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In this paper on DNA methylation-based age clocks, researchers review the history of epigenetic clocks, age acceleration and emerging age-reprogramming strategies.

DNA methylation (DNAm) is one of three types of epigenetic changes that affect gene expression and are reversible [1]. DNAm is partially under the genome’s control but the environment also exerts its influence [2]. Aberrations of DNAm play an essential part in certain human disorders, including cancer or autoimmune diseases [3]. There is also a link between aging and DNAm as it turns out that one-third of all methylation sites are affected by age [4]. These age-related differentially methylated regions (DMRs) serve as reliable biomarkers of aging and form the basis of epigenetic clocks [5].

Longevity.Technology: Two types of epigenetic clocks have made their way into the market. First-generation clocks like Horvath’s, are used to measure the chronological age and are particularly useful in forensics. PhenoAge and GrimAge, second-generation clocks that measure physiological changes, are precise indicators of lifespan and health span. Some clinical trials already demonstrate that you can reset these aging clocks.

Epigenetic age predictors have been in development since 2011 [6]; every new model looks at various numbers of CpG sites, aims for the highest correlation between predicted and actual age and for the lowest age error margin possible. DeepMAge claims to be the most accurate human aging clock to date, with only a 3-year error margin.

Forensics versus clinical medicine

The paper, by researchers from Malopolska Centre of Biotechnology and Central Forensic Laboratory of the Police in Poland and from the University of Medical Sciences in Iran, shows that developing a model that fits both these sciences soon proved to be tricky. Compact and high targeted models work better in forensics to identify the small amounts of trace DNA samples available. But an increased accuracy limits the capture of methylation signatures predictive of longevity and necessary in medicine. Risk assessment models serve as facilitators in the development of aging clocks, for they identify which CpG sites display chronological changes, and which display physiological changes [7].

Second-generation clocks work best as prognostic tools of age-related conditions [6].

Epigenetic age acceleration and age-related diseases

Epigenetic age acceleration (EAA) represents the difference between one’s epigenetic age (DNAm age) and chronological age. A positive EAA indicates that you’re aging faster, while a negative EAA means that your body is aging slower than expected [8].

EAA itself is divided in two distinct measures: intrinsic (IEAA) – a measure independent of changes in blood cell composition – and extrinsic (EEAA) – reflecting changes in cell-type composition [6]. For example, Horvath’s multi-tissue clock measures IEAA and has been able to predict the onset of lung cancer based on blood cell’s DNAm [6].

The paper lists many correlations between EAA and age-related diseases, from neurological conditions like bipolar disorder or Alzheimer’s disease, to metabolic disorders like obesity or dyslipidaemia.

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It is important to note that EAA is affected by lifestyle and the environment. Cholesterol, puberty, stress or alcohol consumption, to cite only a few, are factors that associate with EAA [6]. Sports also modulate one’s EAA. Elite athletes show an accelerated epigenetic age after intense physical training [9]. Generally, the epigenetic aging rate of men was shown to be higher than women’s [6].

 


 

Nuclear reprogramming of somatic cells suggests that the aging hallmarks can be reversed. 

 


 

Rejuvenation potential

Practically, with aging, our body undergoes a progressive organ and tissue deterioration; this implies a gradual loss of functionality which represents a major risk factor for prevalent aging diseases. DNAm plays a part in the aging process, thus reversal strategies are promising to resist aging.

More knowledge on epigenetics through tools such as the DunedinPoAm algorithm, helps increase the efficacy evaluation of senotherapeutics and age-reversing interventions.

Nuclear reprogramming of somatic cells suggests that the aging hallmarks can be reversed [6]. Cell reprogramming with the Yamanaka factors – de-differentiating somatic cells into induced pluripotent stem cells – is also a promising epigenetic rejuvenation strategy. An alternative, partial cell reprogramming with transient mRNA activating the Yamanaka factors, resets the epigenetic age of human cells without the need of de-differentiation [6].

Now, thanks to locus-specific engineering technologies like CRISPR – a gene editing tool – we can already think about editing age-related epigenetic targeted sequences [10].

Where we’re at

Therapies of epigenetic rejuvenation are already ongoing at preclinical phases, and some could soon hit human clinical trials [6]. The authors of the paper remind us that, as ever, we need to remain cautious with the research progress in this field. While there is continuous development and we have robust data from animal studies, this area is still in its infancy and requires longitudinal human investigations, particularly on the potential side effects of the therapeutic strategies.

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[1] https://www.nature.com/articles/nrm4048
[2] https://www.nature.com/articles/ng1089z
[3] https://www.nature.com/articles/nrg1655
[4] https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067378
[5] https://www.nature.com/articles/s41576-018-0004-3
[6] https://www.sciencedirect.com/science/article/pii/S1568163721000611
[7] https://www.nature.com/articles/ncomms14617
[8] https://www.nature.com/articles/s41467-017-02697-5
[9] https://www.aging-us.com/article/101385/text
[10] https://www.sciencedirect.com/science/article/pii/S1934590917303739

Image credit: National Cancer Institute / Unsplash
Eleanor Garth
Deputy Editor Now a science and medicine journalist, Eleanor worked as a consultant for university spin-out companies and provided research support at Imperial College London and various London hospitals in a former life.

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