While knowing the start- and end-points of a journey is all well and fine, without studying the route taken, we may miss some exciting opportunities; a drink in an enchanting country pub, a picturesque stroll by the shores of a beautiful lake, or as a recent study has demonstrated, a potential treatment for aging?
Let’s start with a little background: studies have indicated that the canonical TGF-β/Smad signaling pathway senses environmental stresses and endogenous signals to promote a state of cellular shutdown known as senescence, often as a means to hinder cells from misbehaving and potentially becoming tumorigenic. Of note, the body also accumulates a greater and greater number of senescent cells as we age, and may be one of the reasons why tissue function deteriorates over time. However, while we know the starting point (TGF-β/Smad signaling) and the final destination (senescence) of this cellular journey, the many landmarks on the mechanistic route taken currently remain undescribed.
As epigenetic reprogramming represents a hallmark of senescence and can regulate DNA damage repair, telomere length, metabolic pathways, and senescence-related gene and miRNA expression, a team of researchers led by Wei Tao (Peking University, Beijing, China) sought to discover whether a microRNA and histone methylation cascade links canonical TGF-β/Smad signaling to the onset of senescence.
Here’s how the authors uncovered the some of the landmarks on the journey from TGF-β signaling to cellular senescence and came across a potential treatment for one of the signs of aging:
- Initial simple protein abundance assessments of histone modifications and modifying-enzymes in mouse embryonic fibroblasts (MEFs) as they entered senescence demonstrated the downregulation of mono-, di-, and tri-methylated lysine 20 histone H4 (H4K20) and both H4K20 methyltransferase enzymes (Suv4-20h1 and 2)
- Further Suv4-20h inhibition/downregulation by treatment with short hairpin RNA or a selective Suv4-20h inhibitor (A-196) reduced trimethylated H4K20 (H4K20me3) abundance and induced premature senescence due to the compromise of both DNA damage repair and genome maintenance
- Senescent MEFs also upregulated the expression of microRNAs (miR-29a and miR-29c, as measured by differential miRNA expression analyses) that target Suv4-20h mRNA to reduce Suv4-20h1/2 protein levels and decrease the abundance of H4K20me3
- Activation of the canonical TGF-β signaling pathway by stressors such as oxidative stress increased the expression of miR-29a and miR-29c in a Smad-dependent manner
- This data suggests that an epigenetic cascade mediated by miR-29 regulation of Suv4-20h enzyme levels and H4K20me3 abundance links cell stress signaling to the onset of senescence
- Interestingly, the authors discovered a link between the TGF-β-mediated increase in miR-29 expression and the loss of H4K20me3 and the decline of cardiac function in aging mice
- However, TGF-β signaling disruption by inhibitor treatment and Smad4 depletion reduced cardiac miR-29 expression, restored “youthful” H4K20me3 levels, and partially reversed the signs of cardiac aging
Overall, the description of this microRNA and histone methylation cascade linking TGF-β signaling to senescence may provide targets for the therapeutic modulation of aging, and more specifically, the maintenance of cardiac function over time. This study also begs the question of the existence of additional senescence-inducing epigenetic cascades functioning in other cells/tissues and of the ability to target them as part of an anti-aging treatment strategy.
For more details on how TGF-β signaling, microRNAs, and histone methylation regulate senescence and aging, head over to Nature Communications, July 2018.