PLMI Blog

A recent 2024 review published in Cell Press explores the pivotal role epigenetic mechanisms have in governing the aging process, providing novel insights into the complex and intricate biological processes involved (1). Dysregulation in these critical regulatory mechanisms can impede cellular health and accelerate aging. Epigenetic dysregulation has emerged as a notable hallmark and driving force of aging (1-2).

Modulation of epigenetic mechanisms is essential for healthy biological aging while having widespread systemic benefits. Age-related epigenetic alterations profoundly impact gene expression, revealing robust connections between epigenetics and aging (3). A growing body of research underscores the importance of restoring epigenetic integrity to promote healthier aging and increased longevity.

Epigenetics – Providing a Hallmark of Aging

Epigenetics, encompassing the molecular mechanisms that regulate gene expression without altering the underlying DNA sequence, has evolved as a pivotal mark of aging. Demonstrated biomarkers of aging include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis (3). Dysregulation in epigenetic mechanisms can compound these processes and contribute to the aging process, whereas epigenetic regulation through nutrition and lifestyle helps to mitigate these biological marks of aging.

Age-related epigenetic changes of increased microRNA-31 (miR-31) have been demonstrated to alter gene expression via repression of the circadian regulator gene CLOCK and activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling, resulting in accelerated skin aging (1, 3). Results also correlated N6-methyladenosine (m⁶A) regulation with cellular senescence and aging processes, marking it as a potential therapeutic target (4). Both m⁶A methyltransferases and demethylases are crucial in modulating cellular senescence (2). Notably, the fat mass and obesity-associated protein (FTO) influences aging regulation independently of m⁶A. The absence of FTO leads to reduced levels of its interaction partner, MIS12, accelerating senescence in human mesenchymal stem cells regardless of m⁶A modifications (5). These findings underscore the role of m⁶A and its modulatory effects in aging.

Methylation – A Central Player in Epigenetics

Among the primary epigenetic modifications, DNA methylation predominantly occurs at cytosine bases within CpG dinucleotides. DNA methyltransferases (DNMTs) are essential for adding methyl groups to DNA. DNMT1 maintains existing methylation patterns during cell division, while DNMT3A and DNMT3B establish new patterns (2). Age-related alterations in DNA methylation manifest as hypermethylation or hypomethylation at specific genomic regions, leading to aberrant gene activation or repression, contributing to aging and age-related diseases (1).

The process results in the repression of certain genes (such as ELOVL2) while activating others (such as endogenous retroviruses) (1-5). Differentially methylated regions (DMRs) have emerged as crucial indicators of aging, altering genes associated with various physiological processes. Identifying DMRs is significant for understanding the molecular foundations of aging and developing efficacious, personalized approaches.

Measures of Biological Age – Epigenetic Clocks

Epigenetic clocks based on DNA methylation patterns have become valuable tools for measuring biological age, offering insights into the biological aging process, assessing health function, disease progression, and the effectiveness of nutrition and lifestyle interventions (2). By identifying DMRs, researchers can pinpoint genetic alterations associated with aging, revealing correlations between methylation patterns and lifespan. Various epigenetic clocks utilize DNA methylation patterns to measure biological age across a number of robust biomarkers (6). The development of epigenetic clocks has transformed our understanding of biological aging, providing a more comprehensive view of functional and cellular health.

Histone Modifications & Chromatin Restructuring 

Aging is associated with notable alterations in histone modifications and chromatin remodeling. Histone modifications represent a crucial layer of epigenetic modulation, impacting gene expression and chromatin restructuring evident in aging. Modifications, including acetylation and methylation, are pivotal in regulating chromatin accessibility and influencing gene transcription. Increased histone acetylation, specifically H3K27ac, has been linked to amyloid beta deposition in Alzheimer’s disease (7). These modifications also play a pivotal role in stem cell function and regenerative capacity.

Research demonstrates that certain histone marks can enhance stem cell rejuvenation, while others promote cellular senescence, contributing to the aging process (8). The loss of acetylation in enhancer regions hinders stem cell function, whereas elevated levels of H3K4me3 correlate with active transcription. Complex packaging of eukaryotic DNA into chromatin serves as a barrier to nucleotide-based processes that rely on the recruitment of enzymes and regulatory proteins to their target sites. Histone ubiquitination emerges as a key player in this complexity, influencing aging and revealing distinct markers of cellular senescence, illustrating the dynamic evolution of chromatin over time.

To facilitate essential cellular functions—such as transcription, differentiation, and DNA repair—chromatin must undergo coordinated remodeling at specific locations to enable the effective loading of these critical factors. Understanding these biological modifications offers comprehensive insights into aging, presenting novel therapeutic interventions aimed at enhancing regenerative capacity, restoring regulatory epigenetics, and promoting healthy aging.

RNA Modifications & The Epitranscriptome

Beyond DNA and histones, RNA modifications, particularly m⁶A, contribute to the epitranscriptome, a dynamic layer of gene regulation. The m⁶A methylation process involves methyltransferases, including METTL3 and METTL14, while demethylases such as FTO and ALKBH5 reverse these modifications (9). Alterations in RNA modifications can influence cellular senescence and aging processes, revealing novel approaches for therapeutic intervention (10).

Noncoding RNAs (ncRNAs), including microRNAs and long noncoding RNAs, have integral roles in modulating aging-related processes. The upregulation of miR-31 targets CLOCK, contributing to skin degradation with age (11). Such interactions highlight the complexity of the regulatory networks involved in aging and underscore the potential for ncRNAs as biomarkers for age-related conditions. The exploration of ncRNAs enhances understanding of the epigenetic landscape and its implications for aging.

Similar to DNA, RNA undergoes various chemical modifications, forming an epitranscriptome that adds an essential layer of regulation. Among these, the m⁶A modification in RNA is particularly notable for its dynamic and reversible nature (12). The writer complex, comprising METTL3 and METTL14, adds methyl groups, while eraser proteins, including FTO and ALKBH5, remove them. Reader proteins, such as those containing YTH domains, recognize m6A-modified RNAs, influencing their stability and translation (9)

Furthermore, RNA 5-methylcytosine m⁵C modification may play a role in mitigating inflammaging (1). Various noncoding RNAs, including microRNAs, circular RNAs (circRNAs), and long noncoding RNAs (lncRNAs), play critical roles in regulating aging. Notably, the upregulation of miR-31 during aging targets CLOCK, highlighting the complex interplay between noncoding RNAs and aging processes (3).

Supporting Epigenetics for Improved Healthspan and Increased Longevity

Epigenetic mechanisms extend beyond genetic sequences to influence genetic expression, playing a critical role in aging and related conditions. The multifaceted regulation highlights the importance of assessing epigenetic layers in the aging process that can impede cellular health.

The growing understanding of epigenetic mechanisms in aging facilitates innovative interventions aimed at promoting healthy aging and mitigating age-related disorders. These interventions encompass lifestyle modifications, pharmacological treatments, and advanced gene therapies.

Lifestyle

Following a nutrient-dense diet, getting regular exercise, and sufficient sleep can induce beneficial epigenetic changes by altering DNA methylation patterns, histone modifications, and modulation of noncoding RNAs (12). These practices are linked to favorable changes in DNA methylation patterns associated with longevity. Nutrition and lifestyle modalities also support favorable shifts in the gut microbiome, further promoting favorable genetic expression. Compounds such as resveratrol, taurine, gallic acid, quercetin, and vitamin C have been shown to exhibit rejuvenating effects through the interplay with the epigenome (1).

Intermittent fasting (IF) has been shown to alter DNA methylation patterns and promote histone modification restructuring, potentially slowing the aging process (2). Circadian rhythm balance and mitigating stress also hold promise for reducing age-related epigenetic changes, further underscoring the role of nutrition and lifestyle factors in modulating epigenetic health.

Pharmacological Approaches

Recent clinical trials, such as the CALERIE trial, demonstrate that pharmacological interventions, including metformin and nicotinamide riboside, positively influence aging pathways and epigenetic mechanisms (2). Senolytic therapies, which target and eliminate senescent cells, show promise in reducing the burden of cellular senescence and ameliorating associated health issues. These strategies aim to restore epigenetic integrity, thereby potentially reversing aging phenotypes and promoting improved cellular health and function.

Investigating compounds that modulate epigenetic markers offers novel, targeted potential for developing pharmacological interventions that address cellular health and age-related diseases while enhancing overall health and vitality. These emerging therapies harness the potential of epigenetics to extend healthspan and delay age-related conditions.

Gene & Cell-Based Therapies

Gene-based interventions, such as delivering genes related to longevity or regenerative capacity, are actively being explored. Genetic manipulation of factors, including KAT7 and SIRT2, demonstrates potential in treating age-related conditions such as osteoarthritis and cardiac hypertrophy (1-2). Furthermore, stem cell-derived therapies, especially those involving extracellular vesicles, are emerging as strategies to restore youthful epigenetic states.

These therapeutic approaches address existing age-related conditions and also enhance resilience against future age-related decline. The ability to modify the epigenetic landscape through targeted gene therapies represents a groundbreaking shift in how we approach and understand aging, health, and longevity.

Revolutionizing Health – Promoting Optimal Gene Expression Via Epigenetics

The exploration of epigenetic mechanisms has significantly advanced our understanding of aging. As research progresses, unraveling the interplay of these mechanisms will be crucial for developing effective treatments to address and potentially reverse biological aging and related diseases. Emerging epigenetic biomarkers and single-cell techniques offer valuable insights into the biological foundations of aging, enabling clinicians to monitor and promote beneficial epigenetic alterations while addressing dysregulation.

By targeting these mechanisms through lifestyle changes, pharmacological interventions, and novel therapies, we can potentially mitigate the adverse health effects of aging and enhance healthspan. Ongoing research highlights the critical role of epigenetics in modulating the aging process, underscoring the potential for future therapeutic strategies aimed at promoting healthy aging.

The relationship between epigenetics and aging is a rapidly evolving field, holding immense promise for transforming health. As we continue to uncover the biological intricacies of epigenetic mechanisms, modifications, and their novel impact on health and aging, the development of improved novel targeted strategies to optimize healthspan and longevity will continue to unfold.

Join us for the upcoming webinar: Updates on DNAm: What Works to Reverse Aging from 75 Treatments and Why a Single Test Might Replace the Need for All Others, occurring on November 19th from 5 to 7 pm. Experts Jeff Bland, PhD, Dr. Mike Stone, and Dr. Mathew Dawson will delve into the latest advancements in epigenetics research, providing novel clinical insights into the profound impact epigenetic mechanisms have on cellular health while sharing protocols for robust, healthy epigenetic patterns.

References:

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3. Yu, Y., Zhang, X., Liu, F. et al. A stress-induced miR-31–CLOCK–ERK pathway is a key driver and therapeutic target for skin aging. Nat Aging 1, 795–809 (2021). https://doi.org/10.1038/s43587-021-00094-8
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6. Yu Y, Zhang X, Liu F, Zhu P, Zhang L, Peng Y, Yan X, Li Y, Hua P, Liu C, Li Q, Zhang L. A stress-induced miR-31-CLOCK-ERK pathway is a key driver and therapeutic target for skin aging. Nat Aging. 2021 Sep;1(9):795-809. doi: 10.1038/s43587-021-00094-8. Epub 2021 Aug 16.
7. Nativio, R., Lan, Y., Donahue, G. et al. An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease. Nat Genet 52, 1024–1035 (2020). https://doi.org/10.1038/s41588-020-0696-0
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Yongtai Bai, Kai Li, Jinying Peng, Chengqi Yi, m6A modification: a new avenue for anti-cancer therapy, Life Medicine, Volume 2, Issue 1, February 2023, lnad008,