DISCUSSION
Our re-analysis of the data from Gomes et al 2011 demonstrates that
telomere length has evolved to be shorter with increasing body mass and
lifespan, across 57 species of mammals spanning 15 orders (Fig. 2). This
supports the hypothesis that short telomeres evolved in large,
long-lived mammals to enable replicative senescence as a mechanism to
ameliorate cancer risk conferred by a larger number of cells and longer
time to accumulate oncogenic mutations (Gorbunova et al., 2014; Risques
& Promislow, 2018). Alternatively, since TL was measured in adults,
larger species may erode their telomeres faster than small species,
giving rise to the negative correlation between TL and body mass
(Monaghan & Ozanne, 2018). However, larger species have been shown to
have lower telomere shortening rates across 9 tetrapod species, but this
association was driven by inclusion of a domesticated mouse strain
(Pepke & Eisenberg, 2020). Since telomere loss rates tend to be slower
in longer lived species (Haussmann et al., 2003; Dantzer & Fletcher,
2015), TLs at conception are likely to be even longer in shorter-lived
species than estimated in adulthood.
In contrast to our findings, past studies have shown no significant
associations between TL with mass or lifespan across 15 rodent species
(Seluanov et al., 2007) or between TL and lifespan of 19 bird species
(Tricola et al., 2018). These differences might be explained by these
rodents and birds being relatively small and short-lived compared to
many of the species included here. Among 8 species of relatively large
mammals and birds (all >0.5 kg), longer early-life TL
predicted longer lifespan (the opposite of our findings), but only when
accounting for body mass and telomere shortening rate (Pepke &
Eisenberg, 2020). Gomes et al. (2011) failed to show the association
between TL and mass that we found analyzing the same dataset. While the
reasons for our differing results with Gomes et al. are unclear, they
may be driven by a transformation of telomerase activity in the
multivariate model (discussed below). Regardless, broader taxonomic
studies that are attentive to model construction are needed to unravel
the generality of these patterns.
Our re-analysis of Gomes et al. (2011) showed that telomerase activity
had only inconsistent associations with lifespan and body mass (Tables 1
and S1-4), which call into question past results suggesting that high
telomerase activity has been selected against in larger and longer-lived
species. We found some hints that telomerase activity was inversely
associated with mass when telomerase was either log-transformed or
binary transformed (Tables S3-4 and Fig. S1). Thus, the associations
between telomere biology, mass and lifespan are sensitive to modeling
strategies. While we found an inverse association of binary telomerase
activity with mass, the biological meaning of binary coded telomerase
activity is unclear. Perhaps having any telomerase activity increases
the level of cancer risk, but the particular level of telomerase
activity greater than zero does not change cancer risk. This might
suggest that telomerase activity variation greater than zero has no
meaningful effects on the phenotype under selection with changing body
mass. In contrast, Seluanov et al. (2007) found a strong negative linear
correlation between (untransformed) telomerase activity and body mass
across rodent species. Seluanov et al.’s analysis differed from this
study in that they measured telomerase activity in spleen, liver, and
kidney tissues, while this study depends on telomerase from cultured
cells. Additionally, the rodents in Seluanov et al.’s analysis all
expressed telomerase and had long telomeres (most species
>20 kb), while this analysis includes many species without
detectable telomerase activity and with shorter TLs. The fact that
Seluanov et al.’s analysis showed non-transformed telomerase activity
had an association with mass among animals with only non-zero telomerase
activity argues against using telomerase activity as a binary variable.
Furthermore, small levels of telomerase activity in normal stem cells is
thought to be insufficient to fully maintain telomere lengths (Shay &
Wright, 2010).
Telomere length was a strong predictor of neoplasia rates across 22
species spanning 11 orders (Fig. 3a). Neoplasia rates are a good proxy
for malignancy rates (Fig. S2). In turn, malignancy rates likely reflect
the incidence of development of cancers with fitness consequences (Ewald
& Ewald, 2015). Thus, natural selection against longer telomeres may be
driven by cancer-related mortality. Our findings are consistent with the
hypothesis that shorter telomeres have evolved as a cancer resistance
mechanism across mammals. Larger and longer-lived species did not have
higher neoplasia incidence rates (Fig. 3c), which is a demonstration of
the well-known Peto’s paradox. The negative correlation that we found
between TL and body mass may partly underlie Peto’s paradox; i.e. larger
species have evolved shorter telomeres as an anti-cancer mechanism to
compensate for otherwise higher cancer risks (Caulin & Maley 2011). The
optimal TL in mammals may therefore have been shaped by a trade-off
between the increased cancer risk of long telomeres and the increased
susceptibility to age-dependent degenerative diseases conferred by short
telomeres (Tian et al., 2018; Aviv et al., 2017). We also found some
evidence that binary telomerase activity was associated with higher
cancer rates (Fig. 3d), although this effect was not significant when
controlling for TL (Table 2). High telomerase activity is a prerequisite
for most cancer cells (Wright & Shay, 2005) and may decrease the
threshold for cell immortalization leading to increased cancer risk in
species with somatic telomerase activity.
Although species with short telomeres have lower cancer incidence rates,
some species with long telomeres appear to have lower cancer rates than
expected given their TL. This may be explained by the evolution of
various telomere-independent cancer defense mechanisms in these
typically long-lived species (Seluanov et al., 2018; Erten & Kokko,
2020). The most striking outlier in our analysis is the tiger
(Panthera tigris ), having a large body size (162 kg) despite
having very long telomeres (50 kb), high telomerase activity (10%), but
a moderate neoplasia incidence rate (18%), suggesting the potential for
discovery of novel tumor suppressor mechanisms within this species.
We provided the first evidence
that telomeres are longer across multiple domesticated species spanning
5 orders (mainly members of Artiodactyla, but also of Perissodactyla,
Carnivora, Rodentia and Lagomorpha). Long telomeres may form part of a
“domestication syndrome” in mammals (Darwin, 1868; Wilkins et al.,
2014), although the mechanisms generating this trait change are not
well-known (Eisenberg, 2011). Alternatively, long telomeres were
ancestral in domesticated species, but somehow connected to the early
stages of domestication (Lord et al., 2020). We found that domestication
has resulted in an estimated 38.5% increase in TL (Table 3), which is
equivalent to the effect an 98.4% decrease in body mass would have on
TL (Fig. 1a). There does not appear to be a single directional change in
body sizes of domesticated animals (Lord et al., 2020). However,
domesticated species may have experienced changes related to fertility,
reproductive lifespan, growth rate, degree of inbreeding, parasite load
and energetic constraints (Diamond, 1997; Lord et al., 2020), which are
all effects known to shape intraspecific variation in TL (Weinstein and
Ciszek, 2002; Manning et al., 2002; Bebbington et al., 2016; Monaghan &
Ozanne, 2018; Sudyka, 2019; Giraudeau et al., 2019). Comparisons of TL
and other phenotypes in domesticated species with their wild or feral
cousins might provide more insights into the particular causes of TL
changes with domestication.
Our re-analyses of the valuable dataset generated by Gomes et al. (2011)
showed considerably divergent results from those shown by Gomes et al.
(2011) and that many results are not robust to varying modeling
strategies. Unlike Gomes et al. (2011), we showed that telomere length
decreases with increasing body mass. While Gomes et al.’s results
suggest a reduction in telomerase activity with increasing body mass, we
only found weak evidence for this. Our results suggest that the
co-evolution of telomere biology with lifespan and body mass across
species needs to be reconsidered. The negative association between TL
and mass and lifespan could be explained by the increased cancer risk we
found in species with longer telomeres. Finally, we found that
domesticated species appear to have evolved longer telomeres –
suggesting new avenues to understand telomere evolution through closer
examination of the domestication process and artificial selection
experiments.
Acknowledgements: We thank Amy Klegarth for collaboration on
earlier exploration of these data and Jerry Shay and Chris Venditti for
collegial discussion of our discrepant results. We thank Pat Monaghan
and Dan Nussey for organizing the Diversity in Telomere Dynamics
Workshop, which facilitated the authors meeting and collaborating on
this project. M.L.P. thanks the Research Council of Norway for funding
through its Centres of Excellence scheme (223257).