MicroRNAs as modulators of longevity

Aging is a consequence of complex molecular changes, but the roles of individual microRNAs (miRNAs) in aging remain unclear. One of the few miRNAs that are upregulated during both normal and premature aging is miR-29. We confirmed this finding in our study in both mouse and monkey models. Follow-up analysis of the transcriptomic changes during normal aging revealed that miR-29 is among the top miRNAs predicted to drive the aging-related gene expression changes. We also showed that partial loss of miR-29 extends the lifespan of Zmpste24-/- mice, an established model of progeria, which indicates that miR-29 is functionally important in this accelerated aging model. To examine whether miR-29 upregulation alone is sufficient to promote aging-related phenotypes in vivo, we generated mice in which miR-29 can be conditionally overexpressed (miR-29TG). We found that miR-29 overexpression in mice is sufficient to drive aging-related phenotypes including alopecia, kyphosis, osteoporosis, senescence, and leads to early lethality. Transcriptomic analysis of both young miR-29TG and old WT mice revealed shared downregulation of genes enriched in extracellular matrix and fatty acid metabolism, and shared upregulation of genes in pathways linked to inflammation. Together, these results highlight the functional importance of miR-29 in controlling a gene expression program that drives agingrelated phenotypes.

Starting at approximately one month of age, miR-29TG mice began to display premature graying of hair as well as extensive kyphosis that was confirmed using Computed Tomography (CT) imaging analysis (Figures 3A and 3B). The miR-29TG mice also exhibited severe lipodystrophy characterized by little or absent inguinal fat pads at 2 months (Figure 3C). Further, these mice showed reduced skin thickness in all layers of the dermis and epidermis (Figures 3D and 3E).

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Elastin (ELN) is a major component of the extracellular matrix in arteries that is essential for normal structural integrity and function. In humans, a single ELN gene is found on chromosome 7 and mutations in one allele of the ELN gene can lead to several elastinopathies, including supravalvular aortic stenosis (SVAS) and a congenital narrowing of the ascending aorta or other vessels, SVAS is also a prominent component of Williams-Beuren syndrome (WBS), a frequent heterozygous deletion of a ~1.5 Mb segment at chromosome 7q11.23 that includes ELN. Despite having one intact allele , the expression of elastin is less than 50% of normal in WBS, thus suggesting post-transcriptional modulation of the mRNA.

Elastin is secreted into the extracellular space as soluble tropoelastin, which is cross-linked by lysyl oxidase (LOX) and lysyl oxidase-like 1 (LOXL1) to form insoluble, mature elastin fibrils. Rodent studies have shown that elastogenesis begins during mid-gestation,peaks in the perinatal period, and drops sharply thereafter to low levels that persist into adulthood? Interestingly, tropoelastin pre-mRNA levels remain elevated in adult rat lungs despite considerably reduced steady-state mRNA levels , thus suggesting mRNA post-transcriptional regulation may be a predominant mechanism to regulate elastin mRNA and protein levels in adults.

In the past decade, microRNAs (miRNAs) have emerged as important regulators of gene expression robustness. miRNAs predominantly target the 3’UTR of mRNAs, either destabilizing the mRNA transcript or interfering with its translation into protein. Previous work has shown that miR-29 mimics down-regulate the expression of ELN, COL1A1 and COL3A1. Here we show that inhibition of miR-29a can dramatically increase ELN expression in human cells and miR29 inhibition upregulates ELN levels in cells from patients with ELN haploinsufficiencies and in bioengineered human blood vessels. Thus, antagonizing the actions of miR-29 may promote increased ELN levels during conditions of enhanced elastinolysis or deficiencies.

https://www.ahajournals.org/doi/10.1161/ATVBAHA.111.242412

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MicroRNAs are short non-coding RNAs that play key roles in regulating biological processes. In this study, we explored effects of chronological and photoageing on the miRNome of human skin. To this end, biopsies were collected from sun-exposed (outer arm, n = 45) and sun-protected (inner arm, n = 45) skin from fair-skinned (phototype II/III) healthy female volunteers of three age groups: young, 18–25 years, middle age, 40–50 years and aged, > 70 years. Strict inclusion criteria were used for photoageing scoring and for chronological ageing. Microarray analysis revealed that chronological ageing had minor effect on the human skin miRNome. In contrast, photoageing had a robust impact on miRNAs, and a set of miRNAs differentially expressed between sun-protected and sun-exposed skin of the young and aged groups was identified. Upregulation of miR-383, miR-145 and miR-34a and downregulation of miR-6879, miR-3648 and miR-663b were confirmed using qRT-PCR in sun-exposed skin compared with sun-protected skin. qRT-PCR analysis revealed that miR-383, miR-34a and miR-134 were differentially expressed in all three age groups both in chronological and photoageing, suggesting a synergetic effect of intrinsic and extrinsic ageing on their expression. In conclusion, our study identifies a unique miRNA signature which may contribute to skin ageing.

https://www.nature.com/articles/s41598-018-31217-8

The winners of the 2024 Nobel prize for Medicine/Physiology was recently announced. The discoverers of microRNA…

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