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DNA Methylation and Aging: Best of Friends, Worst of Enemies?

Old Guys Having Fun

By Stuart P. Atkinson, Ph.D.

January 10, 2023

Introduction: DNA Methylation and Aging: Best of Friends, Worst of Enemies?

Researchers appreciate that the old adage "the only two certainties in life are death and taxes" may require updating to include the inevitable changes to various epigenetic modifications that transpire during normal human aging. Unfortunately, epigenetic alterations and aging may be the best of friends and the worst of enemies, as they combine to negatively impact our physiology and promote disease, a point emphasized by two recent DNA methylation-based studies.

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Part One: Clocking Biological Aging to Combat Neurodegenerative Disease – Comparing the Sexes

Researchers led by Anna Kankaanpää (University of Jyväskylä, Finland) examined sex-based differences in biological aging measured by DNA methylation-based epigenetic clocks to fully understand the influence of lifestyle factors such as smoking and body mass index on lifespan. Meanwhile, a team headed by Jongpil Kim (Dongguk University, Korea) reported targeted DNA hypermethylation induced through the application of CRISPR/Cas9 technology as a potential therapeutic strategy for Alzheimer's disease, a neurodegenerative disease whose onset is linked to age-related epigenetic alterations.

While males and females have both experienced recent increases in lifespan, women still enjoy longer life expectancies than men, with sex-based differences likely deriving from the complex intertwined influences of multiple biological and non-biological factors (Mauvais-Jarvis et al.). Men experience a higher risk of death from all causes (Roth et al.), with external causes of death most common among men; however, these factors explain only a fraction of premature deaths. Instead, non-communicable age-related diseases cause most premature deaths (Roth et al.); therefore, the biological/behavioral factors predisposing individuals to said diseases represent essential drivers of sex-based differences in lifespans.

DNA methylation-based epigenetic clocks can help to track and understand biological aging and provide insight into sex-based differences in lifespans and how lifestyle may modify the aging process (Levine 2020, Horvath 2013, Hannum et al., Levine et al., and Lu et al.); notably, previously published results on biological age determined by epigenetic clocks also reported men as older than women (Jylhävä et al., Simpkin et al., Li et al., Crimmins et al., and Oblak et al.).

DNA Methylation Tools

Finnish Twins Help Describe How Sex Influences Aging

A recent study from the laboratory of Anna Kankaanpää (University of Jyväskylä, Finland) examined sex-based differences in biological aging measured with the help of DNA methylation-based epigenetic clocks in cohorts of Finns to assess the impact of lifestyle factors between the sexes and whether age modifies any associations. Kankaanpää and colleagues isolated and assessed blood samples from sets of younger and older twins, including younger opposite-sex twin pairs. Blood-based DNA methylation profiles applied to epigenetic clocks (the Horvath and Hannum epigenetic clocks, DNAm PhenoAge, and DNAm GrimAge) defined biological aging, with pathway modeling then assessing the impacts of lifestyle-related factors on associations between sex and biological aging.

Data confirmed the older biological age of males, with this difference associated with men's unhealthier lifestyle habits. The sex-based difference in biological age became evident in young adulthood and increased with age - men possessed an epigenetic age 1.2–1.3 years older than women in younger twins (21–42 years) and 3.2–4.3 years older than women in older twins (50–76 years). The observed age-related increase in the sex-based difference mainly derived from accelerated epigenetic aging with age in men. Body mass index in all twins mediated the older epigenetic age of men in twins, while smoking mediated the older epigenetic age of men in older twins. Smoking also associated with accelerated epigenetic aging in men, with a stronger association in older twins suggesting a cumulative effect of smoking. Interestingly, the study also noted that the narrowing of sex-based differences in smoking partly explained declining lifespan disparities.

In The Battle of the Sexes – Are We Heading towards a Tie?

The authors believe that their findings will improve our understanding of how lifestyle factors affect biological aging and support the development of measurement methodologies that can determine individual aging trajectories during early adulthood to support investigations into the effects of environmental/societal changes and lifestyle interventions on lifespans. Importantly, these data also suggest that sex-based differences in biological age/lifespan will narrow among future aging generations thanks to the ever-shrinking differences in lifestyle habits between men and women. For more on how the diminishing sex-based differences in lifestyle habits affect DNA methylation-based measures of biological age set by epigenetic clocks, see The Journals of Gerontology: Series A, September 2022.

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Part Two: CRISPR/Cas9-mediated DNA Methylation Battles Back Against Age-Related Neurodegeneration

Altered Epigenetic Modifications and Alzheimer's disease: Can CRISPR Technology Help?

Alzheimer's disease, a progressive neurological disease and common form of dementia (Castellani et al.), is characterized by the accumulation of neurotoxic amyloid beta (Aβ) peptides as plaques in the brain, neural cell death, and neuroinflammation (O'Brien and Wong). Importantly, the production of the Aβ peptides via the proteolysis of the amyloid beta precursor protein (APP) represents a critical step in Alzheimer's disease pathogenesis Castellani et al. and O'Brien and Wong).

Studies have found evidence for the involvement of neuron-specific epigenetic modifications that trigger altered gene expression associated with Alzheimer's disease pathogenesis (Mastroeni et al. and Bennett et al.). Interestingly, promoter hypomethylation of the APP gene in older patients (≥ 70 years of age) prompts excessive overexpression, which induces a significantly increased level of neurotoxic Aβ peptides (McDonald et al., Iwata et al., and Brohede et al.). Therefore, resetting Alzheimer's disease-associated epigenetic (and hence gene expression) profiles may aid the battle against this age-related neurodegenerative disease by reducing Aβ peptide levels.

CRISPR/Cas9-mediated epigenetic editing represents an exciting means of altering DNA/histone modifications at specific sites to alter gene expression levels and potentially treat various diseases. For example, induced DNA methylation through a dCas9-Dnmt3a system has been employed to silence oncogene expression by inducing higher levels of DNA methylation at gene regulatory regions and may represent a potent-antitumor therapy (McDonald et al. and Vojta et al.). In neurodegenerative disease, a dCas9-Tet1 system induced FMR1 gene expression via the targeted inhibition of DNA methylation, which reduced the neuronal abnormalities sociated with fragile X syndrome (Liu et al.).

Could CRISPR/Cas9-mediated epigenetic editing, therefore, represent a platform for the development of novel Alzheimer's disease therapies that reduce APP expression and Aβ peptide levels that go beyond the current treatment strategies that only provide temporary respite to patients? (Birks, 2006).

Can APP-targeted DNA Hypermethylation Reduce Alzheimer's Disease Symptoms?

Researchers from the laboratory of Jongpil Kim (Dongguk University, Korea) sought to explore the efficient and targeted hypermethylation of the APP gene promoter through the implementation of a catalytically inactivated Cas9 fused to the Dnmt3a DNA methyltransferase (dCas9-Dnmt3a) to reduce APP gene expression and therefore inhibit pathological signs of Alzheimer's disease. As a model system, Park, Shin, and Colleagues employed the APP gene knock-in (APP-KI) mouse model (Saito et al.), which recapitulates key pathological features of Alzheimer's disease, including the production of Aβ peptides.

As expected, in vitro cultured APP-KI mouse primary neurons displayed DNA hypomethylation at the APP gene promoter and an elevated correlative level of APP gene expression; however, the addition of dCas9-Dnmt3a prompted a specific increase in DNA methylation at the APP gene promoter, which correlated with a significant decrease in APP gene expression. Additional consequences of APP-targeted DNA methylation included a decrease in multiple additional Alzheimer's disease-associated pathological factors, including neurotoxic Aβ peptide levels and neural cell death.

Excitingly, the authors moved beyond these in vitro analyses and took their APP-targeted dCas9-Dnmt3a approach in vivo into the brains of APP-KI mice. Overall, the increased levels of DNA methylation of the APP gene promoter after dCas9-Dnmt3a exposure in vivo (with minimal off-target effects) induced alterations to the Aβ plaques characteristic of Alzheimer's disease and attenuated associated learning and memory impairments. While epigenetic editing at the APP locus could slow Alzheimer's disease progression or prevent the destruction of nerve cells after plaque formation, the authors discovered that dCas9-Dnmt3a exposure to mice before plaque deposition also effectively modulated Alzheimer's disease pathogenesis. Consequently, the authors believe that epigenetic editing during early-stage disease development may reduce disease risk or delay the onset of severe symptoms.

Epigenetic Editing with CRISPR/Cas9 Combats Age-related Neurodegenerative Disease

While confirming the involvement of aberrant reduced DNA methylation levels at the APP gene promoter in Alzheimer's disease pathogenesis, these fascinating results suggest that targeted DNA hypermethylation at this locus through dCas9-Dnmt3a represents a potentially exciting therapeutic strategy for Alzheimer's disease patients. Furthermore, the authors' findings validate CRISPR/Cas9-mediated epigenetic editing as a highly efficacious targeted epigenome engineering approach for future clinical applications in precision medicine in areas that include neurodegenerative disease treatment and beyond. For more on how CRISPR/Cas9-mediated epigenetic editing supports targeted alterations in gene expression to combat age-related neurodegenerative disease, see Translational Neurodegeneration, September 2022.

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About the author

Stuart P. Atkinson

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

Contact Stuart on Twitter with any questions

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