis and an increase in proliferation of spermatogonia with high testicular telomerase activity causes the TL to be longer [37][38][39]. ...
Article
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Telomeres, markers for cellular senescence, have been found substantially influenced by parental inheritance. It is well known that genomic stability is preserved by the DNA repair mechanism through telomerase. This study aimed to determine the association between parents–newborn telomere length (TL) and telomerase gene (TERT), highlighting DNA repair combined with TL/TERT polymorphism and immunosenescence of the triad. The mother–father–newborn triad blood samples (n = 312) were collected from Ziauddin Hospitals, Pakistan, between September 2021 and June 2022. The telomere length (T/S ratio) was quantified by qPCR, polymorphism was identified by Sanger sequencing, and immunosenescence by flow cytometry. The linear regression was applied to TL and gene association. The newborns had longest TL (2.51 + 2.87) and strong positive association (R = 0.25, p ≤ 0.0001) (transgenerational health effects) with mothers’ TL (1.6 + 2.00). Maternal demographics—socioeconomic status, education, and occupation—showed significant effects on TL of newborns (p < 0.015, 0.034, 0.04, respectively). The TERT risk genotype CC (rs2736100) was predominant in the triad (0.6, 0.5, 0.65, respectively) with a strong positive association with newborn TL (β = 2.91, <0.0011). Further analysis highlighted the expression of KLRG 1+ in T-cells with shorter TL but less frequent among newborns. The study concludes that TERT, parental TL, antenatal maternal health, and immunity have a significantly positive effect on the repair of newborn TL.
... It might likely lead to adverse impact on health outcomes. Second, paternal age has been shown to play a role in the vertical transmission of telomere length [32][33][34]. Previous reports have provided evidence that lung function in children and adults is associated with telomere length [35][36][37][38]. ...
Article
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Background Epidemiological studies suggest that advanced paternal age impact offspring health, but its impact on respiratory health is unclear. This study aimed to investigate the association of paternal age with lung function and fraction of exhaled nitric oxide (FeNO) in children. Methods We analyzed data from 1330 single-born children (576 girls, 43.3%; mean age, 6.4 years), who participated in the Longitudinal Investigation of Global Health in Taiwanese Schoolchildren (LIGHTS) cohort and received measurements of lung function and FeNO at 6-year follow-up visits. Covariate-adjusted regression analyses were applied. Results Every 5-year increase in paternal age at birth was associated with 0.51% decrease in FEV1/FVC ratio (95% CI − 0.86 to − 0.15; p = 0.005) and 19.86 mL/s decrease in FEF75 (95% CI: − 34.07 to − 5.65; p = 0.006). Stratified analyses revealed that increasing paternal age at birth was associated with decreasing FEV1/FVC ratio and FEF75 only among children with prenatal exposure to environmental tobacco smoke (ETS) or not being breastfed. Sensitivity analyses using paternal age as a categorical variable found decreasing FEV1/FVC ratio and FEF75 in the groups of paternal age 35–39 and ≥ 40 years. There was no association of paternal age at birth with FeNO. Conclusion Our findings provide novel evidence linking advanced paternal age at birth with decreasing lung function in children at school age. Children with prenatal exposure to ETS or not being breastfed are more vulnerable to the adverse effect of advanced paternal age on childhood lung function. Further studies are warranted to confirm this novel adverse effect of advanced paternal age.
... Furthermore, the AGR breed is also characterized by high genome stability, probably due to the environment and mild zootechnical selective pressure (Ciotola et al., 2005). Both AGR and HFR were healthy, sampled simultaneously, and reared in the same area and under similar conditions, confirming that telomeres are also determined by heritable quantitative traits derived from both genetic and epigenetic mechanisms (Eisenberg & Kuzawa, 2018). Furthermore, we noticed that relative TL in AGR is naturally longer than in HFR at the same age and lactation stages ( Table 1). ...
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Studies into telomere length in cattle are relatively recent and have focused mainly on the Holstein Friesian cattle breed, making it arduous to evaluate the correlation with ageing due to the early age of culling in this breed. Telomere length provides information about the productive lifespan and the quality of farm management, complying with the ‘One Health’ approach. This study evaluated telomere length in Agerolese cattle, an autochthonous dairy breed characterized by a long productive lifespan (13 years). Multiplex quantitative PCR estimated telomere length in DNA extracted from blood and milk matrices. Interestingly, the results showed longer telomeres in Agerolese (compared to the Holstein Friesian cattle control group), with a negative correlation between telomere length and increasing age and a synchronous trend between blood and milk samples, with a positive correlation between them.
... Still, a stressful environment rather than vertical transmission may have a stronger influence on telomere shortening in BD ( Powell et al., 2018 ;Shalev et al., 2013 ;Valdes et al., 2005 ). Indeed, sperm telomere length increases with age in humans, and as a result offspring of older fathers inherit longer telomeres ( Eisenberg and Kuzawa, 2018 ). ...
Article
Parenthood age may affect the risk for the development of different psychiatric disorders in the offspring, including bipolar disorder (BD). The present systematic review and meta-analysis aimed to appraise the relationship between paternal age and risk for BD and to explore the eventual relationship between paternal age and age at onset of BD. We searched the MEDLINE, Scopus, Embase, PsycINFO online databases for original studies from inception, up to December 2021. Random-effects meta-analyses were conducted. Sixteen studies participated in the qualitative synthesis, of which k = 14 fetched quantitative data encompassing a total of 13,424,760 participants and 217,089 individuals with BD. Both fathers [adjusted for the age of other parent and socioeconomic status odd ratio – OR = 1.29(95%C.I. = 1.13–1.48)] and mothers aged ≤ 20 years [(OR = 1.23(95%C.I. = 1.14–1.33)] had consistently increased odds of BD diagnosis in their offspring compared to parents aged 25–29 years. Fathers aged ≥ 45 years [adjusted OR = 1.29 (95%C.I. = 1.15–1.46)] and mothers aged 35–39 years [OR = 1.10(95%C.I. = 1.01–1.19)] and 40 years or older [OR = 1.2(95% C.I. = 1.02–1.40)] likewise had inflated odds of BD diagnosis in their offspring compared to parents aged 25–29 years. Early and delayed parenthood are associated with an increased risk of BD in the offspring. Mechanisms underlying this association are largely unknown and may involve a complex interplay between psychosocial, genetic and biological factors, and with different impacts according to sex and age range. Evidence on the association between parental age and illness onset is still tentative but it points towards a possible specific effect of advanced paternal age on early BD-onset.
... One reason is that males accumulate deleterious mutations in their germ-line at an ever-increasing rate as they age (Beck and Promislow, 2007), thereby reducing the quality of genes passed on to the next generation, which potentially favors cancer (e.g., see Choi et al., 2005 for an example that older paternal age increases the risk of breast cancer in female offspring). In addition, in several species -at least in humans and chimpanzees -sperm telomere length is positively correlated with male age, leading to a positive correlation between paternal age at conception and offspring telomere length (Eisenberg and Kuzawa, 2018;Eisenberg, 2019;Eisenberg et al., 2019). Longer telomeres in descendants of old fathers are likely to predispose the novel generation to a higher risk of cancer since cells have a greater chance to accumulate bad mutations before replicative senescence occurs and eliminates them (e.g., Aviv et al., 2017). ...
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Reproduction is one of the most energetically demanding life-history stages. As a result, breeding individuals often experience trade-offs, where energy is diverted away from maintenance (cell repair, immune function) toward reproduction. While it is increasingly acknowledged that oncogenic processes are omnipresent, evolving and opportunistic entities in the bodies of metazoans, the associations among reproductive activities, energy expenditure, and the dynamics of malignant cells have rarely been studied. Here, we review the diverse ways in which age-specific reproductive performance (e.g., reproductive aging patterns) and cancer risks throughout the life course may be linked via trade-offs or other mechanisms, as well as discuss situations where trade-offs may not exist. We argue that the interactions between host-oncogenic processes should play a significant role in life-history theory, and suggest some avenues for future research.
... It is possible that the role of parental age on TL has different biological explanations. Increased maternal age may be a marker of a slower rate of biological aging and longevity, and this potentially reflects possible genetic variants that may play a role in exceptional survival [52,53], whereas increased paternal age is associated with elongated sperm TL [54,55], both of which may correlate with longer TL in the offspring. Furthermore, when assessing other early life environmental factors that are associated with the TL-ADHD association, we found that increased infant SHS exposure at one month was independently associated with shortened infant TL and increased ADHD symptoms at age two years. ...
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Environmental factors can accelerate telomere length (TL) attrition. Shortened TL is linked to attention deficit/hyperactivity disorder (ADHD) symptoms in school-aged children. The onset of ADHD occurs as early as preschool-age, but the TL-ADHD association in younger children is unknown. We investigated associations between infant TL and ADHD symptoms in children and assessed environmental factors as potential confounders and/or mediators of this association. Relative TL was measured by quantitative polymerase chain reaction in cord and 12-month blood in the birth cohort study, the Barwon Infant Study. Early life environmental factors collected antenatally to two years were used to measure confounding. ADHD symptoms at age two years were evaluated by the Child Behavior Checklist Attention Problems (AP) and the Attention Deficit/Hyperactivity Problems (ADHP). Associations between early life environmental factors on TL or ADHD symptoms were assessed using multivariable regression models adjusted for relevant factors. Telomere length at 12 months (TL12), but not at birth, was inversely associated with AP (β = −0.56; 95% CI (−1.13, 0.006); p = 0.05) and ADHP (β = −0.66; 95% CI (−1.11, −0.21); p = 0.004). Infant secondhand smoke exposure at one month was independently associated with shorter TL12 and also higher ADHD symptoms. Further work is needed to elucidate the mechanisms that influence TL attrition and early neurodevelopment.
... The activity of telomerase differs between germ cells and somatic cells. Thus, the effect of telomere length and maintenance may be different in the germline versus somatic cells or cancer [67]. Telomerase is the ribonucleoprotein enzyme responsible for synthesising telomere repeats onto the ends of chromosomes to maintain telomere stability and length [68]. ...
Article
Background: Genetically predicted leukocyte telomere length (LTL) has been evaluated in several studies of childhood and adult cancer. We test whether genetically predicted longer LTL is associated with germ cell tumours (GCT) in children and adults. Methods: Paediatric GCT samples were obtained from a Children's Oncology Group study and state biobank programs in California and Michigan (N = 1413 cases, 1220 biological parents and 1022 unrelated controls). Replication analysis included 396 adult testicular GCTs (TGCT) and 1589 matched controls from the UK Biobank. Mendelian randomisation was used to look at the association between genetically predicted LTL and GCTs and TERT variants were evaluated within GCT subgroups. Results: We identified significant associations between TERT variants reported in previous adult TGCT GWAS in paediatric GCT: TERT/rs2736100-C (OR = 0.82; P = 0.0003), TERT/rs2853677-G (OR = 0.80; P = 0.001), and TERT/rs7705526-A (OR = 0.81; P = 0.003). We also extended these findings to females and tumours outside the testes. In contrast, we did not observe strong evidence for an association between genetically predicted LTL by other variants and GCT risk in children or adults. Conclusion: While TERT is a known susceptibility locus for GCT, our results suggest that LTL predicted by other variants is not strongly associated with risk in either children or adults.
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The length of the telomeric DNA and polymorphism of the TERT (Telomerase Reverse Transcriptase) gene can be the basis for the development of molecular genetic markers for the productive traits of agricultural animals, in particular pigs. The purpose of the work was to analyze the databases of the primary structure of the pig TERT gene, to determine single nucleotide polymorphisms (SNPs), to develop a DNA system for animal typing based on the TERT gene. Samples of biomaterials (blood, bristles) for DNA typing were selected from the leading farms of Ukraine in groups of 4 breeds of pigs and hybrid animals. Isolation of DNA from biomaterial was carried out using the Chelex 100 reagent. Genotyping of animals by the telomerase locus was carried out on the basis of standard methods of polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The alignment of nucleotide sequences during the analysis of the primary structure of the TERT gene was carried out using the MegaX software and the Blast service. Design of the structure of oligonucleotide primers for PCR was carried out using the computer program Primer3Plus. During the development of the method of pigs genotyping according to TERT gene, a database analysis was carried out regarding the primary structure of the gene, a region of the gene with a significant number of SNPs was identified, and oligonucleotide primers were designed for PCR amplification of this region of the gene. The study presents the conditions of amplification of the TERT gene fragment, its cleavage by restriction endonuclease RsaI at the location of SNP rs698799571, electrophoresis of the obtained restriction DNA fragments in an 8% polyacrylamide gel, and the genotypes of the animals are also determined. The developed DNA typing technique for the TERT gene was used to analyze its polymorphism in groups of 4 purebred pigs and a group of hybrid anjmals. Monomorphic homozygous TERTAA genotype was present in purebred pigs. The polymorphism of the TERT gene by SNP rs698799571 was detected in a group of pigs of the final Irish hybrid (LW x L) x Maxgro (TERTAT genotype). Considering the fact that studies on the telomerase gene and determination of the TERT polymorphism for SNP rs698799571 in pigs have not yet been conducted in Ukraine, the developed technique of DNA typing by the telomerase gene has a perspective for further determination of the distribution of alleles and genotypes in domestic and imported breeds, as well as in marker-associated selection.
Article
The purpose of this chapter is to offer an evolutionarily framed overview of human male reproductive health. The chapter is situated within key themes of the overall volume: the relevance of evolutionary and life history theory; sex differences in reproductive effort and their relevance to lifespan and health; the complementary distinctions between proximate and ultimate causation; the importance of context; and the consistent relevance of senescence for understanding aspects of male reproductive health. The structure of the chapter features precopulatory, copulatory, and postcopulatory sections, with key concepts and illustrations presented. The precopulatory section highlights male reproductive health consequences of intrasexual selection, courtship, and sexual coercion. These consequences include male injuries, death, and concerns over status and secondary sexual characteristics such as muscle that have shaped ancestral, if not also contemporary, reproductive success. The copulatory section covers sexual desire, erectile function, semen parameters, genetic parameters, and sexual satisfaction. Patterns in these aspects of male reproductive health commonly vary with age, health status, and partnership dynamics. Other facets of postcopulatory male reproductive health include reproductive constraints (e.g., contraception), sexually transmitted infections, and prostate cancer. Postcopulatory reproductive health touches on key domains such as partnership and sexual dynamics, metabolic consequences (e.g., physical activity and body composition), mental health (e.g., depression), and neuoroendocrine mechanisms (e.g., brain activity and hormone differences associated with paternal care). The scope of this review encompasses key concerns (e.g., erectile dysfunction, testosterone treatment, infertility) of biomedical approaches to male reproductive health while also expanding the scope to include more precopulatory and postcopulatory aspects, all framed within an overarching evolutionary and life history perspective.
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Evolutionary biology and biomedicine have seen a surge of recent interest in the possibility that telomeres play a role in life-history trade-offs and ageing. Here, I evaluate alternative hypotheses for the role of telomeres in the mechanisms and evolution of life-history trade-offs and ageing, and highlight outstanding challenges. First, while recent findings underscore the possibility of a proximate causal role for telomeres in current–future trade-offs and ageing, it is currently unclear (i) whether telomeres ever play a causal role in either and (ii) whether any causal role for telomeres arises via shortening or length-independent mechanisms. Second, I consider why, if telomeres do play a proximate causal role, selection has not decoupled such a telomere-mediated trade-off between current and future performance. Evidence suggests that evolutionary constraints have not rendered such decoupling impossible. Instead, a causal role for telomeres would more plausibly reflect an adaptive strategy, born of telomere maintenance costs and/or a function for telomere attrition (e.g. in countering cancer), the relative importance of which is currently unclear. Finally, I consider the potential for telomere biology to clarify the constraints at play in life-history evolution, and to explain the form of the current–future trade-offs and ageing trajectories that we observe today. This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
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In humans, the effect of paternal age at conception (PAC) on offspring leukocyte telomere length (LTL) is well established, with older fathers thought to pass on longer telomeres to their offspring in their sperm. Few studies have looked for PAC effects in other species, but it has been hypothesised that the effect will be exacerbated in polygamous species with higher levels of sperm competition and production. We test for maternal (MAC) and paternal age at conception effects on offspring LTL in Soay sheep, a primitive breed experiencing strong sperm competition. We use qPCR to measure relative telomere length in 389 blood samples (n = 318 individuals) collected from an unmanaged population of sheep on St Kilda, where individual age and parentage are known. We find no evidence that either MAC or PAC are associated with LTL in offspring across the age range, or when considering only young lambs (n = 164). This is the first study to test for parental age effects on offspring LTL in a wild mammal population, and the results contrast with the findings of numerous human studies that find a PAC effect, as well as predictions of a stronger PAC effect in polygamous species.
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In the general population, older age is associated with short leukocyte telomere length and with high risk of infections. In a recent study of allogeneic hematopoietic cell transplantation for severe aplastic anemia, long donor leukocyte telomere length was associated with improved survival in the recipients. These findings suggest that leukocyte telomere length could possibly be a marker of immune competence. Therefore, we tested the hypothesis that shorter leukocyte telomere length is associated with higher risk of infectious disease hospitalization and infection related death. Relative peripheral blood leukocyte telomere length was measured using quantitative polymerase chain reaction in 75,309 individuals from the general population and the individuals were followed for up to 23 years. During follow-up, 9,228 individuals were hospitalized with infections and infection related death occurred in 1508 individuals. Shorter telomere length was associated with higher risk of any infection (hazard ratio 1.05 per standard deviation shorter leukocyte telomere length; 95% confidence interval 1.03-1.07) and pneumonia (1.07;1.03-1.10) after adjustment for conventional infectious disease risk factors. Corresponding hazard ratios for infection related death were 1.10 (1.04-1.16) for any infection and 1.11 (1.04-1.19) for pneumonia. Telomere length was not associated with risk of skin infection, urinary tract infection, sepsis, diarrhoeal disease, endocarditis, meningitis or other infections. In conclusion, our findings indicate that leucocyte telomere length may be a marker of immune competence. Further studies are needed to determine whether risk of infections in allogeneic hematopoietic cell transplantation recipients can be reduced by considering donor leukocyte telomere length when selecting donors.
Article
Age-associated telomere shortening in oocytes and granulosa cells is considered a sign of ageassociated decline in oocyte quality. The present study examined the effect of aging on telomere lengths (TLs) in bovine oocytes, embryos, and granulosa cells, as well as the relationship between the TLs in oocytes and granulosa cells. TL was directly assessed by real-time PCR, using a telomeric standard of 84 bp length TTAGGG, repeated 14 time). TLs in immature oocytes derived from early antral follicles (EAFs) and antral follicles (AFs) as well as for in vitro matured oocytes derived from aged cows (>120 months) were shorter than their respective counterparts in younger cows (20–70 months, 0.45-, 0.82-, and 0.84- fold, respectively, P < 0.05). Telomeres elongate extensively during embryo development until the blastocyst stage (4.2-fold, P < 0.05); however, TLs in the blastocysts did not differ between the two age groups. TLs in the granulosa cells of both AFs and EAFs were shorter in aged cows than in younger cows, and showed a positive correlation with TLs in oocytes (r=0.66, P < 0.05). In conclusion, aging affects TL in oocytes, and the TLs in granulosa cells and oocytes are correlated. Age-associated telomere shortening in oocytes and granulosa cells is considered a sign of ageassociated decline in oocyte quality. The present study examined the effect of aging on telomere lengths (TLs) in bovine oocytes, embryos, and granulosa cells, as well as the relationship between the TLs in oocytes and granulosa cells. TL was directly assessed by real-time PCR, using a telomeric standard of 84 bp length TTAGGG, repeated 14 time). TLs in immature oocytes derived from early antral follicles (EAFs) and antral follicles (AFs) as well as for in vitro matured oocytes derived from aged cows (>120 months) were shorter than their respective counterparts in younger cows (20–70 months, 0.45-, 0.82-, and 0.84- fold, respectively, P < 0.05). Telomeres elongate extensively during embryo development until the blastocyst stage (4.2-fold, P < 0.05); however, TLs in the blastocysts did not differ between the two age groups. TLs in the granulosa cells of both AFs and EAFs were shorter in aged cows than in younger cows, and showed a positive correlation with TLs in oocytes (r=0.66, P < 0.05). In conclusion, aging affects TL in oocytes, and the TLs in granulosa cells and oocytes are correlated.
Article
Individuals with short telomeres should be at increased risk for cancer, since short telomeres lead to genomic instability – a hallmark of cancer. However, individuals with long telomeres also display an increased risk for major cancers, thus creating a cancer-telomere length (TL) paradox. The two-stage clonal expansion model we propose is based on the thesis that a series of mutational hits (1st Hit) at the stem-cell level generates a clone with replicative advantage. A series of additional mutational hits (2nd Hit) transforms the expanding clone into cancer. By proposing that the 1st Hit is largely telomere length-independent, while the 2nd Hit is largely TL-dependent, we resolve the paradox, highlighting a regulatory role of telomeres in cancer.
Article
Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. Data sources: Genomewide association studies (GWAS) published up to January 15, 2015. Study selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. Data extraction and synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. Main outcomes and measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). Conclusions and relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
Article
Objectives: Telomeres are repetitive DNA at chromosomes ends that shorten with age due to cellular replication and oxidative stress. As telomeres shorten, this can eventually place limits on cell replication and contribute to senescence. Infections are common during early development and activate cellular immune responses that involve clonal expansion and oxidative stress. As such, a high infectious disease burden might shorten blood telomere length (BTL) and accelerate the pace of immune senescence. Methods: To test this, BTL measured in young adults (21.7 ± 0.3 years old) from the Philippines (N = 1,759) were linked to prospectively collected early life data on infectious burden. Results: As predicted, increased early life diarrheal prevalence was associated with shorter adult BTL. The association was most marked for infections experienced from 6 to 12 months, which corresponds with weaning and maximal diarrheal burden. A standard deviation increase in infections at 6-12 m predicts a 45 bp decrease in BTL, equivalent to 3.3 years of adult telomeric aging in this population. Contrary to expectations, breastfeeding duration was not associated with BTL, nor did effects vary by sex. Conclusions: These findings show that infancy diarrheal disease predicts a marker of cellular aging in adult immune cells. These findings suggest that early life infectious burden may influence late life health, or alternatively, that short TL in early life increases infectious disease susceptibility.
Article
Objectives: Here, we examine the PAC-effect in chimpanzees (Pan troglodytes). The PAC-effect on TL is thought to be driven by continual production of sperm-the same process that drives increased de novo mutations with PAC. As chimpanzees have both greater sperm production and greater sperm mutation rates with PAC than humans, we predict that the PAC-effect on TL will be more pronounced in chimpanzees. Additionally we examine whether PAC predicts TL of grandchildren. Materials and methods: TL were measured using qPCR from DNA from blood samples from 40 captive chimpanzees and 144 humans. Results: Analyses showed increasing TL with PAC in chimpanzees (p = .009) with a slope six times that in humans (p = .026). No associations between TL and grandpaternal ages were found in humans or chimpanzees-although statistical power was low. Discussion: These results suggest that sperm production rates across species may be a determinant of the PAC-effect on offspring TL. This raises the possibility that sperm production rates within species may influence the TL passed on to offspring.
Article
Background Results regarding telomere length and cancer risk are conflicting. We tested the hypothesis that long telomeres are associated with increased risk of any cancer and specific cancer types in genetic and observational analyses. Methods Individuals (N = 95 568) from the Copenhagen City Heart Study and the Copenhagen General Population Study had the telomere length-associated genotypes rs7726159 (TERT), rs1317082 (TERC), and rs2487999 (OBFC1) determined, and 65 176 had telomere length measured. A total of 10 895 individuals had had a cancer diagnosis. Endpoints were any cancer and 25 specific cancer types. We conducted Cox regression analyses and logistic regression analyses. The three genotypes were combined as an allele sum. Results Telomere length increased 67 base-pairs [95% confidence interval (CI) 61–74] per allele. In logistic regression models, the per-allele odds ratio (OR) for cancer was 1.05 (95% CI 1.03–1.07) for the allele sum, 1.05 (1.02–1.09) for rs7726159, 1.05 (1.02–1.08) for rs1317082 and 1.07 (1.02–1.12) for rs2487999. In contrast, the hazard ratio for any cancer was 1.01 (1.00–1.01) per 200-base-pair increase in telomere length in multivariable adjusted observational analysis. In genetic analyses according to specific cancer types, the per-allele odds ratio was 1.19 (1.12–1.27) for melanoma and 1.14 (1.06–1.22) for lung cancer. Conclusions Genetic determinants of long telomeres are associated with increased cancer risk, particularly melanoma and lung cancer. This genetic predisposition to enhanced telomere maintenance may represent a survival advantage for pre-cancerous cells, allowing for multiple cell divisions leading to cancer development.
Article
Background: Telomere length (TL) is a marker of cellular aging, with the majority of lifetime attrition occurring during the first 4 y. Little is known about risk factors for telomere shortening in childhood. Objective: We evaluated the relation between early life feeding variables and preschool TL. Design: We assessed the relation between dietary, feeding, and weight-associated risk factors measured from birth and TL from blood samples taken at 4 y of age (n = 108) and 5 y of age (n = 92) in a cohort of urban, Latino children (n = 121 individual children). Feeding variables were evaluated in children with repeat measurements (n = 77). Results: Mean TL (in bp) was associated with exclusive breastfeeding at 4-6 wk of age (adjusted coefficient: 353.85; 95% CI: 72.81, 634.89; P = 0.01), maternal TL (adjusted coefficient: 0.32; 95% CI: 0.11, 0.54; P < 0.01), and older paternal age (adjusted coefficient: 33.27; 95% CI: 4.10, 62.44; P = 0.03). The introduction of other foods or drinks in addition to breast-milk or replacement-milk substitutes before 4-6 wk of age was associated with mean TL at 4 and 5 y of age (adjusted coefficient: -457.01; 95% CI: -720.50, -193.51; P < 0.01). Infant obesity at 6 mo of age and soda consumption at 4 y of age mediated the relation in part between exclusive breastfeeding at 4-6 wk of age and mean TL at 4 and 5 y of age. High soda consumption at 3 y of age was associated with an accelerated attrition from 4 to 5 y of age (adjusted coefficient: -515.14; 95% CI: -986.06, -41.22; P = 0.03). Conclusion: Exclusive breastfeeding at 4-6 wk of age may have long-term effects on child health as evidenced by longer TL at 4 and 5 y of age.