Citation: Eisenberg DTA (2019) Paternal age at conception effects on offspring telomere length across species—What explains the variability? PLoS Genet 15(2): e1007946. https://doi.org/10.1371/journal.pgen.1007946
Editor: Gregory P. Copenhaver, The University of North Carolina at Chapel Hill, UNITED STATES
Published: February 14, 2019
Copyright: © 2019 Dan T. A. Eisenberg. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: DTAE's telomere research has been supported by NSF (BCS-1519110, BCS-0962282) and Wenner Gren foundation (8111) grants. The funders had no role in the preparation of the article.
Competing interests: The author has declared that no competing interests exist.
Telomeres, the repeating DNA sequences found at the ends of chromosomes, are dynamic and complex parts of the genome with important health and fitness consequences. In this issue of PLOS Genetics, Bauch and colleagues  help to extend our understanding of telomere biology in important ways. Although telomeres are DNA, they do not act like DNA is “supposed” to. Telomeres get shorter with each round of mitosis due to the end replication problem and in response to DNA damage. They can be extended by telomerase, among other mechanisms. This means that telomere length (TL) may change over an organism’s life (as soon as a fertilized egg begins dividing) and do so differentially across cells in the body, reflecting the particular replicative and telomere maintenance mechanisms experienced by a cell lineage.
Growing evidence suggests that gametes are not exempt from these complex telomere dynamics and that TL does not adhere to canonical DNA inheritance patterns. First, the telomeres contained on particular chromosome ends within an egg and sperm cell are the telomeres that a fertilized egg begins its life with . Conventional genetic polymorphisms have been shown to predict TL in humans. These genetic polymorphisms could influence TL via effects on TL dynamics from the first mitotic division of the fertilized egg on. However, genetic polymorphisms could also predict TL via indirect genetic effects on telomere dynamics in the mother or father’s gamete cell lineages, which are then passed on to offspring. Although the gametes of female animals are generally produced before birth, males must continually produce sperm. Consistent with this, paternally transmitted TL appears to be dynamic, whereas maternally transmitted TL is less so. In particular, paternal age at conception (PAC) seems to influence sperm TL, and subsequently the TL of offspring, whereas maternal age at conception (MAC) does not .
Further complicating the picture, telomere dynamics vary considerably across species (Table 1). In cross-sectional studies of humans and chimpanzees, sperm TL and, correspondingly, offspring TL appears to increase with PAC. Other species have tended to show either no association between PAC and offspring TL, or a negative association.
Bauch and colleagues’ study  extends the literature on parental age and offspring TL in particularly robust ways. They take advantage of a long-term study of jackdaw birds to marshal a large, longitudinal and family-based sample. TL was carefully measured using telomere restriction fragment (TRF) analysis and met high–quality-control standards. Additionally, a cross-fostering experiment was also conducted. Because of these combined strengths, the results allow better causal inferences than is typical in studies of TL inheritance patterns.
Although converging evidence strongly suggests that the PAC association with offspring TL in humans is caused by a progressive increase in sperm TL as men age , most studies in humans and other species have been cross-sectional and observational. Therefore, doubt often remains about the degree to which PAC associations represent changes in gamete TL versus other causal pathways. For example, TL may predict longevity and health such that males who start life with longer TL tend to live to a later age and transmit their own longer telomeres to offspring. Such a dynamic could create a correlation between PAC and TL without requiring a lengthening of sperm TL with age.
By comparing siblings sired by the same father at different PACs, Bauch and colleagues  showed clear evidence that TLs of offspring are likely shortened as fathers age. Cross-fostering, buttressed these findings by showing that biological, but not foster-father, ages predicted offspring TL. Similar analyses showed no apparent effect of MAC on offspring TL. Although it is possible that other factors confound this analysis, such as mothers adjusting egg contents based on the age of their mates, this study provides strong evidence that telomeres are shortened with paternal age in this species.
It remains unclear what the mechanistic and evolutionary explanations for the PAC effects on TL are, and why the effect varies across species. One explanation for cross-species variability that has garnered some support is that species with higher sperm production rates show a greater increase in sperm TL with age [3–5]. Surveying the most recent evidence of PAC associations with TL across species (Table 1), an alternative possible explanation emerges. It appears that increases in TL with PAC are generally found more in longer-lived and larger species, whereas shorter-lived and smaller species generally show negative PAC effects or no effect at all. Past studies have shown that long-lived species generally have shorter TL, whereas larger species generally have lower somatic telomerase activity (TA) [6, 7]. Lower somatic TA in large organisms is thought to be driven by the greater risk of cancer development in these species, which selects against the cancer promoting effects of TA. Therefore, the diversity of these PAC effects on TL is all the more puzzling because the most prominent suggested cause of a positive PAC effect is high expression of testicular TA. If larger body size increases TA-promoted cancers in both somatic and germ line tissues, the expectation is that long-lived species should have decreased testicular TA and more negative PAC effects on TL, not more positive ones. Examination of testicular TA levels across species may help better reveal the extent to which testicular TA levels underlie cross-species variation in PAC effects.
This contradiction between expected testicular TA levels and PAC effects on TL suggest that explanations other than testicular TA should also be further explored. There is evidence that changes in sperm TL in humans are, at least partly, driven by selective survival or proliferation of spermatogonial stem cells with longer TL [3, 8]. Given this, future studies of the PAC effect in humans and other species should consider not just changes in mean TL with PAC, but changes in TL distributions. For example, the TRF analysis deployed by Bauch and colleagues provides data on the distribution of TL, which could be analyzed in future studies to help address whether there are shifts not only in the TL mean, but also the TL distribution with PAC.
Regardless of mechanisms, the PAC effect on TL has intriguing health and evolutionary implications. Strong converging evidence suggests that TL influences health and longevity. The basic inheritance patterns of DNA as well as empirical evidence in humans suggests that the PAC effect persists across generations . Therefore, if ages of reproduction change in a lineage/population in which PAC effects exist, then the TL of descendants could be rapidly and durably shifted in ways that change their health and fitness. This raises the question of why PAC effects persist if they cause such phenotypic instability. I have suggested that the positive PAC effect in humans might represent a unique type of adaptive intergenerational genetic plasticity wherein descendants’ TL are progressively adjusted based on average age of reproduction among male ancestors . If ages of reproduction of ancestors are predictive of the environment descendants will experience, such a mechanism could allow a more appropriate TL for that environment. Specifically, in lineages with later ages of reproduction, longer TL may promote increased maintenance effort that improves fitness in the context of low extrinsic mortality environments. How do we square this with the emerging evidence from Bauch and colleagues as well as others (Table 1) that the PAC effect on TL is usually nonexistent or negative in smaller and shorter-lived species? Adaptive intergenerational effects are more likely to emerge when intragenerational plasticity is constrained . Because larger species tend to have low somatic TA, this might constrain their intragenerational plasticity in TL and thereby increase selection for intergenerational plasticity.
- 1. Bauch C, Boonekamp JJ, Korsten P, Mulder E, Verhulst S. Epigenetic inheritance of telomere length in wild birds. PLoS Genet 15(2): e.1007827 https://doi.org/10.1371/journal.pgen.1007827
- 2. Delgado DA, Zhang C, Gleason K, Demanelis K, Chen LS, Gao J, et al. The contribution of parent-to-offspring transmission of telomeres to the heritability of telomere length in humans. Hum Genet. 2018. pmid:30536049.
- 3. Eisenberg DTA, Kuzawa CW. The paternal age at conception effect on offspring telomere length: mechanistic, comparative and adaptive perspectives. Philosophical Transactions of the Royal Society B: Biological Sciences. 2018;373(1741). pmid:29335366
- 4. Eisenberg DTA, Tackney J, Cawthon RM, Cloutier CT, Hawkes K. Paternal and grandpaternal ages at conception and descendant telomere lengths in chimpanzees and humans. Am J Phys Anthropol. 2016;162(2):201–7. pmid:27731903; PubMed Central PMCID: PMC5250553.
- 5. Bouwhuis S, Verhulst S, Bauch C, Vedder O. Reduced telomere length in offspring of old fathers in a long-lived seabird. Biol Lett. 2018;14(6). pmid:29899134
- 6. Gomes NM, Ryder OA, Houck ML, Charter SJ, Walker W, Forsyth NR, et al. Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination. Aging Cell. 2011;10(5):761–8. Epub 2011/04/27. pmid:21518243; PubMed Central PMCID: PMC3387546.
- 7. Seluanov A, Chen Z, Hine C, Sasahara T, Ribeiro A, Catania K, et al. Telomerase activity coevolves with body mass not lifespan. Aging Cell. 2007;6(1):45–52. pmid:17173545
- 8. Kimura M, Cherkas LF, Kato BS, Demissie S, Hjelmborg JB, Brimacombe M, et al. Offspring's leukocyte telomere length, paternal age, and telomere elongation in sperm. PLoS Genet. 2008;4(2):e37. pmid:18282113; PubMed Central PMCID: PMC2242810.
- 9. Eisenberg DT, Hayes MG, Kuzawa CW. Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants. Proc Natl Acad Sci. 2012;109(26):10251–6. Epub 2012/06/13. pmid:22689985; PubMed Central PMCID: PMC3387085.
- 10. Eisenberg DTA. An evolutionary review of human telomere biology: The thrifty telomere hypothesis and notes on potential adaptive paternal effects. Am J Hum Biol. 2011;23(2):149–67. pmid:21319244.
- 11. Kuijper B, Hoyle RB. When to rely on maternal effects and when on phenotypic plasticity? Evolution. 2015;69(4):950–68. pmid:25809121
- 12. McLennan D, Armstrong JD, Stewart DC, McKelvey S, Boner W, Monaghan P, et al. Links between parental life histories of wild salmon and the telomere lengths of their offspring. Mol Ecol. 2018;27(3):804–14. pmid:29274177.
- 13. Olsson M, Pauliny A, Wapstra E, Uller T, Schwartz T, Blomqvist D. Sex Differences in Sand Lizard Telomere Inheritance: Paternal Epigenetic Effects Increases Telomere Heritability and Offspring Survival. PLoS ONE. 2011;6(4):e17473. pmid:21526170
- 14. Heidinger BJ, Herborn KA, Granroth-Wilding HMV, Boner W, Burthe S, Newell M, et al. Parental age influences offspring telomere loss. Funct Ecol. 2016;30(9):1531–8.
- 15. Criscuolo F, Zahn S, Bize P. Offspring telomere length in the long lived Alpine swift is negatively related to the age of their biological father and foster mother. Biol Lett. 2017;13(9). pmid:28904178
- 16. Noguera JC, Metcalfe NB, Monaghan P. Experimental demonstration that offspring fathered by old males have shorter telomeres and reduced lifespans. Proceedings of the Royal Society B: Biological Sciences. 2018;285(1874). pmid:29540524
- 17. Asghar M, Bensch S, Tarka M, Hansson B, Hasselquist D. Maternal and genetic factors determine early life telomere length. Proc Biol Sci. 2015;282(1799):20142263. pmid:25621325; PubMed Central PMCID: PMCPMC4286038.
- 18. Froy H, Bird EJ, Wilbourn RV, Fairlie J, Underwood SL, Salvo-Chirnside E, et al. No evidence for parental age effects on offspring leukocyte telomere length in free-living Soay sheep. Scientific Reports. 2017;7(1):9991. pmid:28855677
- 19. de Frutos C, López-Cardona AP, Fonseca Balvís N, Laguna-Barraza R, Rizos D, Gutierrez-Adán A, et al. Spermatozoa telomeres determine telomere length in early embryos and offspring. Reproduction. 2016;151(1):1–7. pmid:26475708.
- 20. Gardner JP, Kimura M, Chai W, Durrani JF, Tchakmakjian L, Cao X, et al. Telomere dynamics in macaques and humans. J Gerontol A Biol Sci Med Sci. 2007;62(4):367–74. Epub 2007/04/25. pmid:17452729.