Aging, Environment, & DiseaseDNA Methylation and HydroxymethylationImprinting and Inheritance

Advanced Paternal Age at Conception Increases Risk of Age-Related Diseases in Offspring

Sperm transfer aged epigenome to offspringAs a person ages, they become more prone to diseases, including cancer and neurodegeneration. Having children when you are older can also affect the health of your offspring, increasing the risk for neuropsychiatric disorders, among many others [1], [2]. Sperm contribute epigenetic information to the zygote [3] that can affect the physiological state of the offspring [4]–[6]. Using a mouse model system, Xie et al analyzed the epigenome of sperm and offspring of old and young fathers to research whether the age of the fathers affects lifespan and age-related phenotypes in the offspring.

The first measurements of health that Xie et al analyzed were lifespan and telomere length. Median lifespan of old father (>21 mo) offspring (OFO) was ~6.6% lower than young father (4 mo) offspring (YFO). In the hippocampus, OFO mice showed decreased telomere length, in relation to YFO mice. Decreased lifespan and telomere length both indicate an accelerated onset of aging phenotypes in OFO mice.

Next, the study tested for changes in the epigenome of OFO vs. YFO mice. DNA in the sperm of old, 19 month, mice had 299 hypomethylated and 185 hypermethylated gene promoters compared to young, 6 month old mice. Xie et al also found an overall decrease in methylation of Alu and LINE-1 elements, in sperm from old mice. OFO mice also showed lower methylation of Alu and LINE-1 elements in the hippocampus, compared to YFO, indicating that methylation patterns in sperm were carried over to the offspring.

When looking at miRNA expression, ~40% of the miRNAs detected had altered expression and ~98% of these differentially expressed miRNAs were less expressed in aged sperm when compared to young mouse sperm. Many of the genes affected by altered miRNA levels belong to age-related signaling pathways, including mTOR, PTEN, growth factor, and p53 signaling, along with immune-regulatory pathways. Genes part of the mTOR signaling pathway that were targeted by differentially expressed miRNAs overlapped with gene promoters that were hypomethylated in the sperm of old mice. Additionally, downstream effectors of mTORC1 (S6, p70S6K, and 4E-BP1) all have increased phosphorylation in the hippocampus, lung, and liver of OFO mouse. This indicates mTORC1 overactivity in OFO mice. To test if overactive mTORC1 signaling is a significant part of the OFO aging phenotype, OFO mice were treated for 15 months with rapamycin, an mTORC1 inhibitor. Rapamycin treatment reduced several age-related changes in OFO mice, including thyroid follicle morphology and myocardial fibrosis.

This study gives evidence that having children later in life can have detrimental effects on the offspring, mainly through epigenetic changes in sperm cells. These effects include lifespan and telomere shortening. The mTOR signaling pathway appears to be an integral part of the changes seen in OFO, compared to YFO mice. The aging phenotype differences between OFO and YFO mice can be reduced by long-term rapamycin treatment.


Original Article

  1. K. Xie et al., “Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice.,” Proc. Natl. Acad. Sci. United States Am., Feb. 2018.


  1. Y. Lu et al., “Parents’ ages at birth and risk of adult-onset hematologic malignancies among female teachers in California.,” American journal of epidemiology, vol. 171, no. 12, pp. 1262–1269, Jun. 2010.
  2. L. Bertram, R. Busch, M. Spiegl, N. T. Lautenschlager, U. Müller, and A. Kurz, “Paternal age is a risk factor for Alzheimer disease in the absence of a major gene.,” Neurogenetics, vol. 1, no. 4, pp. 277–280, Aug. 1998.
  3. S. Seisenberger et al., “The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells.,” Mol. cell, vol. 48, no. 6, pp. 849–862, Dec. 2012.
  4. Q. Chen et al., “Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder.,” Science (New York, N.Y.), vol. 351, no. 6271, pp. 397–400, Jan. 2016.
  5. D. P. Ryan et al., “A paternal methyl donor-rich diet altered cognitive and neural functions in offspring mice.,” Molecular psychiatry, Apr. 2017.
  6. A. B. Rodgers, C. P. Morgan, S. L. Bronson, S. Revello, and T. L. Bale, “Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation.,” The Journal of neuroscience: the official journal of the Society for Neuroscience, vol. 33, no. 21, pp. 9003–9012, May 2013.
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Aaron Barnett

Aaron Barnett