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Trending With Impact: Humanin G Treatment in AMD Reduces Inflammation

By Kathryn Atkins June 3, 2022 August 9, 2022 Blog

In the cover paper published in Aging-US Volume 14, Issue 10, researchers investigated a potential therapeutic intervention to reduce chronic inflammation in age-related macular degeneration (AMD).

Trending With Impact: Humanin G Treatment in AMD Reduces Inflammation

The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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One of the leading causes of vision loss among aging populations in the United States, and worldwide, is age-related macular degeneration (AMD). The progression of this disease is known to be driven by inflammatory processes. However, the exact inflammation-associated proteins and the mechanisms that drive them have not yet been fully elucidated.

“Inflammation plays a crucial role in the etiology and pathogenesis of AMD (Age-related Macular Degeneration).”

In a new study in Aging (Aging-US), researchers from the University of California Irvine and the University of Southern California investigated a potential therapeutic intervention to reduce chronic inflammation in AMD and delay or prevent retinal degeneration. On May 16, 2022, this trending research paper was published on the cover of Aging’s Volume 14, Issue 10, and entitled, “Effect of Humanin G (HNG) on inflammation in age-related macular degeneration (AMD).”

“Our discovery is novel and may contribute to the development of therapeutics/ tools for reducing inflammation to alleviate AMD disease pathology.”

The Study

Humanin G (H NG) is a naturally produced peptide that may play a pivotal role in tissue homeostasis and normal functioning throughout the body—including the eyes. Previous studies have shown that high-intensity exercise and resistance training positively correlate with protein levels of Humanin G in human plasma and skeletal muscle. Studies have also shown that Humanin G protein levels negatively correlate with aging. In this study, researchers investigated the impact of exogenous Humanin G on markers of inflammation in AMD cells.

“Moreover, treatment with exogenous Humanin G is known to reduce the expression of markers associated with aging-related disorders [32]. Therefore, we tested the effects of Humanin G on inflammatory markers in this study.”

First, the researchers measured levels of inflammation-associated proteins (including cell adhesion molecules, cytokines and chemokines) among samples of AMD plasma and normal (control) plasma. AMD plasma showed higher protein levels of inflammation markers compared to control plasma samples. Next, the researchers used the ELISA assay to measure Humanin G protein levels in the plasma of both AMD patients and normal subjects. They found that, in AMD patients, protein plasma levels of Humanin G were significantly lower compared to normal subjects.

“In the current study, we found that the plasma levels of endogenous Humanin protein were significantly lower by 36.58 % in AMD patients compared to that in age-matched normal subjects.”

Exogenous Humanin G was then added to AMD and normal (control) cybrids derived from clinically characterized AMD patients and normal (control) subjects. Cell lysates were extracted from untreated and Humanin G-treated AMD and normal cybrids. Levels of inflammatory proteins were measured using the Luminex XMAP multiplex assay. The researchers observed that protein levels of inflammation markers previously elevated in AMD cells were reduced after Humanin G treatment.

“To our knowledge, this is the first report that confirms the protective role of Humanin G against inflammation in AMD RPE transmitochondrial cybrid cells and it is significant because reducing ocular inflammation could alleviate its damaging effects observed in the RPE cells that eventually lead to retinal degeneration in AMD pathogenesis.”

Conclusion

“In conclusion, we present novel findings that: A) show reduced Humanin protein levels in AMD plasma vs. normal plasma; B) suggest the role of inflammatory markers in AMD pathogenesis, and C) highlight the positive effects of Humanin G in reducing inflammation in AMD.”

Results in this study are significant because treatment with exogenous Humanin G may be able to revert the abnormal levels of inflammatory proteins that are found in AMD patients back to (or near) normal ranges. These findings may lead to novel therapeutics that can improve AMD disease trajectory.

“Further studies are required to gain an in-depth understanding of the mechanisms underlying Humanin G-mediated suppression of inflammation in AMD and to establish Humanin G’s therapeutic potential as an inhibitor of AMD-associated inflammation. Furthermore, in addition to administration of Humanin G, knockdown or knock-out of the studied inflammatory markers using siRNA or CRISPR editing, may present a new line of treatment for AMD.”

Click here to read the full research paper published by Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available at no cost to readers on Aging-us.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

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Trending With Impact: Neuromodulation in Alzheimer’s Disease Treatment

By Kathryn Atkins May 27, 2022 May 28, 2022 Blog

Dr. Fabrizio Vecchio wrote about the potential synergistic effects of neuromodulation combined with cognitive training to treat Alzheimer’s disease.

Neuromodulation in Alzheimer’s Disease Treatment

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Many neurodegenerative disorders among elderly populations share some common characteristics. In dementias, for example, neurons and glial cells undergo a progressive loss of structure or function in the brain and spinal cord. Alzheimer’s disease (AD) is the most common form of dementia and the main cause of cognitive impairment. Studies have confirmed that cognitive treatments, such as cognitive stimulation, training and rehabilitation, can improve brain function by increasing brain plasticity.

Recently, researcher Fabrizio Vecchio, from IRCCS San Raffaele Roma‘s Brain Connectivity Laboratory, discussed innovative treatment options for Alzheimer’s disease. On April 27, 2022, Dr. Vecchio published his new editorial paper in Volume 14, Issue 9, of Aging (Aging-US), entitled, “Cognitive training and neuromodulation for Alzheimer treatment.”

“Neuromodulation techniques are having a growing consensus as a therapeutic approach of incipient and mild to moderate dementia because of their capability to be modulated both in space, i.e. in different cortical and subcortical areas of the brain, and time.”

Neuromodulation

Neuromodulation is a considerably recent development in the medical field. This promising treatment option therapeutically alters nerve activity within specific neurological sites of the body using the targeted delivery of electrical stimulation or chemical agents. Neuromodulation can be used not only for patients with dementia but also for those with a number of other disorders, including chronic pain, epilepsy and psychiatric disorders. However, the demonstrated value of cognitive treatments has not been discounted by Dr. Vecchio. In his editorial paper, he discussed the potential synergistic effects of neuromodulation combined with cognitive training (COG).

“Together with cognitive treatments one of the possible innovative strategies to be undertaken is the neuromodulation that involves non-invasive brain stimulation techniques (NIBS) such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS).”

Dr. Vecchio described his recent study on repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training. In this randomized, double-blind, sham-controlled trial, researchers evaluated the efficacy of rTMS-COG treatment in Alzheimer’s patients. Before, immediately after and 40 weeks after rTMS-COG treatment, patients were assessed using neuropsychological and electroencephalography (EEG) examinations. The researchers evaluated six regions of the brain and analyzed neuropsychological and neurophysiological data derived from EEG. After six weeks of intensive daily treatment, immediate results showed an improvement in cognitive scales. At the 40-week follow-up evaluation, improvements in brain connectivity emerged.

“Based on these assumptions and promising results, particularly of rTMS and COG, some researchers hypothesized that a treatment combining rTMS and COG may result in synergic effects more effective [in] respect to applying the two therapies separately.”

Conclusion

Although more research must be conducted to confirm the clinical efficacy of neuromodulation for the treatment of Alzheimer’s disease, initial results are promising. Cognitive treatments should not be discounted either, as they have been shown to improve brain function. Dr. Vecchio suggests a potentially efficacious combination of neuromodulation and cognitive training that may offer significant benefits for patients with Alzheimer’s disease.

“In conclusion, rTMS combined with cognitive training, can be regarded as a potentially useful treatment for AD, not modifying the neuropathological changes, but slowing down their effects on brain networks and providing important groundwork for future studies to build upon. Derived EEG parameters can be awarded the role of diagnostic and predictive biomarkers of AD progression.”

Click here to read the full editorial paper published by Aging (Aging-US).

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Trending With Impact: Tobacco PEBP Increases Lifespan in Fruit Flies

By Kathryn Atkins April 29, 2022 April 29, 2022 Blog

Researchers conducted an interspecies analysis to determine the effects on aging that occur when certain plant proteins are expressed in animals and animal proteins are expressed in plants.

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The proteostasis network is a cellular quality control system that ensures proteins fold correctly, damaged proteins are eliminated and protein pools are replenished. During the aging process, the proteome and respective signaling pathways frequently become error-prone. A class of proteins believed to play a role in aging-related processes is the phosphatidylethanolamine-binding proteins (PEBPs). These conserved regulators of signaling networks are found in plants, animals and other organisms.

In a previous 2021 study, researchers from Fraunhofer Institute for Molecular Biology and Applied Ecology IME, University of Münster and Twyman Research Management demonstrated that a PEBP found in the tobacco plant, NtFT4, improves vitality, growth and protein yield when transfected in human cells. In a recent study, published in Aging (Aging-US) Volume 14, Issue 7, these same researchers transfected plant PEBPs in animals, and animal PEBPs in plants, to further investigate changes in activity within their respective aging processes. The research paper was published on April 8, 2022, and entitled, “The tobacco phosphatidylethanolamine-binding protein NtFT4 increases the lifespan of Drosophila melanogaster by interacting with the proteostasis network.”

“To investigate the functions of PEBPs in more detail, we undertook interspecies analysis and determined the molecular, cellular and organism-level effects of animal PEBPs expressed in Arabidopsis (Arabidopsis thaliana) and tobacco (Nicotiana tabacum) and plant PEBPs expressed in Drosophila.”

The Study

Specifically, the team used tobacco plant PEBPs (NtFT2 and NtFT4), fruit fly (Drosophila melanogaster) PEBPs (CG7054 and Pebp1) and human PEBPs (RKIP and hPEBP4). They found that the expression of animal PEBPs in the thale cress (Arabidopsis) and tobacco plants had no effect on flowering or growth. However, the expression of tobacco PEBPs in animals did have an intriguing impact. The researchers observed that the tobacco PEBP NtFT4 increased the lifespan of fruit flies by interacting with the proteostasis network—through mechanisms such as heat shock protein 26 (HSP26). NtFT4 expression in older flies promoted longevity by prolonging Hsp26 gene expression and maintaining protein integrity. After the PEBP CG7054 was knocked down in fruit flies, overall lifespan significantly decreased and approximately 20% of adult flies died within two days.

“In contrast, the expression of plant PEBPs in Drosophila increased the adult fly lifespan by up to one third, whereas the silencing of the endogenous PEBP CG7054 reduced longevity.”

Conclusion

“The heterologous expression of NtFT4 in flies revealed new aspects of PEBP activity that point to a role in proteostasis, improving health and lifespan [41].”

This study provides new insights into the role of PEBPs in plants and animals and how they might contribute to the aging process. Plants may use different cellular mechanisms than animals when it comes to aging-related processes such as the regulation of signaling networks. The results of this study highlight the unique role that plants may play in understanding the aging process. Further studies are needed to better understand the molecular mechanisms behind these effects, as well as their potential applications for aging interventions in humans.

“We found that heterologous expression of the tobacco (Nicotiana tabacum) PEBP NtFT4 in Drosophila melanogaster significantly increased the lifespan of adult flies and reduced age-related locomotor decline. Similarly, overexpression of the Drosophila ortholog CG7054 increased longevity, whereas its suppression by RNA interference had the opposite effect.”

Click here to read the full research paper published by Aging (Aging-US).

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Trending With Impact: Underlying Mechanisms of Replicative Senescence

By Kathryn Atkins April 21, 2022 April 26, 2022 Blog

Published on the cover of Aging’s Volume 14, Issue 7, researchers conducted a new study investigating the role of IGFBP5 in replicative senescence.

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In 1961, Leonard Hayflick and Paul Moorhead proposed a theory later named the Hayflick Limit. They discovered that a normal human cell can divide between 50 and 70 times before it can no longer proliferate and eventually dies. Researchers have since continued to explore this phenomenon and, today, this aging process is known as cellular (replicative) senescence.

“There are currently several experimental models of cellular senescence. Hayflick and Moorhead observed that primary human fibroblasts in culture exhibit a limited proliferative capacity [6]. This growth arrest during passages is called replicative senescence.”

This permanent cessation of the cell cycle is universally found in biology due to known and unknown causes, including the shortening of telomeres. While telomere shortening plays an important role, it is not the only event responsible for inducing cellular senescence. Thus, researchers have spent decades under the microscope experimenting with cellular models of replicative senescence.

In a new study released on April 4, 2022, researchers from Sapporo Medical University in Sapporo, Japan, investigated mechanisms of replicative senescence in vitro. Their trending research paper was published on the cover of Aging (Aging-US) Volume 14, Issue 7, and entitled, “Downregulation of IGFBP5 contributes to replicative senescence via ERK2 activation in mouse embryonic fibroblasts.”

The Study

Cellular senescence is typically characterized by cell growth arrest, an increase of cells positive for SA-β -gal staining, and upregulation of p16 and p19. To begin this study, the team cultured embryonic mouse fibroblasts (MEFs) and conducted cell passages according to the 3T3 method. They found that the MEFs underwent senescence after the 5th passage (P5). The team also found that at P8, the expression of insulin-like growth factor binding protein 5 (IGFBP5) mRNA was significantly reduced when compared with that of P2 MEFs.

Next, the team performed a knockdown of IGFBP5 in the MEF cells. Results showed that IGFBP5 knockdown induced premature cellular senescence in P2 MEFs. Knockdown of IGFBP5 increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) but did not affect expression levels of Akt or p16 repressors. The researchers also found that supplementing the cell culture growth medium with additional exogenous IGFBP5 delayed growth arrest and reduced replicative senescence in the MEF cells.

“To examine whether activated ERK1 and ERK2 by IGFBP5 knockdown are involved in the induction of senescent phenotypes, we examined effects of knockdown of ERK1 and ERK2 using a combination with IGFBP5 siRNA in P2 MEFs.”

Upon further analysis of ERK1/2’s role in IGFBP5-knockdown cells, the team found that the silencing of ERK2, and not ERK1, blocked the increase in the number of SA-β-GAL-positive cells. ERK2 knockdown attenuated the reduction in the cell number and upregulation of p16 and p21 in IGFBP5-knockdown cells. This study provides evidence that downregulation of IGFBP5 contributes to replicative senescence via ERK2 activation in mouse embryonic fibroblasts.

Conclusion

For the first time, the role of IGFBP5 in replicative senescence was demonstrated in MEFs. Their findings suggest that ERK2 underlies cellular senescence induced by IGFBP5 downregulation. Cellular senescence appears to be a complex process with many moving parts. While more research is needed to fully understand the role of IGFBP5 in replicative senescence, this study provides new insights into the underlying mechanisms involved in this complex process.

“In conclusion, the results of the present study demonstrated that downregulation of IGFBP5 during serial passage contributes to replicative senescence via an ERK2-dependent mechanism (Figure 6). The results suggest that IGFBP5 counteracts replicative senescence in MEFs.”

Figure 6. Schematic summary of our findings. MEFs at early passage secrete certain levels of IGFBP5. Secreted IGFBP5 proteins inhibit MEK/ERK2 by attenuating their phosphorylation (P) in the neighboring cell, leading to suppression of cellular senescence. IGFBP5 secretion is decreased during serial passage, causing activation of ERK2 and cellular senescence.

Click here to read the full research paper published by Aging (Aging-US).

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Protein Linked to Aging-Related Muscle Loss

By Kathryn Atkins April 14, 2022 April 15, 2022 Blog

Researchers investigated the mitochondrial protein GRSF1 for its role in the physiology of skeletal muscle aging.

Figure 1. Expression of GRSF1 across myogenesis. (A) RT-qPCR analysis of GRSF1 mRNA levels in proliferating (0 h) and differentiating (24-120 h) human myoblasts; n=3. GRSF1 mRNA levels were normalized to the levels of GAPDH mRNA. (B) Western blot analysis of the levels of GRSF1 at the indicated times during differentiation; n=2. (C) Immunofluorescence detection of GRSF1 (green) and mitochondria (red) in proliferating myoblasts and differentiating myotubes. Arrowheads indicate GRSF1 signals; n=3. Scale bar, 50 μm.

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Skeletal muscle is responsible for regulating physical movement and comprises between 30 and 40% of the human body’s mass. The loss of skeletal muscle has major impacts on overall health and quality of life—leading to frailty and a decreased ability to perform activities of daily living. The most common cause of muscle loss is aging, and a prevalent pattern of aging-associated muscular decline is known as sarcopenia.

“With advancing age, the progressive loss of skeletal muscle mass and function, known as sarcopenia, leads to reduced muscle strength and diminishes individual mobility, quality of life, and lifespan [12].”

In a research paper published in Aging (Aging-US) Volume 13, Issue 11, researchers from the National Institutes of Health’s National Institute on Aging and Chungnam National University investigated a protein that may play a role in aging-related muscle loss. Their paper was published on June 2, 2021, and entitled, “GRSF1 deficiency in skeletal muscle reduces endurance in aged mice.”

Skeletal Muscles and Mitochondrial Proteins

The healthy operation of skeletal muscle is dependent on well-regulated mitochondrial functioning. Skeletal muscle is extremely rich in mitochondria, as mitochondria supply muscle cells with the energy they need to help move the body, known as adenosine 5′-triphosphate, or ATP. With age, the mitochondria in skeletal muscles begin to progressively malfunction. The exact mechanisms involved in this decline have not been fully elucidated.

“In aging skeletal muscle, mitochondria display reduced function, altered morphology, and increased production of reactive oxygen species (ROS), which contribute to a progressive loss of muscle mass and strength [13, 14].”

The guanine-rich RNA sequence binding factor 1 (GRSF1) protein is widely distributed in mammalian organs, and primarily enriched in mitochondria organelles. This makes the skeletal muscle an ideal organ in which researchers can study GRSF1, and other mitochondrial proteins, to investigate their role in aging-related processes such as sarcopenia. Although GRSF1 has been well-studied for its role in maintaining mitochondrial function, the involvement of GRSF1 in skeletal muscle aging had not yet been investigated until this study.

The Study

In this study, the researchers used Grsf1cKO mice—a mouse model in which GRSF1 is specifically knocked out in murine skeletal muscle cells. The mice appeared normal until 7-9 months of age. At 16-18 months of age, however, the researchers observed a reduction in muscle endurance compared to wild-type (WT) control mice. The authors postulated that these results suggested the loss of GRSF1 in skeletal muscle may not alter muscle function until later in life.

“The Grsf1cKO mice at this age ran about a 30% shorter treadmill distance on average relative to WT controls (Figure 3A).”

Upon further transcriptomic analysis, the team found that more than 200 muscle genes were differentially expressed in the GRSF1-deficient mice compared to the control mice. Some of the differentially expressed RNAs that were elevated in the Grsf1cKO mice were the hypoxia-inducible Mgarp mRNA, the mRNA encoding Sarcolipin (SLN), the pro-inflammatory proteins CXCL10 and NFKB2, and the transcription factor ATF3. The authors suggested that increased SLN mRNA may also potentially contribute to the decline in skeletal muscle endurance seen in Grsf1cKO mice.

“The reduction of endurance in Grsf1cKO muscle was accompanied by differential expression of several mRNAs, including some that encoded mitochondrial proteins, inflammatory proteins, ion transporters, and transcription factors (Mgarp, Sln, Cxcl10, Nfkb2, and Atf3 mRNAs).”

Conclusion

The researchers found that the absence of GRSF1 in murine skeletal muscle cells led to a decrease in muscle endurance. Initially, the researchers had anticipated that GRSF1 knock-out would lead to a dramatic loss in muscle function. However, their study revealed that the function of GRSF1 in skeletal muscle appeared to only be moderate. Overall, this is an important finding, as it provides new insights into the role of GRSF1 in muscle physiology and opens up new avenues for research into potential therapies for aging-related muscle loss.

“This modest in vivo effect suggests that there are redundant or compensatory mechanisms that prevent catastrophic damage from GRSF1 loss in aging muscle, and that identifying such factors might be of therapeutic benefit in diseases caused by impaired function of muscle mitochondria and impaired muscle regeneration.”

Click here to read the full priority research paper published in Aging (Aging-US).

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Trending With Impact: Plasma Injection Improves Poor Response to IVF

By Kathryn Atkins April 7, 2022 April 8, 2022 Blog

Researchers investigated the effects of injecting platelet-rich plasma in women with a poor ovarian response to in vitro fertilization (IVF).

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In a day and age when women and men are beginning families later in the life cycle, women of advanced age (or with some health conditions) often have trouble becoming pregnant. Today, in vitro fertilization (IVF) is a widely-used form of assisted reproductive technology. This manual process of fertilization is achieved first by combining an egg and a sperm outside of the uterus and then helping the fertilized egg become implanted in the uterus.

The world’s first IVF baby was born in Lancashire, England, in 1978. Since then, this technique has solved reproductive issues for millions of women and men around the world. While this procedure has helped build many families, there is a subset of reproductively challenged women who exhibit resistance to IVF. Researchers have observed accelerated ovarian aging in women who demonstrate a poor ovarian response (POR) to IVF.

“These women are labeled ‘poor ovarian response’ (POR) or ‘poor responders’ due to a combination of low parameters of ovarian reserve and previous low oocyte yield after ovarian stimulation.”

In previous small-scale cohort and in vitro studies, exposure to platelet-rich plasma (PRP) has demonstrated improvements in ovarian tissue repair, regeneration and follicular development. In a new study, published in Aging (Aging-US) on March 22, 2022, researchers— from Acibadem Maslak Hospital, Acibadem University, IVI RMA New Jersey, Thomas Jefferson University, and Yale School of Medicine—sought to validate these small-scale results by assessing the effects of intra-ovarian injection of autologous PRP in a cohort of 510 women with POR. Their trending research paper can be found in Volume 14, Issue 6, entitled, “Ovarian reserve parameters and IVF outcomes in 510 women with poor ovarian response (POR) treated with intraovarian injection of autologous platelet rich plasma (PRP).”

The Study

This prospective observational study took place in Acibadem Maslak Hospital in Istanbul, Turkey, in 2020. The study’s inclusion criteria admitted women who were diagnosed with POR, between 30 and 45 years old, had at least a one-year history of infertility, and had at least one ovary. After the exclusion criteria were accounted for, 510 women with POR were included in the study. Patients were divided into three groups for subgroup assessment: patients younger than 38 years old, patients between 38 and 42 years old and patients between 42 and 45 years old.

Before IVF, autologous PRP was administered to participants through intra-ovarian injections. (Learn more about PRP and IVF materials and methods in the study.) The team then assessed the effects of PRP on ovarian reserve parameters and IVF outcomes. Ovarian reserve parameters included antral follicle count (AFC), ovarian volume, serum anti-Müllerian hormone (AMH) level, and serum follicle-stimulating hormone (FSH) level. IVF outcomes were defined by the number of oocytes retrieved (an oocyte is an immature ovum, or egg cell) and the number and quality of embryos that developed, including embryos in cleavage and blastocyst stages.

The Results

Compared to baseline measures before treatment, PRP injections resulted in higher AFC, higher serum AMH, lower serum FSH, and a higher number of mature oocytes and cleavage/blastocyst stage embryos. In this cohort of women with POR, the PRP intervention yielded a total pregnancy rate of 20.5% and a sustained implantation/livebirth rate of 12.9%.

“After PRP injection, 22 women (4.3%) conceived spontaneously, 14 (2.7%) were lost to follow up, and 474 (92.9%) attempted IVF. Among women who attempted IVF, 312 (65.8%) generated embryos and underwent embryo transfer, 83 (17.5%) achieved a pregnancy, and 54 (11.4%) achieved sustained implantation/live birth (SI/LB).”

The researchers found that the greatest increase in IVF outcomes was seen in women 38 years old or younger. They also performed a receiver operating characteristic curve analysis and found that the cut-off for patients who would not benefit from PRP was 40 years old. The authors explained that this was due to a lack of ovarian response.

Conclusion

The researchers suggest that PRP may be considered for IVF cycles in women with POR, especially for those younger than 38 years old. However, the authors also caution that PRP should not be recommended as part of routine treatments until further prospective randomized trials test for clinical efficacy in wider clinical applications. Intra-ovarian injection of autologous PRP may someday be the standard of care for women with POR seeking IVF.

“In conclusion, intraovarian injection of autologous PRP might be considered in women with POR. The ideal population that may benefit from this approach can be summarized as patients <40 years old, with an FSH < 21.2 mIU/mL, AMH > 0.23 ng/ml, with at least one antral follicle, and a mean ovarian volume > 4.30 cm3.”

Click here to read the full research paper published by Aging (Aging-US).

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PandaOmics Identifies Dual-Targets of Aging and Age-Related Diseases

By Kathryn Atkins March 31, 2022 April 1, 2022 Blog

Researchers used PandaOmics software to identify potential drug targets that could treat both aging and age-related diseases.

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What if drugs designed to treat conditions such as diabetes, osteoporosis and rheumatoid arthritis could at the same time provide patients with anti-aging benefits? On March 29, 2022, researchers—from Insilico Medicine, University of Chicago, George Mason University, University of Liverpool, and Buck Institute for Research on Aging—released a new study on the cover of Aging (Aging-US) Volume 14, Issue 6, about Insilico’s next-generation artificial intelligence (AI)-powered discovery software, called the PandaOmics platform. Their trending research paper is entitled, “Hallmarks of aging-based dual-purpose disease and age-associated targets predicted using PandaOmics AI-powered discovery engine.”

PandaOmics

The PandaOmics platform is a software based on an enormous database of research that is constantly being updated and refined. The database consists of over 1,500 diseases and 10,000 disease subtypes, approximately 1.9 trillion data points derived from over 10 million samples with microarrays, RNA sequencing, proteomes, methylomes, and other data types, 1.3 million drug compounds and biologics, and information embedded from over 40 million text-based sources and documents. This evolving omics database is then used to inform an intricate AI algorithm designed to identify patterns within the data.

The Hallmarks of Aging

While the underlying molecular mechanisms of aging are still technically in debate, researchers have basically agreed upon a consistent series of biochemical changes that have been identified in the aging process, known as the hallmarks of aging. There are nine classic hallmarks of aging, as well as three newer additions, which include: 1) altered intercellular communications, 2) cellular senescence, 3) deregulated nutrient signaling, 4) epigenetic shift, 5) genomic instability, 6) impaired proteostasis, 7) mitochondrial dysfunction, 8) stem cell exhaustion, 9) telomere attrition, 10) inflammation, 11) extracellular matrix stiffness, and 12) retrotransposons.

Researchers have observed that substantial overlap exists between genes involved in the hallmarks of aging and in age-associated diseases (AADs). The goal of this study was to use the PandaOmics platform and the hallmarks of aging to identify dual-purpose drug targets that can be used to treat both aging and AADs.

“Hence, identifying potential targets that are implicated in multiple age-associated diseases, and also play a role in the basic biology of aging, may have substantial benefits.”

The Study

In this study, the researchers used the PandaOmics platform to generate a list of promising new or traditional aging-associated targets that may be used for drug discovery and repurposing. The team started by investigating genes that are dysregulated in multiple aging-associated diseases, as well as in aging itself. The researchers decided only to analyze 33 diseases. This decision was based on whether or not age is a strong risk factor for the disease’s onset, if there are strong confounding factors and on the availability of public datasets. Cancers and cardiovascular diseases were excluded from this list of selected diseases (this list can be found in the study).

The selected diseases were separated into AADs (n=14) and non-age-associated diseases (NAADs) (n=19). The team then programmed the PandaOmics platform to identify aging-associated patterns by prioritizing the top dysregulated genes in these diseases based on their involvement in the hallmarks of aging. The researchers compared the top-AAD and -NAAD genes and identified 145 overlapping common targets.

Results

“In this study, we used a variety of target identification and prioritization techniques offered by the AI-powered PandaOmics platform, to propose a list of promising novel aging-associated targets that may be used for drug discovery. We also propose a list of more classical targets that may be used for drug repurposing within each hallmark of aging.”

They found that most aging-associated targets were not specific to a single hallmark but were instead involved in multiple hallmarks. The team also found that most of the top targets played a role in the 10) inflammation and 11) extracellular matrix stiffness hallmarks of aging. Four targets were connected to all 12 hallmarks; these targets were AKT1, MTOR, SIRT1, and IGF1. Primary conclusions drawn from the study were that the hallmarks of aging are implicated in multiple AADs and NAADs, and that these hallmarks can be used to identify aging-associated targets for drug discovery and repurposing.

Figure 3. Targets associated with hallmarks of aging. — **Figure 3.** **Targets associated with hallmarks of aging.**

Conclusion

The researchers were forthcoming about limitations in this study. Nevertheless, this exciting research provides valuable insight into the use of AI-powered discovery engines to uncover novel aging-associated targets for drug discovery. The PandaOmics platform is a valuable resource for aging researchers and offers the potential to identify new or traditional targets for the treatment of aging and age-related diseases.

“In conclusion, we successfully established an approach to identify potential dual-purpose targets for aging and AADs, enabling biologists and clinicians to further investigate their therapeutic potential in a cost-saving and time-efficient manner for drug discovery. These promising results underscore the ability of PandaOmics to identify novel targets not only for specific disorders, but across multiple types of diseases.”

Click here to read the full cover paper published in Aging (Aging-US).

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Trending With Impact: How Biological Sex Impacts Alzheimer’s Disease

By Kathryn Atkins March 24, 2022 March 25, 2022 Blog

Men and women are disproportionately impacted by Alzheimer’s disease (AD). Researchers investigated AD mice for potential sex differences in synaptic function.

Figure 1. The diagram shows sex-specific alterations in plasticity and memory and the associated changes in amyloid beta (Aβ) pathology and inflammatory response in APP/PS1 mice.

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As the worldwide elderly population continues to expand, the symptoms of dementia, including Alzheimer’s disease (AD), are simultaneously increasing around the globe. Researchers are driven to investigate new ways to detect and treat AD in earlier stages—before symptoms become more difficult or impossible to overturn. An important piece of data to consider is that dementia is more prevalent among women than among men; dementia affects 8.1 % of women and 5.4% of men. Many AD studies have not used gender/sex as a variable to cross-examine their research findings. This information may be a key factor that leads to developing more efficacious strategies for AD detection and treatment in all patients, and especially in women.

“In the long run, the underrepresentation of female biology in biomedical research will hamper the development of effective drugs with negative consequences on women’s health.”

In a recent editorial paper published on March 12, 2022, by Aging (Aging-US) in Volume 14, Issue 5, researchers from the National Univers i ty of Singapore discussed the importance of understanding sex differences in Alzheimer’s disease. Their trending editorial paper, entitled, “Sex matters in Alzheimer’s disease?“, was based on results from their previous study published in 2021.

Sex-Specific Synaptic Dysfunction

In AD patients, researchers have observed a loss of function in the sites where nerve cells communicate with each other—in the synapses. Synaptic dysfunction is an early event in AD and can be observed years before other symptoms appear. In the research study being discussed in this editorial, the research team examined differences between the synaptic activity of male and female mice with two mutations associated with early-onset Alzheimer’s disease (APP/PS1).

“To characterize molecular changes in the AD brain that is attributed to sex differences, we performed RNA sequencing and immunohistochemistry of the hippo-campus and showed accelerated pathology, stronger immune response and higher microglial activation in AD female mice compared to males [5].”

Their findings revealed a number of differentially expressed genes and plasticity-related genes were sex-regulated. Plasticity-related genes are important for learning, memory and other cognitive abilities. The study also found that female AD mice had an accelerated Alzheimer’s pathology, stronger immune response and higher microglial activation—all of which contribute to dementia symptoms. These results suggested that sex differences in early-stage synaptic function may have important implications for understanding the higher prevalence of Alzheimer’s disease in women, and the related mechanisms may be potential targets for diagnosis and treatment.

Conclusion

In their editorial paper, the authors acknowledge that, although more research needs to be done on this topic, these findings could lead to new strategies for detecting and treating Alzheimer’s disease. The authors conclude by writing that synaptic dysfunction among males and females with Alzheimer’s disease revealed sex-regulated differentially expressed genes and plasticity-related genes as potential targets for early AD intervention. Overall, sex differences should be considered when developing custom-tailored strategies for early AD detection, prevention and treatment.

”Our work, along with others in this field, also emphasises the importance of including biological sex as variable in many research settings, particularly studies exploring aging [7] and how they impact different disease states [8].”

Click here to read the full editorial paper published by Aging (Aging-US).

Click here to read Aging’s Special Collection on Alzheimer’s Disease.

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Trending With Impact: Intestinal Balance, Colorectal Cancer and Muc4

By Kathryn Atkins March 17, 2022 March 18, 2022 Blog

Researchers investigated the functional significance of Muc4 in intestinal homeostasis and colorectal cancer progression.

Figure 3. Absence of Muc4 alters other mucins expression.

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With age, humans undergo bodily changes which include a decline in organ and tissue function. The average age men and women are diagnosed with colorectal cancer (CRC) is 68 and 72 years old, respectively. Healthy intestinal epithelial cells are usually lined with a sufficient layer of mucus; important components in this mucus layer, called mucins, help to maintain physiological homeostasis. While transmembrane mucin 4 (Muc4) has been found to be overexpressed in pancreatic, ovarian and breast cancers, Muc4 expression is decreased in patients with CRC. The functional role and implications of Muc4 in CRC’s intestinal pathology have not yet been adequately investigated.

Researchers—from the University of Nebraska Medical Center, Baylor College of Medicine, University of California San Diego, and VA San Diego Healthcare System—sought to better understand the role of Muc4 in CRC by developing genetically engineered mouse (GEM) models. Their priority research paper was published as the cover of Aging-US Volume 14, Issue 5, and entitled, “Depletion of transmembrane mucin 4 (Muc4) alters intestinal homeostasis in a genetically engineered mouse model of colorectal cancer.“

“Therefore, to understand the functional significance of MUC4 in intestinal homeostasis and CRC progression, we developed a GEM model by crossing mice carrying a conditional mutation of Apc [adenomatous polyposis coli] gene with colon-specific caudal type homeobox transcription factor 2 (Cdx2)-Cre fused with estrogen receptor.”

The Study

The researchers first conducted an analysis of CRC patients using The Cancer Genome Atlas. They found that CRC patients had decreased Muc4 levels compared to normal patients and that lower Muc4 expression is associated with a worse prognosis in CRC patients. In CRC, the most frequent mutations were found to occur in the Apc gene. Therefore, the researchers tested control mice and two mouse models in this study. The AMC GEM model had an Apc mutation, and Muc4 was knocked out. The AC GEM model was AMC’s contemporary littermate control and had only the Apc mutation—Muc4 was not knocked out. Tamoxifen was then intraperitoneally administered to exert conditional control of gene expression in the mice.

Next, the team conducted mucin staining to characterize goblet cell function. Goblet cells protect the intestine by secreting mucins. In addition to Apc mutations, many CRC patients have Kras gene mutations. Therefore, the researchers also crossed the AMC mouse model with a mutated Kras mouse model. Finally, the researchers examined two human CRC cell lines in vitro. They performed a knockdown of Muc4 and conducted a cellular fractionation study of the cell lines.

“Knockdown (KD) of MUC4 increased the expression of β-catenin, cyclin-D1, and CD44 at the transcript level in LS-180 and HCT-8 cells (Supplementary Figure 3C).”

The Results

The researchers found that Muc4 deletion in the AMC mice resulted in more colorectal tumors with high-grade dysplasia compared to AC and normal mice. Immunohistochemistry staining revealed that AMC and AC mice did not produce any visible goblet cells.

“We observed that in both AMC and AC mice, there was a complete absence or loss of staining in the goblet cells of colon adenoma (Figure 2E), suggesting that disruption of goblet cell function alters the mucin production.”

Muc4 knock-out in AMC mice was associated with an upregulation of Muc13 and a significant loss of Muc2 and Fam3D in CRC tissues. The researchers observed that Muc4 deletion resulted in defective mucus barrier function, reduced intestinal homeostasis and up-regulated β-catenin signaling. In the Kras/AMC mice, they found that the addition of the Kras mutation further aggravated tumors and reduced survival.

Conclusion

The research team found that, in the AMC GEM model (lacking mucin expression), there was an increase in inflammation, DNA damage, tumor burden, and CRC cell proliferation. The study’s findings provide evidence that Muc4 expression is essential for the proper maintenance of the mucus layer and intestinal homeostasis. Furthermore, this research suggests that reduced expression of Muc4 may be associated with aging and a predisposition to colorectal cancer.

“In conclusion, our study suggests that Muc4 has a protective role in CRC progression in an Apc mutant GEM mice model. Muc4 maintains the intestinal homeostasis by upregulation of Muc2 and Fam3D (guardians of the gut) and downregulation of cancer-promoting mucin (Muc13). Additionally, presence of Muc4 prevents the invasion of microbiota and reduction of proinflammatory cytokines and decrease in epithelial cell proliferation by inhibiting β-catenin, c-Myc and CD44 expression. Additional studies are needed to understand the role of Muc4 in conditional KO mouse models and various sub-types of CRC.”

Click here to read the full priority research paper published by Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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Trending With Impact: Do Biomarkers of “Long COVID” Exist?

By Kathryn Atkins March 10, 2022 March 11, 2022 Blog

In a recently published Aging-US paper, researchers investigated potential biomarkers of severe COVID-19 among recovered patients.

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Among people who have been fortunate to recover from COVID-19, at least 40% had or have long-term lingering effects from this disease. Frequently appearing months after recovery, these “long covid” effects can include (not limited to) fatigue, trouble sleeping, difficulty concentrating, joint or muscle pain, and respiratory issues, such as shortness of breath and chest pain. Researchers are still unsure as to whether or not lasting COVID-19 effects in the lungs are associated with the severity of disease at the time of infection.

“Thus, prospective studies related to outcomes following recovery from COVID-19 might improve our understanding of this disease, its sequelae, and possible interventions to improve this situation.”

Researchers—from Hospital Universitario San Pedro, Centro de Investigación Biomédica de La Rioja, Universidad de Córdoba, Hospital Universitario Reina Sofía, Hospital Costal de Sol, HCU Lozano Blesa, Hospital Universitario Marqués de Valdecilla, Unidad de Enfermedades Infecciosas, Hospital Universitario de Burgos, Vitro Laboratory, Instituto de Investigación-IdiPaz, and Universidad Rey Juan Carlos—conducted a new study aimed at identifying biomarkers of severe disease in patients after hospitalization for COVID-19. Their research paper was published by Aging (Aging-US) on February 16, 2022, and entitled, “Elevated levels of serum CDCP1 in individuals recovering from severe COVID-19 disease.”

The Study

A total of 108 recovered COVID-19 patients admitted to hospitals throughout Spain (46.2% of whom had severe cases) were enrolled in this study. Lung function was measured by the capacity to diffuse carbon monoxide. Samples of serum and induced sputum (phlegm) were collected from the patients and used to evaluate the relationships between patients with residual inflammation in the lungs. Within these samples, the researchers analyzed and compared the levels of 92 protein biomarkers, including various chemokines, cytokines, growth factors, interleukins, and the CUB domain-containing protein 1 (CDCP1)—a cell surface glycoprotein. High levels of CDCP1 were previously observed in some severe cases of COVID-19 in children.

“In COVID-19-infected children who developed acute vasculitis, CDCP1 was one of the most significantly upregulated genes [25], but this complication was not observed in our study.”

The Results

Of all 92 biomarkers, multivariate analysis showed only elevated levels of serum CDCP1 in individuals recovering from severe COVID-19. To their surprise, they also found a positive relationship between CDCP1 and TGFb1 in sputum samples (irrespective of severity). The researchers found a significant difference in lung function (as measured by diffusing capacity for carbon monoxide (DLCO)) between those who had severe cases of COVID-19 and those who had mild/moderate cases. Differences in serum proinflammatory cytokines were not observed between the two groups of recovered COVID-19 patients, indicating that these biomarkers subside after recovery. Correlations between serum and induced sputum levels were detected for only a few biomarkers.

“Independent predictors of severe disease were DLCO <80% and the serum CDCP1 value.”

Conclusion

The authors were forthcoming about the limitations of their study. The team did not use a control group, although, the goal of this study was to investigate the severity of COVID-19. The cohort was relatively small, and the researchers note the need to further study the role of CDCP1. They also suggest that prospective studies should follow patients in recovery from COVID-19 in order to continue improving our understanding of this still novel virus. Such information could aid in the development of interventions to improve patient prognoses long-term.

“In conclusion, although the long-term impact of high serum levels of CDCP1 is still unknown, we should be alert to the potential implications for lung disease. For this reason, it is necessary to follow such patients for longer periods of time to detect and adequately treat potential pulmonary sequelae.”

Click here to read the full research paper published by Aging (Aging-US).

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