How to Slow down the Ticking Clock: Age-Associated Epigenetic Alterations and Related Interventions to Extend Life Span

Abstract

Epigenetic alterations pose one major hallmark of organismal aging. Here, we provide an overview on recent findings describing the epigenetic changes that arise during aging and in related maladies such as neurodegeneration and cancer. Specifically, we focus on alterations of histone modifications and DNA methylation and illustrate the link with metabolic pathways. Age-related epigenetic, transcriptional and metabolic deregulations are highly interconnected, which renders dissociating cause and effect complicated. However, growing amounts of evidence support the notion that aging is not only accompanied by epigenetic alterations, but also at least in part induced by those. DNA methylation clocks emerged as a tool to objectively determine biological aging and turned out as a valuable source in search of factors positively and negatively impacting human life span. Moreover, specific epigenetic signatures can be used as biomarkers for age-associated disorders or even as targets for therapeutic approaches, as will be covered in this review. Finally, we summarize recent potential intervention strategies that target epigenetic mechanisms to extend healthy life span and provide an outlook on future developments in the field of longevity research.

Dietary intervention improves health metrics and life expectancy of the genetically obese Titan mouse

“…Interestingly, the liver of Titan mice showed overall decreased histone 4 acetylation at the 4–17 motif, specifically histone acetylation motifs such as H4K16 and H4K12K16 acetylation, which is in correlation with a reduction in the expression of acetyl-CoA synthases ( Accs2 and Pdhx ) which may imply reduced acetyl-CoA availability. This could underlie the general alteration in histone acetylation levels 41 , 69 and might also link this epigenetics phenotype to lifespan regulation 70 , 71 .…”

Gut metabolite trimethylamine N-oxide induces aging-associated phenotype of midbrain organoids for the induced pluripotent stem cell-based modeling of late-onset disease

“…In our organoid model, we observed an increased expression of p53, p21, and p16 following treatment with TMAO. In addition, epigenetics, known as an accurate cellular clock and epigenetic change, are strong indicators of biological aging ( Galow and Peleg, 2022 ). Long-term TMAO treatment resulted in a tendency to decrease H3K9me3 in midbrain organoids, suggesting the possibility of epigenetic aging.…”

Cross-Talk between the Cytokine IL-37 and Thyroid Hormones in Modulating Chronic Inflammation Associated with Target Organ Damage in Age-Related Metabolic and Vascular Conditions

“…Metformin acts by activating AMPK and SIRT1, energy-dependent metabolic cell sensors involved in maintaining cell cycling under stress conditions [ 52 , 120 ]. Included among the diverse roles of SIRT1, a NAD-dependent histone deacetylase, in maintaining body homeostasis are also those involved in cytokine production, epigenetic changes associated with trained immunity, and hormonal regulation of energy metabolism via homeostasis regulation in the HPT axis [ 121 , 122 , 123 , 124 ]. The links between insulin resistance, IL-37, and TSH under aging conditions should therefore be searched within those circuits involving regulation via oxidative metabolism and SIRT1, but accounting for differences in cell and tissue specificities and phases of tissue remodeling [ 122 ].…”