New research into DNA methylation to accurately predict maximum lifespan and support longevity R&D.

The study of reversible DNA modifications, known as epigenetics, has played a key role in the study of aging research. DNA methylation (DNAm) of histones is a modification that affects how scrunched up our chromosomes are, which changes the accessibility of genes and thus regulates their expression.

Longevity.Technology: Epigenetic clocks have been getting more and more attention – Dr Steve Horvath’s pioneering work and novel messenger RNA-based clocks are notable examples. These aging clocks aim to determine chronological and biological age, the latter assessing how healthy we are, our longevity prospects and how old our bodies are on a cellular level.

Even though understanding mechanisms behind aging epigenetics is complex, one thing is clear – DNA methylation based-clocks have the most unprecedented accuracy when predicting chronological age and longevity. This perhaps is unsurprising as it is established that in humans, global DNAm increases with age [1].

Based on this, the aforementioned Steve Horvath strikes again in a new collaboration with Gerald Wilkinson from the University of Maryland; together they conducted a study based on bats.

Bats have an interesting and unique property, in that their wings have regenerative properties. Hence biopsies of bat wing tissue are minimally harmful to the animal, but allow researchers to establish their age. Not only this, but they are long-lived species that demonstrate remarkable longevity; in fact, telomeres in the longest-lived species of bats do not shorten with age. So, based on 712 known-age bats from 26 species, the University of Maryland team set out to answer these three key questions:

1) Q: How accurately can chronological age be estimated in bats? A: Very accurately!

2) Q: Can DNAm that is identified to be age-related predict maximum lifespan? A: Yes – the rate of DNAm change at age-associated sites predicts maximum lifespan at the bat species level.

3) Q: How does age-related DNAm affect genes? A: Genetic analysis showed that “specific hypermethylated sites are disproportionately located in promoter regions of key transcription factors” as well as on histones and chromatin. Both result in transcriptional regulation, supporting aging being a change in systemic regulation.

Accurate clocks could allow therapeutic investigations to be conducted for human lifespan analysis as an individual would not have to die in order to analyse mortality.

Interestingly, age-related methylation was influenced by growth and development whilst longevity-related methylation was associated with the boosting of the innate immune system and tumour-suppressor genes. This provides support for stimulating the immune system and ensuring normal function of cancer protecting genes [2].

These key results highlight the beneficial role of epigenetic stability in longevity in bats. Yet this conclusion is supported throughout the literature in both mammals [3] and vertebrates [4]. Similar research should be tested and applied to human cases, in order to truly make it translatable.

Research would benefit tremendously from a validated clock, particularly in the longevity field as accurate clocks could allow therapeutic investigations to be conducted for human lifespan analysis as an individual would not have to die in order to analyse mortality. Furthermore, aging mechanisms would be clarified as more key biological makers are identified, paving way for better drug candidate design and personalised medicine.

As Horvath told us, methylation is a “huge signal” when it comes to aging – perhaps his latest research will allow science to refine it as a bat signal.
[1] https://pubmed.ncbi.nlm.nih.gov/29363785/
[2] https://www.nature.com/articles/s41467-021-21900-2
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940106/
[4] https://www.nature.com/articles/s41598-019-54447-w

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