Cellular senescence is a persistently hypoproliferative state with diverse stressors in a specific aging microenvironment. Senescent cells have a double-edged sword effect: they can be physiologically beneficial for tissue repair, organ growth, and body homeostasis, and they can be pathologically harmful in age-related diseases. Among the hallmarks of senescence, the SASP, especially SASP-related extracellular vesicle (EV) signalling, plays the leading role in aging transmission via paracrine and endocrine mechanisms. EVs are successful in intercellular and interorgan communication in the aging microenvironment and age-related diseases. They have detrimental effects on downstream targets at the levels of immunity, inflammation, gene expression, and metabolism. Furthermore, EVs obtained from different donors are also promising materials and tools for antiaging treatments and are used for regeneration and rejuvenation in cell-free systems. Here, we describe the characteristics of cellular senescence and the aging microenvironment, concentrating on the production and function of EVs in age-related diseases, and provide new ideas for antiaging therapy with EVs.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jev2.12154

Roles of extracellular vesicles in the aging microenvironment and age-related diseases.

Piwi-interacting RNAs (piRNAs) are a novel type of small noncoding RNAs, which are 26–30 nt in length and bind to Piwi proteins. These short RNAs were originally discovered in germline cells and are considered as key regulators for germline maintenance. A growing body of evidence has now extended our views into piRNA biological significance showing that they can also regulate gene expression in somatic cells through transposon silencing, epigenetic programming, DNA rearrangements, mRNA turnover, and translational control. Mounting studies have revealed that the dysregulation of piRNAs may cause epigenetic changes and contribute to diverse diseases. This review illustrates piRNA biogenesis, mechanisms behind piRNA-mediated gene regulation, and changes of piRNAs in different diseases, especially in cancers.

The Biogenesis and Functions of piRNAs in Human Diseases.

PIWI‐interacting RNAs (piRNAs) are abundantly expressed in heart. However, their functions and molecular mechanisms during myocardial infarction remain unknown. Here, a heart‐apoptosis‐associated piRNA (HAAPIR), which regulates cardiomyocyte apoptosis by targeting N‐acetyltransferase 10 (NAT10)‐mediated N4‐acetylcytidine (ac4C) acetylation of transcription factor EC (Tfec) mRNA transcript, is identified. HAAPIR deletion attenuates ischemia/reperfusion induced myocardial infarction and ameliorate cardiac function compared to WT mice. Mechanistically, HAAPIR directly interacts with NAT10 and enhances ac4C acetylation of Tfec mRNA transcript, which increases Tfec expression. TFEC can further upregulate the transcription of BCL2‐interacting killer (Bik), a pro‐apoptotic factor, which results in the accumulation of Bik and progression of cardiomyocyte apoptosis. The findings reveal that piRNA‐mediated ac4C acetylation mechanism is involved in the regulation of cardiomyocyte apoptosis. HAAPIR‐NAT10‐TFEC‐BIK signaling axis can be potential target for the reduction of myocardial injury caused by cardiomyocyte apoptosis in ischemia heart diseases.

PIWI‐Interacting RNA HAAPIR Regulates Cardiomyocyte Death After Myocardial Infarction by Promoting NAT10‐Mediated ac4C Acetylation of Tfec mRNA

Small extracellular vesicles (EVs) play a significant role in intercellular communication through their non-coding RNA (ncRNA) cargo. While the initial examination of EV cargo identified both mRNA and miRNA, later studies revealed a wealth of other types of EV-related non-randomly packed ncRNAs, including tRNA and tRNA fragments, Y RNA, piRNA, rRNA, and lncRNA. A number of potential roles for these ncRNA species were suggested, with strong evidence provided in some cases, whereas the role for other ncRNA is more speculative. For example, long non-coding RNA might be used as a potential diagnostic tool but might also mediate resistance to certain cancer-specific chemotherapy agents. piRNAs, on the other hand, have a significant role in genome integrity, however, no role has yet been defined for the piRNAs found in EVs. While our knowledgebase for the function of ncRNA-containing EVs is still modest, the potential role that these EV-ensconced ncRNA might play is promising. This review summarizes the ncRNA content of EVs and describes the function where known, or the potential utility of EVs that harbor specific types of ncRNA.

https://www.mdpi.com/2072-6694/12/6/1445/pdf

The Long and Short of It: The Emerging Roles of Non-Coding RNA in Small Extracellular Vesicles.

Cardiovascular diseases (CVDs) are the leading causes of death worldwide. Increasing reports demonstrated that non-coding RNAs (ncRNAs) have been crucially involved in the development of CVDs. Piwi-interacting RNAs (piRNAs) are a novel cluster of small non-coding RNAs with strong uracil bias at the 5′ end and 2′-O-methylation at the 3′ end that are mainly present in the mammalian reproductive system and stem cells and serve as potential modulators of developmental and pathophysiological processes. Recently, piRNAs have been reported to be widely expressed in human tissues and can potentially regulate various diseases. Specifically, concomitant with the development of next-generation sequencing techniques, piRNAs have been found to be differentially expressed in CVDs, indicating their potential involvement in the occurrence and progression of heart diseases. However, the molecular mechanisms and signaling pathways involved with piRNA function have not been fully elucidated. In this review, we present the current understanding of the piRNAs from the perspectives of biogenesis, characteristics, biological function, and regulatory mechanisms, and highlight their potential roles and underlying mechanisms in CVDs, which will provide new insights into the potential applications of piRNAs in the clinical diagnosis, prognosis, and therapeutic strategies for heart diseases.

Piwi-interacting RNAs (piRNAs) as potential biomarkers and therapeutic targets for cardiovascular diseases.

Objective Heart failure is a leading cause of cardiovascular mortality in industrialized countries. Increasing evidence has highlighted the relationship between noncoding regulatory RNAs, especially microRNAs, and heart failure. However, few studies address the role of piRNAs in heart failure. Therefore, we compared exosomal piRNAs between heart failure patients and healthy volunteers to investigate the role of piRNAs in heart failure. Patients and methods First, exosomes were isolated from the serum of heart failure patients and healthy volunteers. After confirming exosome identity by electron microscopy, nanoparticle analysis, and Western blotting, RNA was extracted from exosomes. The expression of piRNAs was then compared by RNA sequencing and bioinformatics analysis. Results Serum exosomes from heart failure patients and healthy volunteers were successfully isolated and identified. Serum exosome presence was increased in heart failure patients compared to healthy volunteers. RNA sequencing and bioinformatics analysis revealed that 585 piRNAs were upregulated in heart failure patients, and 4,623 piRNAs were downregulated. Among these piRNAs, has-piR-020009 and has-piR-006426 were the most downregulated. Conclusions Collectively, a dramatic difference in the expression of piRNAs in serum exosomes of heart failure patients was observed. Altogether, these data suggest that piRNAs are potential biomarkers of heart failure and that serum exosome isolation may provide a clinically relevant source of piRNAs for sequencing analysis.

Exosomal piRNA sequencing reveals differences between heart failure and healthy patients.

Objective Aging is now considered as an independent risk factor for cardiac fibrosis. However, the mechanisms underlying aging-related cardiac fibrosis remain unknown. Here, we examine the role of serum exosomes in this process. Materials and methods Experiments were conducted using 6-week-old or 24-week-old male Sprague-Dawley (SD) rats. Cardiac sections were treated with Masson's trichrome stain to evaluate fibrosis. Exosomes were isolated from the serum, characterized and quantified using Western blot, electron microscopy, and qNano analysis, and co-cultured with transforming growth factor-β1 (TGF-β1)-induced primary cardiac fibroblasts (CF). Co-cultures were also carried out in the presence of a hot shock protein 70 (HSP70) inhibitor (gefitinib) or inducer (geranylgeranylacetone) to evaluate the role of HSP70 in cardiac fibrosis. Results Cardiac fibrosis as well as serum exosomes levels were increased during senescence. We observed an increase in fibroblast proliferation and myofibroblast differentiation when CF were co-cultured with exosomes from old rats, compared to those from young mice. Observing a decrease in surface HSP70 expression on the exosomes derived from old rats, we tested the effects of HSP70 inhibition or overexpression on the CF co-cultures. HSP70 inhibition increased fibroblast proliferation and myofibroblast differentiation in CF co-cultures containing exosomes from the young rats, while HSP70 overexpression attenuated fibroblast proliferation and myofibroblast differentiation in CF co-cultures containing exosomes from the old rats. Conclusions Using an animal model of cardiac fibrosis, we show a decrease in HSP70 expression on the exosomal surface with aging, which may contribute to cardiac fibrosis.

Decreased HSP70 expression on serum exosomes contributes to cardiac fibrosis during senescence.

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Exosomal piRNA sequencing reveals differences between heart failure and healthy patients.

Decreased HSP70 expression on serum exosomes contributes to cardiac fibrosis during senescence.