Great looks, a well-worn leather jacket, and a wide-ranging collection of old vinyl records represent great examples of inheritances that fathers happily pass on to their grateful children. However, new findings from the lab of Dan Ehninger (German Center for Neurodegenerative Diseases, Bonn, Germany) show that older dads can also pass on an intergenerational effect that detrimentally affects healthy aging in their not so grateful offspring.
Wide-ranging studies already established that children of older fathers suffer from a higher risk of disease susceptibility (including schizophrenia and Alzheimer’s disease); however, the full impact of an older father and the mechanisms controlling detrimental inheritances remain relatively unknown. To garner fresh insight, Xie and colleagues combined epigenomic, transcriptomic, and biochemical analysis to study mouse sperm and the male offspring of old (>21 months) and young (4 months) fathers.
Here’s a brief summary of the data that the authors passed on in their new report:
- Male mice born of older fathers display reduced lifespan and worsened aging traits when compared to mice born of younger fathers
- Genome-wide epigenetic comparisons (via reduced representation bisulfite sequencing [RRBS]) demonstrated that sperm from older males and mice born of older fathers share differentially methylated regions in promoters of genes that regulate evolutionarily conserved longevity pathways
- The 14 differentially-methylated promoter regions controlled genes encoding components of mTOR-related cell signaling and immune-regulatory pathways
- Epigenetic alterations correlate with changes in the expression of genes associated with cell growth and proliferation, cancer, and organismal survival
- A combination of Ribotag technology, RNA-sequencing, and protein analyses confirmed the over-active nature of mTOR Complex 1 (mTORC1) signaling in sperm from older fathers and mice born of older fathers
- mTOR represents a key regulator of lifespan and influences various aspects of aging and age-related pathologies via broad effects on cell growth, proliferation, metabolism, immune functions, and proteostasis
- Interestingly, mTOR inhibition by rapamycin treatment during normal aging inhibited the development of many aging traits observed in mice born of older fathers, although drug treatment did not alter DNA methylation levels in the short term
This research focused on a mouse model, so whether human fathers will pass on a similar unwanted inheritance remains an open topic for discussion. “What we have described here are fundamental mechanisms in a mammalian model organism. These could also be relevant for humans. However, whether this is the case and, if so, to what extent has not been tested by our study and remains unknown. In this respect, our results cannot be directly applied to humans,” says Ehninger. “However, our results provide a good reason to take a closer look at this.”
To read more about some potentially unwelcome inheritance from dad, transmit yourself over to PNAS, February 2018.