Hallmarks of Aging Series Part II: Epigenetics, Protein Homeostasis, and Autophagy

Wrapping up the final 3 "primary" aging hallmarks.

Greetings!

Last week, I published part I of an ongoing series of the Hallmarks of Aging.

Aging “hallmarks” are defined by three primary criteria: the time-dependent manifestation of aging-related alterations, the ability to accelerate aging through experimental manipulation, and the potential to slow down or reverse aging through therapeutic interventions.

In 2013, 9 hallmarks were identified: DNA instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. 

Recently, 3 new hallmarks were added to this list: disabled macroautophagy, chronic inflammation, and dysbiosis.¹

In last week’s post, the hallmarks telomere attrition and genomic instability were discussed, as were strategies that may intervene in these processes.

This week, we’ll be taking a look at the last 3 “primary” hallmarks: epigenetic alterations, a loss of proteostasis, and disabled macroautophagy.

Epigenetic alterations: an overview 🧬

Epigenetics (literally “on top of genetics”) refers to the study of heritable changes in gene expression and cellular phenotype that do not involve alterations in the underlying DNA sequence. 

Epigenetic modifications can influence gene activity by altering the accessibility of DNA to the cellular machinery that controls gene expression. Importantly, epigenetic changes can be reversible and are responsive to environmental factors, thereby playing a critical role in the regulation of development, cellular differentiation, and various physiological processes such as aging and disease development.

Epigenetics - Wikipedia 

Epigenetic alterations play a significant role in aging, encompassing various changes that impact gene expression and cellular functions. These alterations include:

DNA Methylation: DNA methylation is a fundamental epigenetic modification that involves the addition of a methyl group (CH3) to the cytosine base of DNA molecules. This modification typically occurs at cytosine bases that are immediately followed by a guanine base, forming a “CpG island.” 

Changes in DNA methylation patterns are observed with aging. While early studies highlighted global hypomethylation, further research has revealed that specific loci, including tumor suppressor genes may actually become hypermethylated with age. DNA methylation status has been used to predict chronological age and mortality risk — it’s the basis for many recently developed biological aging clocks. However, the direct causal relationship between DNA methylation changes and aging is not yet definitively established.

Histone modifications: alterations in histones, the proteins around which DNA is wound, are associated with aging. Changes in histone acetylation and methylation patterns can lead to transcriptional shifts, a loss of cellular balance, and age-related metabolic dysfunction. Modulation of histone modifiers, such as deacetylases and acetyltransferases, can impact longevity through effects on genomic stability, DNA repair, and metabolic pathways.

Chromatin remodeling: Chromatin is the complex of DNA, histone proteins, and other associated proteins that make up the structural framework of a chromosome within a cell's nucleus. It serves as a dynamic and organized packaging system for DNA, allowing the long DNA molecules to be efficiently packed into the confined space of the cell nucleus while also facilitating essential cellular processes, such as gene expression, replication, and repair.

Chromatin architecture changes with age due to alterations in chromosomal proteins and remodeling factors. These changes involve the loss of heterochromatin marks and redistribution. Loss-of-function mutations in chromatin-related proteins impact lifespan in invertebrates (fruit flies and worms), and similar studies in mammals indicate that maintaining heterochromatin integrity promotes longevity.

Non-coding RNAs (ncRNAs): a diverse group of ncRNAs, including long ncRNAs and micro RNAs, are implicated in aging. These molecules can post-transcriptionally influence components of longevity networks or regulate stem cell behavior. Gain- and loss-of-function studies demonstrate that certain micro RNAs can modulate longevity and contribute to aging-related pathologies.

Derepression of retrotransposons: Retrotransposons, mobile genetic elements, are reactivated in senescent cells and during aging. This reactivation leads to genetic and epigenetic changes and triggers immune responses and inflammation. Inhibitors of retrotransposition have been shown to extend lifespan and improve healthspan in animal models.

Gene expression changes: epigenetic alterations ultimately converge on changes in gene expression. Aging leads to increased transcriptional noise, aberrant mRNA production, and maturation. Comparative studies between young and old tissues have identified age-related transcriptional signatures associated with epigenetic changes. Certain biological processes, such as inflammation, protein folding, regulation of the extracellular matrix, and mitochondrial function, show deregulation with aging, and this is likely due to changes in gene expression.

Collectively, all of the above epigenetic changes contribute to the aging process. Unfortunately, many of these changes are associated with aging in humans, but a causal relationship has yet to be established.

Fixing epigenetic alterations 🛠️

Preventing epigenetic alterations associated with aging is a complex challenge, but there are several interventions and strategies that have been proposed to help mitigate these changes, including a diet rich in antioxidants, vitamins, and polyphenols; regular physical activity, stress management, caloric restriction, sleep, and minimizing exposure to environmental pollution and toxins. More state-of-the-art interventions include the use of epigenetic modulators and nutrients like resveratrol that have “anti-aging” properties, inhibitors of DNA methylation and histone deacetylation, genetic/epigenetic editing using technology like CRISPR, and senolytics — drugs that neutralize senescent “zombie” cells.

Loss of proteostasis: an overview 📁

Loss of proteostasis is a hallmark of aging associated with impaired protein homeostasis, resulting in the accumulation of misfolded, oxidized, glycated, or ubiquitinylated proteins that form intracellular inclusion bodies or extracellular amyloid plaques. 

This disruption of intracellular proteostasis is linked to several age-related diseases, including ALS, Alzheimer's disease, Parkinson's disease, and cataract, among others.