The Intersection of Epigenetics and Senolytics in Mechanisms of Aging and Therapeutic Approaches

Abstract

The biological process of aging is influenced by a complex interplay of genetic, environmental, and epigenetic factors. Recent advancements in the fields of epigenetics and senolytics offer promising avenues for understanding and addressing age-related diseases. Epigenetics refers to heritable changes in gene expression without altering the DNA sequence, with mechanisms like DNA methylation, histone modification, and non-coding RNA regulation playing critical roles in aging. Senolytics, a class of drugs targeting and eliminating senescent cells, address the accumulation of dysfunctional cells that contribute to tissue degradation and chronic inflammation through the senescence-associated secretory phenotype. This scoping review examines the intersection of epigenetic mechanisms and senolytic therapies in aging, focusing on their combined potential for therapeutic interventions. Senescent cells display distinct epigenetic signatures, such as DNA hypermethylation and histone modifications, which can be targeted to enhance senolytic efficacy. Epigenetic reprogramming strategies, such as induced pluripotent stem cells, may further complement senolytics by rejuvenating aged cells. Integrating epigenetic modulation with senolytic therapy offers a dual approach to improving healthspan and mitigating age-related pathologies. This narrative review underscores the need for continued research into the molecular mechanisms underlying these interactions and suggests future directions for therapeutic development, including clinical trials, biomarker discovery, and combination therapies that synergistically target aging processes.

Keywords: DNA methylation; aging mechanisms; cellular senescence; epigenetic clock; epigenetics; healthspan extension; senolytics.

Figure 1

The primary epigenetic mechanisms involved in aging include DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs. During aging, there is a general trend of genome-wide hypomethylation, though specific regions may undergo either hypermethylation or hypomethylation. Aged cells also exhibit heterochromatin loss, which is reflected in changes to histone content and modification patterns. Additionally, the formation of senescence-associated heterochromatin foci (SAHFs) is a notable feature of cellular aging. Finally, miRNA deregulation, driven by impaired miRNA biogenesis, is observed across various species and tissues as part of the aging process. Abbreviations: DNMT, DNA methyltransferase; HAT, histone acetyltransferase.

Figure 2

The action of senolytic agents on senescent cells. The schematic illustrates the transition from normal to senescent cells and the impact of senolytic agents on aging and healthspan. On the left, various normal cell types (e.g., neurons, fibroblasts, epithelial cells) maintain tissue function. As aging progresses, these cells accumulate damage and enter a state of senescence. Senescent cells exhibit the senescence-associated secretory phenotype (SASP), releasing inflammatory cytokines, matrix metalloproteinases (MMPs), and chemokines, which contribute to tissue dysfunction and promote age-related diseases. Senolytic agents target these dysfunctional senescent cells, as shown in the lower right section, selectively inducing apoptosis and reducing their burden. This “hit-and-run” approach helps decrease SASP factors and supports tissue homeostasis, ultimately extending healthspan by reducing inflammation and delaying the onset of age-related diseases.