Aging, Sex and Hormones – Here’s How Hormone Replacement Therapy Saves Lives

Aging and Sex Hormones Modulate the Exosome Transport of Micro RNAs:  Why Hormone Level Should be Kept High –if you want to Live a Full Life

This research is first study showing that age and the use of HRT are associated with the microRNA contents of the circulating exosomes in women 
These results suggest that the postmenopausal HRT users are more similar to premenopausal women in terms of microRNA regulated cell proliferation than postmenopausal non-users. 
 Our findings suggest that the serum exomiRs are sensitive to hormonal changes among women and carry important regulatory messages between cells. 
We were able to identify microRNA groups related to more positive or negative health outcomes in which the systemic E2 concentration played a significant role as a divider. Our findings suggest that the serum exomiRs are sensitive to hormonal changes among women and carry important regulatory messages between cells. The results can be used as a directional starting point for the usage of miR signature, obtained by NGS, as a medical tool for prognostics and diagnostics in aging women. In addition, the miR signature can potentially be applied when evaluating the benefits of HRT usage and its individual suitability in personalized medicine.
When comparing the groups, of pre or post menopausal women and postmenopausal twins either on HRT or not,  differentially expressed microRNAs were predicted to affect cell proliferation processes showing inactivation with younger age and HRT usage. In this research, microRNAs formed two hierarchical clusters being indicative of positive or negative health outcomes involving associations with body composition, serum 17β-estradiol, fat-, glucose- and inflammatory markers.  
The results were clear, suggesting that that the Exosome carried microRNAS could be used as indicators of metabolic and inflammatory status affected by hormonal changes at menopause.   Furthermore, the individual effects of HRT-usage could be evaluated based on the serum exomiR signature.  Based on this genetically controlled study, these effects are achieved to most part by the HRT usage. 
These miRs have been shown to function as regulators of cellular homeostasis. Hierarchical clustering analysis revealed two miR-clusters, one indicating negative association with E2 parallel to positive association with markers of adiposity and inflammation and the other being opposite in the associations with E2 and metabolic health markers. These results suggest that female E2 status may be a mediator of the change in exomiR content that in turn is associated with change in health metabolic status known to occur within menopause.
The study was the first to show that specific exosome-packed microRNAs are sensitive to the in the circulation, which is influenced both by age and the use of hormonal therapies. The results can be exploited in evaluating the effects of hormonal contraceptives and hormone replacement therapies on the overall physiological status of women. When the regulatory mechanisms of the microRNAs are better understood, the microRNA profile can be used for recognizing individuals with a high risk for metabolic disorders, or even lowering the risk.

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Link: Estrogen explains the exosome-carried messenger profile in the circulation among postmenopausal women
Estrogens, female sex steroid hormones, have broad systemic effects on different cell types through their receptors. As known, the levels of systemic estrogens, especially 17β-estradiol (E2), change dramatically at the time of menopause in women.
Estrogen sensitivity of microRNA  regulation and their expression in different cell types has been recently demonstrated in several studies previous studies have shown that circulating cell free microRNAs, including miR-21 and miR-146a differ between postmenopausal genetically identical twin sisters who are discordant for the estrogen based hormone replacement therapy (HRT) suggesting that systemic estrogen levels affect microRNAs profile 
A very recently published study demonstrated an association between accelerated aging, measured by the epigenetic age i.e. DNA methylation status of blood, and early onset of menopause15. In the present study, we investigated whether the age or/and the use of postmenopausal HRT associates with the miR content of the circulating exosomes. We extracted exosomes from the serum of healthy premenopausal women (n = 8) not using external estrogen products and from healthy postmenopausal monozygotic (MZ) twin sisters discordant for the use of HRT (n = 10 pairs

These small membrane vesicles do much more than clean up a cell’s trash—they also carry signals to distant parts of the body, where they can impact multiple dimensions of cellular life.


Secreted vesicles known as exosomes were first discovered nearly 30 years ago. But, considered little more than garbage cans whose job was to discard unwanted cellular components, these small vesicles remained little studied for the next decade.

Over the past few years, however, evidence has begun to accumulate that these dumpsters also act as messengers, actually conveying information to distant tissues. Exosomes contain cell-specific payloads of proteins, lipids, and genetic material that are transported to other cells, where they alter function and physiology.


Exosomes are spherical nanoscale lipid vesicles that serve as “messenger molecules” They bud from the late endosomes in the cytoplasm forming multivesicular bodies (MVB) and either remain in the cells they are formed or are fused with the plasma membrane and exported to the extracellular matrix or further to the circulation
Given their complex structures, exosomes can have a much more potent influence on the physiology of the cells they encounter than single-molecule mediators, such as lipids, hormones, or cytokines.
For one, exosomes carry specific patterns of ligands and receptors on their surface, which likely allows targeting of specific cell types bearing the right counterligands. Furthermore, the numerous proteic, lipidic, and even nucleic acid components they carry can affect multiple signaling pathways inside target cells, while single molecules that bind to a single receptor on the target cell surface will initiate only a single pathway.
They are formed inside the cell in compartments known as multivesicular endosomes (MVE), which take up bits of the cytoplasm and its contents into membrane-bound vesicles. They are small (<100 nm in diameter) spherical bilayer proteolipid vesicles produced by various cell types under both normal and pathological conditions. 
MVE were originally thought to merely help traffic extracellular molecules to lysosomes, where they are degraded. But about 25 years ago, researchers described the opposite process—MVE in developing red blood cells fused with the plasma membrane and released their contents, including numerous small vesicles (later dubbed exosomes), outside the cell.
Now we know that  changes induced by exosomes upon interaction with recipient cells can vary widely depending on the type and physiological state of the secreting cell, and can either help ward off disease or, in some cases, exacerbate it.
These small packages carry microRNA moleculesbetween  cells regulating gene function ”  MicroRNAs (miRs) are a class of epigenetic regulators, small non-coding RNAs, which bind to their target mRNAs leading to RNA silencing and further to translational suppression.  
microRNAs  are localized in various cell types as well as in all body fluids  
In 1996,  Raposo published her discovery that immune cells such as B lymphocytes also secreted exosomes, and that these vesicles carried membrane-bound molecules essential for the adaptive immune response
Recent studies of exosomes purified in vitro showed that the vesicles can be captured by other cells, thus transferring any information enclosed in and/or on the exosome. Antigen-presenting cells, for example, share captured and digested pathogens via exosomes, increasing the range and intensity of the immune response against the invaders. Other exosome-bound molecules can induce the inactivation or even the death of the target cell they encounter
Macrophages infected with nonpathogenic mycobacteria release exosomes that have been shown to bear bacterial antigens, which then are taken up by other antigen-presenting cells and promote immune responses  
Exosomes secreted by cancer cells carry antigens from the tumors, and can be captured by dendritic cells and used to present tumor antigens that would activate immune cells against the cancer. However, these exosomes also contain various immunosuppressive molecules, which can inactivate T lymphocytes or natural killer cells, or promote the differentiation of regulatory T lymphocytes or myeloid cells, which suppress immune responses.
In 2007, a group led by Jan Lötvall in Sweden discovered messenger RNA and microRNA inside exosomes.[5. H. Valadi et al., “Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells,” Nat Cell Biol, 9:654-59, 2007.]
There’s a fine historical survey (up until a few years ago) of the realizations of the importance of Exosomes here in “The Scientist”:   Exosome Explosion
Exosome miRs (exomiRs)
Exosomes consist of lipids, proteins and different sized RNA molecules including miRs  Exosome miRs (exomiRs) are known to be relatively stable in the circulation 
They participate in intercellular messaging by transporting bioactive lipid-, protein- and RNA-molecules and -complexes.recent studies have demonstrated that the messages, delivered by the secreted exosomal RNAs, can generate changes in the gene expressions and protein concentrations of the recipient cells, suggesting the functionality of the exosome content in the target cells
The content of the exosomes is affected by their source and also supposedly due to the physiological condition of the exosome secreting cell.   The contents of the exosomes reflect the physiological status of an individual making exosomes promising targets for biomarker analyses. 
When these exosome packages are delivered to the target tissues, the contents are released to the correct recipient cell. These delivered messages change the function of the cell,”  Different microRNA  carrier systems share a bunch of common miRs but they also seem to have a unique content which differs from the other microRNA  vehicles and, also, from the cell of origin  Exosomes have been shown to deliver gene-based intercellular messages adding to the complexity of cell-cell communication. 
Estrogen Levels and Menopause: 
A very recently published study demonstrated an association between accelerated aging, measured by the epigenetic age i.e. DNA methylation status of blood, and early onset of menopause.   Menopause is recognized as a risk factor for the development of metabolic dysfunctions
The loss of circulating E2 is followed by androgen dominance and further by body fat accumulation around the abdominal area In our study the premenopausal women had healthier profile in terms of metabolic measures such as waist circumference and plasma glucose levels compared to postmenopausal women. the most prominent predicted upstream regulators of the studied miRs include insulin as well as estrogen receptorsIn addition, fat percentage was significantly higher among the postmenopausal women who were not under HRT compared to their co-twins under HRT.
The excess amount of adipose tissue leads to unbalanced cytokine profile which is seen as increased levels of IL-6, TNF-α, IL-1β, resistin and leptin among other inflammatory molecules 
These circulating pro-inflammatory cytokines form a base for systemic low-grade inflammation also known to be associated with aging  In addition to adipose tissue initiated release of pro-inflammatory cytokines, also issues of glucose metabolism,  such as insulin resistance play a role in the systemic inflammation  
Furthermore, endothelial dysfunction and atherosclerosis are adding to the chronic inflammatory state . earlier studies have also shown beneficial effects of postmenopausal HRT on body composition measures, including fat, muscle and bone properties   
In our study the premenopausal women had healthier profile in terms of metabolic measures such as waist circumference and plasma glucose levels compared to postmenopausal women. In addition, fat percentage was significantly higher among the postmenopausal women who were not under HRT compared to their co-twins under HRT. We were able to see a slight increase in TNF-α levels due to age, whether under HRT or not, but no significant differences in other classical pro-inflammatory markers between any of the studied groups
Relation of Estrogen Levels to Exosome MIRs and Physiology
Aging and serum exomiR content in women-effects of estrogenic hormone replacement therapy
We demonstrated that the differential expression patterns were emphasized among exomicroRNAs interplaying with cellular homeostasis, glucose- and lipid metabolism as well as inflammation. 
Furthermore, we were able to identify microRNAs groups related to more positive or negative health outcomes in which the systemic E2 concentration played a significant role as a divider.
 The present study revealed six different miRs which were associated (FDR < 0.05) with serum E2 levels either positively (miR-106b-5p) or negatively (miR-148a-3p, -27-3p, -126-5p, -28-3p and -30a-5p)   To our knowledge two of these miRs have been previously shown to have an association with E2 in breast cancer cells..
Based on recent publications, some of the E2 associated miRs identified in the present study have connections to aging. MiR-10b-5p has been shown to be associated with the motor onset in both Parkinson’s and Huntington’s diseases26 indicating its function in the development of age-associated neurodegenerative disorders. Also, the role of circulating miR-10b-5p in osteogenic differentiation after fracture at postmenopausal age has been recognized27. In addition, changes in miR-28-3p levels during early senescence were observed in endothelial cells, thus, indicating miR’s possible regulatory role in the aging of vascular endothelium. Even though no direct effect of E2 has been stated in the mentioned studies, it has been well demonstrated that estrogen has a role as a neuro-, osteo- and vascular protector
Of particular interest is the fact that MiR-27b-3p has been shown to regulate fat metabolism and inflammation by targeting RXRα and PPARγ    In the present study, mir-27b-3p was one of the most interesting single miRs belonging to the negative outcome cluster.
 In addition, interesting associations with serum E2 concentrations and differentially expressed miRs, inflammation, glucose metabolism and adiposity -related markers were found.
Our data indicated higher levels of mir-27b-3p in the circulating exosomes of the postmenopausal twins compared to premenopausal women indicating an age association. 
 This microRNA  was negatively associated with serum E2, HDL and adiponectin (last 2 nominal) whereas positive associations were detected with other adiposity markers such as fat percentage and triglycerides and nominally with LDL. 
(The connection between lipoproteins, vascular inflammation and exosomes has also been recognized by others)  In addition, the levels of miR-27b-3p were positively associated with serum hsCRP and resistin as well as insulin and plasma glucose concentrations, all of these markers indicative of unbeneficial metabolic and inflammatory status.  
These results support the link between the systemic E2 levels, insulin signaling and the studied miRs.  
Altogether, these results support the function of miR-27b-3p (and miR-148a-3p) in the regulation of lipid and glucose metabolism and further reveal its possible negative role in women’s aging with hormonal changes.

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