Aging, Environment, & DiseaseArticle SummariesDNA Methylation and Hydroxymethylation

DNA Methylation Rate May Determine Lifespan in Mammals

DNA Methylation & LifespanSpecies within the class Mammalia have a wide range of lifespans, from mice with a lifespan of 2 years to humans with a lifespan of over 100 years. Several non-molecular theories have been proposed to explain these lifespan variations, including body mass and metabolic rate [1]. Alternatively, research on ageing-associated differentially methylated positions (aDMPs) shows age-associated methylation dynamics in humans [2], [3], mice [4] and whales [5]. By looking at several mammals with a broad range of maximum lifespans (Tmax) Lowe et al wanted to determine if age-related methylation changes in aDMPs can predict lifespan and biological age.

The study analyzed aDMPs from mice (Tmax = 4 years), dogs (Tmax = 24 years), naked mole rats (Tmax = 31 years), rhesus macaques (Tmax = 40 years), humpback whales (Tmax = 95 years) and humans (Tmax = 122 years), on a weekly basis, to extend knowledge of the link between Tmax and rate of aDMP methylation. First, Lowe et al looked at the two extremes, mice and humans. Overall, in mice aDMPs had a significantly higher change in methylation than in humans. When looking at all of the mammalian species, aDMPs had a decreased change in methylation the greater the Tmax of the species. Independent of body mass, the change in methylation of aDMPs in humpback whales was higher compared to human aDMPs.

To research if the negative correlation between change in methylation of aDMPs and Tmax holds true within a species, aDMPs from two breeds of dogs, miniature long-haired dachshunds (Tmax = 12-15 years) and flat-coated retrievers (Tmax = 8-10 years) were analyzed. All six conserved aDMPs from the flat-coated retriever showed a significantly increased rate of change in methylation compared to aDMPs from the miniature long-haired dachshund. Finally, the authors determined that the cellular environment causes age-related aDMP methylation changes by using a transchromosomic mouse containing a human chromosome 21 (Tc1 mice). Using 15 human aDMPs to analyze only the human chromosome 21 DNA in these mice, methylation of the aDMPs changed 21 times faster than the same aDMPs in human cells.

This study aimed to find a molecular analysis to determine the lifespan of mammals. Analysis of aDMPs in humans, mice, naked mole rats, dogs, rhesus macaques and humpback whales, found a negative correlation between changes in aDMP methylation and Tmax of the species. This lifespan-associated difference in change of aDMP methylation holds true for dog breeds with different lifespans. Lowe et al also showed that body mass does not always determine lifespan due to humpback whales having a lower Tmax and faster aDMP methylation changes than humans. Further research is needed to determine what the exact role of methylation changes in aDMPs is with respect to mammalian aging.

 

Original Article

  1. Lowe et al., “Ageing-associated DNA methylation dynamics are a molecular readout of lifespan variation among mammalian species.,” Genome Biol., vol. 19, no. 1, p. 22, Feb. 2018

References

  1.  S. N. Austad, “Comparative biology of aging.,” journals Gerontol. Ser. Biol. Sci. Med. Sci., vol. 64, no. 2, pp. 199–201, Feb. 2009.
  2. G. Hannum et al., “Genome-wide methylation profiles reveal quantitative views of human aging rates.,” Mol. cell, vol. 49, no. 2, pp. 359–367, Jan. 2013.
  3. J. T. Bell et al., “Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.,” PLoS Genet., vol. 8, no. 4, p. e1002629, Apr. 2012.
  4. H. Spiers, E. Hannon, S. Wells, B. Williams, C. Fernandes, and J. Mill, “Age-associated changes in DNA methylation across multiple tissues in an inbred mouse model.,” Mech. Ageing Dev., vol. 154, pp. 20–23, Mar. 2016.
  5. A. M. Polanowski, J. Robbins, D. Chandler, and S. N. Jarman, “Epigenetic estimation of age in humpback whales.,” Mol. Ecol. Resour., vol. 14, no. 5, pp. 976–987, Sep. 2014.
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Aaron Barnett

Aaron Barnett

  • Clarence A. ‘Sonny’ Williams

    Excellent summary of a good research paper, but Aaron Barnett’s title troubles me. The term “determine” implies causation, and yet the paper does not establish causation at all (nor can it, as DNA methylation is a follower, not a leader of gene expression changes). The excellent underlying paper “simply” correlates whole-blood assays of DNA methylation changes with ageing (and, of course, whole blood assays have serious drawbacks; single cell, temporally sensitive analysis is required). The paper demonstrates that DNA methylation changes are good “markers” of ageing. They are not causal and are not “determiners.”