Fight Aging!

Over time, ever increasing funding and interest has been devoted to the development of epigenetic clocks based on age-related changes in the DNA methylation status of various CpG sites on the genome. This is one of the epignetic mechanisms shaping the packaging of nuclear DNA, and thus which sections are exposed to transcription machinery, which proteins are manufactured, and consequent cell behavior. DNA methylation patterns can produce a fair estimate of chronological age, and are thought to reflect biological age, the burden of damage and dysfunction that gives rise of age-related disease and mortality. Given a wealth of data from many species, one can start to look beyond the individual at how DNA methylation patterns and their changes over time relate to species characteristics such as maximum life span. Interestingly, it appears that the relationships are quite different between (a) pace of aging for an individual and DNA methylation versus (b) species maximum life span and DNA methylation.

Today's open access paper is a lengthy discussion of this point, a review of some years of work focused on processing DNA methylation data in search of insights and correlations. When it comes to answers to the most interesting questions, this is only the starting point, however. It remains to be seen as to how the details of DNA methylation can map to a better understanding of the mechanisms that drive differences in species longevity. There is the hope that, given the sizable difference in life span between a mouse, a human, and a whale, somewhere in all of this data are the seeds of practical enhancement biotechnologies that will produce significant gains in healthy life span. It is far too early to say whether or not that is the case, and I would wager that this will be a slower, harder path than repair-based biotechnologies described in the Strategies for Engineered Negligible Senescence vision, but nonetheless, there you have it.

Fundamental equations linking methylation dynamics to maximum lifespan in mammals

We established the Mammalian Methylation Consortium with two primary objectives. The first objective was to develop DNA methylation-based measures to track the passage of time, culminating in the creation of the pan-mammalian methylation clock. The second objective aimed to understand the epigenetic correlates of maximum mammalian lifespan, a goal explored through a trilogy of papers. In the first paper, we developed multivariate predictors of maximum lifespan based on cytosine methylation. This predictor can estimate species-specific characteristics, such as maximum lifespan, from a DNA sample, even if the species is unknown. The second paper characterized individual CpGs and clusters of CpGs (modules) that correlate with maximum lifespan, providing insights into the methylation landscape of long-lived species. Interestingly, this study found only a weak overlap between CpGs that correlate with maximum lifespan and those associated with chronological age. While we understand that a species characteristic like maximum lifespan is genetically hardwired and does not change with the individual's age, this finding challenges the intuitive hypothesis that individual aging (the passage of time) must relate to maximum lifespan (a species characteristic).

Prior studies have linked the rate of change in methylation to maximum lifespan in smaller samples of mammalian species, and have suggested a strong position correlation between slower average rate of change in methylation and increased species maximum lifespan. But this is not always the case. By leveraging the large dataset from our Mammalian Methylation Consortium and a careful mathematical framework we demonstrate that the strong correlation between slower average rate of change in methylation and increased species maximum lifespan is only found in certain chromatin states such as bivalent promoters. In other chromatin states, the correlation is either not present or even reversed. Future studies might delve deeper into which chromatin regions result in the opposite interpretation, where a rapid rate of change correlates with an increased maximum lifespan.