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Trending With Impact: Can Singing Improve Aging?

By Kathryn Atkins November 11, 2021 November 12, 2021 Blog

In a two-year study, researchers compared the effects of choral singing with the effects of health education in an elderly cohort.

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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There may be many paths that lead to the cessation of aging, or there may only be one—this mystery has yet to reveal itself. However, there is a wide array of evidenced methods capable of preserving youth by slowing down the aging process, and even mildly reversing it. Some known natural interventions are healthy diets, consistent exercise and avoiding aging-related risk factors, including carcinogens such as alcohol, cigarettes and excess sun exposure. Researchers have also studied less intuitive repetitive behaviors that appear to improve the cognitive decline associated with aging. For example, in a study published in 2015, researchers found that active singing led to cognitive improvements in participants with dementia.

“People engaging in lifelong music-making have been found to have better cognitive outcomes later in life.”

In a research study published in 2020, 30 researchers—from National University of Singapore, Singapore Institute for Clinical Sciences, National University Health System, University of Cambridge, University of London, Singapore Immunology Network, Maurine Tsakok Inc, Voices of Singapore Choral Society, Presbyterian Community Services, NTUC Health Co-operative Limited, Beijing Chui Yang Liu Hospital, Fudan University, Massachusetts General Hospital, Harvard Medical School, Nanyang Technological University, Imperial College London, and Genome Institute of Singapore—conducted the world’s first study designed to compare the impact of choral singing versus health education on cognitive function and aging in a randomized controlled trial (RCT). Their trending research paper was published by Aging (Aging-US) in 2020 and entitled, “Effects of choral singing versus health education on cognitive decline and aging: a randomized controlled trial”.

“In this RCT, we hypothesized that choral singing would improve cognitive health and/or reduce cognitive decline in elderly with high risk of dementia.”

The Study

This study, based out of Singapore, was designed for half of the subjects to participate in a choral singing program for one hour every week, over the course of two years. This program was conducted at the National University of Singapore’s Yong Siew Toh Conservatory of Music. In these sessions, professional musicians taught the fundamental concepts and mechanics of “good” singing, including breathing techniques, harmonies, memorization and listening skills. Participants also prepared to sing in public performances to promote motivation, purpose, pride and accomplishment.

“Each session incorporated the musical, social, and physical aspects of choral singing.”

Forty-seven participants were randomly assigned to the choral singing intervention (CSI) arm, and 46 were assigned to the health education program (HEP) arm. Parallel to the CSI participants, HEP participants completed a weekly one-hour health education session at the Training and Research Academy at Jurong Point for two years. Family physicians, specialist clinicians and community nurses facilitated these sessions, which included short talks on health-related topics, group activities, memory work, and physical activities (not including singing).

At baseline, the researchers collected demographic and clinical characteristics from each participant. Characteristics included: age, gender, education, marital status, living situation, status of hypertension, diabetes mellitus, heart diseases, average composite cognitive test score, Singapore Modified Mini-Mental State Examination (SM-MMSE) score, and Geriatric Depression Scale (GDS). Follow-up assessments were conducted at two additional times throughout the study—after year one and year two of the programs. Researchers assessed the effects of both these programs on brain imaging, immune system and oxidative damage markers.

“Our study is the first randomized trial in the world that systematically assessed the effects of singing on cognitive decline in aging and the potential effects on brain imaging, immune system and oxidative damage markers.”

Results and Conclusion

The researchers were forthcoming about limitations in this study. The cohort was small and they did not include a non-intervention control arm; researchers were only able to compare the effects of choral singing to the effects seen in the health education cohort. The team did, however, observe an increase in the mean composite cognitive test scores among participants in the singing group, and a decrease in the mean composite cognitive test scores among participants in the health education group. They did not observe differences in brain aging, oxidative damage or immunosenescence.

“Our findings from the very first RCT on this topic suggest that choral singing is a potentially useful intervention for the promotion of cognitive health in aging. Choral singing is a safe and enjoyable activity, and is likely to be embraced by the community. Policy makers may consider promoting choral singing for healthy and active aging of seniors in the community. This is especially relevant for countries where existing resources are available.”

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 monthly in all fields of aging research and other topics. 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.

For media inquiries, please contact media@impactjournals.com.

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Trending With Impact: Machine Learning Predicts Human Aging

By Kathryn Atkins November 5, 2021 November 5, 2021 Blog

Machine learning and a broad range of biochemical and physiological traits were used to develop a new composite metric as a potential proxy for an underlying whole-body aging mechanism.

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Will you age quickly or slowly? Is it possible to predict how long you will live based on your genetics, lifestyle and other traits? In a new study, a team of researchers—from the National Institutes of Health’s National Institute on Aging, University of California San Diego, University of Michigan, Consiglio Nazionale delle Ricerche, Azienda Sanitaria di Firenze, and ViQi, Inc.—sought to answer these questions by developing a novel framework designed to estimate human physiological age and aging rate. Their trending paper was published by Aging (Aging-US) in October 2021, and entitled, “Predicting physiological aging rates from a range of quantitative traits using machine learning”.

“We present machine learning as a promising framework for measuring physiological age from broad-ranging physiological, cognitive, and molecular traits.”

Machine Learning

Machine learning is an important development in computer science that uses artificial intelligence. Algorithms and data (figured and input by human intelligence) are programed to automatically learn and improve through experience and new data. Machine learning approaches allow researchers to build mathematical models onto training data to predict target variables—target variables including human physiological age and rate of aging.

“Here we use a machine learning approach with a broad range of biochemical and physiological traits including blood phenotypes (e.g., high-density lipoprotein), cardiovascular functions (e.g., pulse wave velocity) and psychological traits (e.g., neuroticism) as main groups from the SardiNIA longitudinal study of aging [48, 49] to estimate human physiological age, a metric for phenotypic and functional age progression [7].”

Subjects and Traits

Two very interesting study populations were included in this particular aging model. People living in Sardinia—an island off the coast of Italy and one of the first identified “Blue Zones”—are well-known for their long lives. They are currently contributing to a large longitudinal study on human aging, known as the SardiNIA Project. Data from the SardiNIA Project was used to develop the aging model in the current study.

“Funded by the National Institute on Aging in 2001, the SardiNIA Project (age range 14.0 to 101.3 years, with a mean of 43.7 years; 57% female) is a longitudinal study of human aging on the island of Sardinia, which is notable for its long-lived population [48, 49].”

The second cohort included in the current study was collected from the InCHIANTI study. Participants in this longitudinal population-based study were predominantly older adults living in Tuscany, Italy. After collecting the initial datasets from both cohorts, the researchers reduced the datasets using a “cleaning” strategy they developed. After cleaning, the number of subjects in the study went from 6165 to 4817, and the number of traits included in the algorithms went from 183 to 148. The researchers then configured the selected subjects and traits using computational algorithms and machine learning. Traits were ranked based on importance and weighted accordingly using algorithms the researchers developed. Study methods and materials were detailed thoroughly in the paper and its supplemental materials.

Supplementary Figure 1. Computational workflow for measuring physiological age and physiological aging rates (PAR) using the machine learning framework.

Conclusion

The team developed a promising new composite metric and was able to closely predict chronological age using their machine learning strategy. After they effectively estimated physiological age and validated their results, the researchers then used the ratio of physiological and chronological age to determine physiological aging rate, or PAR. Interestingly, the researchers observed that PAR was highly correlated with the epigenetic aging rate (EAR), which is a DNA methylation-based measure of aging. In addition, the researchers demonstrated that individuals with lower PARs outlived individuals with higher PARs. PAR may be a new proxy for an underlying whole-body aging mechanism.

“The efficacy of treatments aimed at slowing the aging process has traditionally been evaluated using individual biomarkers or limited collections of related biomarkers. Our current study has shown that PAR is a significant predictor for survival and correlated with epigenetic aging rate, providing evidence for a good measurement of ‘aging’.”

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

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Trending With Impact: Is Iron a Driver of Aging?

By Kathryn Atkins October 29, 2021 October 29, 2021 Blog

In a trending theory article, Dennis Mangan proposes several reasons why iron may be a key driver of aging.

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Iron is a mineral naturally found in the environment on Earth, within food sources and in all living organisms. A number of biochemical systems require this mineral and, in humans, the lack of iron results in anemia and a deficiency in hemoglobin—the protein responsible for supplying the body with oxygen. Anemia can also be caused by iron dysregulation. This occurs when iron damages the protein it should be safely stored in, such as ferritin, and then reacts in a toxic manner with surrounding cellular structures and organs. While iron is essential, the chemical properties of iron can make it a harmful substance if it is not tightly regulated.

“The very property of iron that makes it useful, its ability to accept or donate electrons, also gives it the ability to damage molecules and organelles via the Fenton reaction, in which iron reacts with hydrogen peroxide, leading to the formation of the highly reactive and toxic free radical, hydroxyl.”

Dennis Mangan (P. D. Mangan) is a clinical biochemist/microbiologist, researcher, author, health and fitness expert, and anti-aging specialist. In October of 2021, he authored a new theory article that positions iron as a potential driver of aging. This trending paper was published in Aging (Aging-US) Volume 13, Issue 19, and entitled, “Iron: an underrated factor in aging.”

Iron and mTOR

There is an undeniable correlation between the accumulation of iron, DNA damage and age-related diseases. Excess iron levels are measurable in age-related illnesses, including cardiovascular disease, diabetes, cancer, and Alzheimer’s disease. In his paper, Mangan explains the important relationship between iron and the mammalian target of rapamycin (mTOR). Iron can act as a growth factor to activate mTOR. Crosswise, mTOR is capable of regulating iron metabolism.

“mTOR activation in diabetes may be responsible for the accumulation of excess iron seen in this illness; alternatively, accumulation of iron might activate mTOR, leading to diabetes.”

Researchers have demonstrated that inhibiting mTOR can extend lifespan and healthspan in animal models. The inhibition of mTOR, by drugs such as rapamycin, inhibits the accumulation of iron through an iron-regulating hormone called hepcidin. Therefore, it would be reasonable to assert that the over-activation of mTOR in diseases such as diabetes may be due to excess iron, or, excess iron may lead to diabetes through the over-activation of mTOR.

Sans Iron

Studies on experimental organisms, such as fruit flies, brewers yeast, roundworms and mice, have shown that the inhibition of iron leads to life extension. Mangan uses a number of natural iron chelators as examples, such as green tea catechins and curcumin. Calorie restriction is a highly effective life-extending intervention, and also a powerful regulator of iron metabolism. He lists iron inhibiting/chelating drugs, such as metformin, enalapril, quercetin, aspirin, tannic acid, ciclopirox, acetaminophen, bacitracin, berberine and baicalein.

“Thus, we can see that a large number of life-extending compounds also interact with iron, either by chelation, inhibition of absorption, or increased iron loss.”

Mangan also refers to a 2020 study which replaced 50% of blood plasma with saline, plus 5% albumin. To summarize their study, the researchers observed “rejuvenating” effects due to the dilution of old factors in the blood plasma. Similarly, elderly blood donors have experienced rejuvenating effects after donating blood. Mangan proposes that the critical old factor that was diluted was iron.

“Other components of plasma may be removed or diluted as well, but iron may be the critical element here.”

Conclusion

Mangan wrote a thought-provoking paper—far more detailed than this blog summary. He emphasizes that, since iron is both biologically needed and likely contributes to aging and disease, sufficient iron storage and regulation may be critical for the efficacy of upcoming anti-aging therapies that may be developed to extend lifespan.

“In sum, iron satisfies many of the conditions we might look for in a universally pro-aging substance. It accumulates with age; it is associated with many age-related diseases such as cardiovascular disease, cancer, and Alzheimer’s disease; it catalyzes the formation of cellular junk molecules and helps to prevent their turnover; removal of iron from plasma may be rejuvenating; and people with lower levels of body iron – blood donors – have a lower mortality rate.”

Click here to read the full theory article published by Aging (Aging-US).

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Trending With Impact: Green Tea Enhances Fitness and Lifespan in Worms

By Kathryn Atkins October 22, 2021 October 22, 2021 Blog

The mechanisms and pathways involved in the health and aging benefits conveyed by green tea were investigated in C. elegans.

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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Boiled or iced with water or milk, blended in smoothies, condensed into shots or even baked into pastries—humans are infatuated with green tea. Today, green tea is one of the most widely consumed beverages in the world. Molecules found in this plant, named catechins, are known to have numerous evidence-based health benefits, including weight loss and age delaying properties. However, the mechanism by which these effects take place have yet to be fully elucidated.

“The popularity of green tea makes it crucial to study its impact on health and aging.”

Researchers from Friedrich Schiller University Jena, Huazhong Agricultural University, ETH Zurich, and the Medical University of Graz investigated green tea catechins and their effects in roundworms, known as Caenorhabditis elegans (C. elegans), and isolated rodent mitochondria. Their trending paper was published in October of 2021 by Aging (Aging-US), and entitled, “Green tea catechins EGCG and ECG enhance the fitness and lifespan of Caenorhabditis elegans by complex I inhibition.”

“We have designed the current study to investigate the impact and to unveil the target of the most abundant green tea catechins, epigallocatechin gallate (EGCG) and epicatechin gallate (ECG).”

The Study

In this study, the researchers focused on testing two of the most common green tea catechins, epigallocatechin gallate (EGCG) and epicatechin gallate (ECG), in isolated mitochondria from murine liver and C. elegans. C. elegans are approximately one millimeter long nematodes, or roundworms, and have been used in a variety of biomedical studies. The reason C. elegans were chosen for this study is likely due to the fact that many genes in C. elegans have functional counterparts in humans. (C. elegans also have the ability to “smell” cancer.)

Over the course of 24 hours or seven days, C. elegans and rodent mitochondria were treated with 2.5 μM of EGCG and/or ECG compounds. To analyze the green tea catechins’ effects on cellular metabolism, reactive oxygen species (ROS) homeostasis, stress resistance, physical exercise capacity, health- and lifespan, and on the underlying signaling pathways, the researchers conducted lifespan analyses, locomotion assay, paraquat stress resistance assay, basal oxygen consumption rate, ROS quantification, glucose oxidation assay, ATP quantification, activity assays for catalase and superoxide dismutase, fat content analysis, quantification of complex I activity in mitochondria, quantification of oxygen consumption rate in mitochondria, and statistical analyses.

“We conclude that applying the green tea catechins EGCG and ECG at a low dose extends the lifespan of C. elegans via inducing a mitohormetic response.”

They found that the catechins hindered mitochondrial respiration in C. elegans after 6–12 hours, the activity of complex I in isolated rodent mitochondria and temporarily increased ROS levels. Then, after 24 hours and through adaptive responses, catechins reduced fat content, enhanced ROS defense and, in the long term, improved healthspan in C. elegans.

Conclusion

Mechanisms and pathways observed to be involved in this process of C. elegans fitness and lifespan extension by green tea were further described in the paper. The researchers note that additional studies will be required to determine the best timing and dosage for administering catechins. They also acknowledge that the low bioavailability of green tea catechins may limit the lifespan extending effects of green tea in humans, despite the promising effects demonstrated in C. elegans.

“Despite the promising results obtained in animal experiments, the low bioavailability of EGCG [7] still raises the question of whether green tea catechins can reliably provoke beneficial effects in humans. Consequently, additional efforts might be needed to identify complex I inhibitors with increased bioavailability.”

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 monthly in all fields of aging research and other topics. 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.

For media inquiries, please contact media@impactjournals.com.

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Trending With Impact: Retired Sled Dogs in Aging Research

By Kathryn Atkins October 15, 2021 December 28, 2021 Blog

Researchers adopted 103 retired sled dogs for a longitudinal study on canine aging that may one day be used to increase human healthspan and longevity.

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Whether they are sprinters or distance runners, sled dogs are known for their competitive nature and athletic prowess. With age, however, these athletes eventually run out of steam—just as humans inevitably do. Canines of all breeds are affected by aging, including a loss of resilience, accumulation of molecular damage and age-related diseases. These relatively short-lived, large mammals are one of the few to share environments with humans, and even have access to advanced medical care. Many believe the canine aging process resembles human aging the closest compared to any other animal.

A team of scientists—from Cornell University, North Carolina State University, Tauber Bioinformatic Research Center, and Roswell Park Comprehensive Cancer Center—saw the opportunities and advantages of studying canine aging in a controlled environment. Co-founders Andrei Gudkov, PhD, Dr Sci, Katerina Andrianova, PhD, and Daria Fleyshman, PhD, established a non-profit organization called Vaika Inc. In 2018, Vaika allowed these researchers to begin collaborating in a longitudinal study on the mechanisms of aging among 103 retired sled dogs. The researchers authored a trending research perspective about the details of their long-term study. In September 2021, their paper was published on the cover of Aging (Aging-US)’s Volume 13, Issue 18, and entitled, “Development of infrastructure for a systemic multidisciplinary approach to study aging in retired sled dogs.”

THE STUDY

The researchers chose to adopt retired sled dogs for this study in particular for a variety of reasons: 1) Based on the type of events they partake in, sled dogs usually have a record of health and performance that can be used for reference as they age. 2) Sled dogs are selected for performance, but are not limited to a particular breed and can be crossbred. This provides a somewhat homogeneous population to study while being less prone to breed-specific biases. 3) Sled dogs are used to working with many handlers, therefore, the transition into the kennel/research facility may be easier for them to adjust to. 4) Over their career, these dogs have been exposed to environmental pathogens in frequent group interactions. This provides the researchers a sufficient immune system model to study. 5) Sled dogs are used to living in packs, but forming short-term bonds—making them adaptable to living with a variety of handlers in a population of 103 other dogs.

“Thus, it is essential to establish a reference set of ‘healthy aging’ parameters specifically for each dog model, and we see this as one of the main goals of our sled dog study.”

The optics of caring for 103 retired sled dogs between the ages of eight and 11 (when the study began) may initially sound problematic, but all indications suggest that these dogs are living better than many humans. Their 8,254-square foot kennel is located on the Baker Institute campus of the College of Veterinary Medicine at Cornell University. The researchers designed the study so that the dogs are thoroughly examined, observed, fed, socialized, exercised, vaccinated and anything else they may need. The dogs’ personalities and special needs are taken into consideration when cohabitating with other dogs, in their separate rooms and during playtime outside. They have in-house veterinarians and researchers to monitor their health. Importantly, the researchers are monitoring not only the dogs’ health but also parameters of their individual aging experience.

“Our goal is not just to assess the state of health of a given dog but rather to dissect the aging process into its two key components: (i) declining resilience and (ii) acquisition of aging-related diseases.”

In order to observe declining resilience and aging-related diseases, the dogs participate in regular physical fitness (treadmill and pull tests) and cognitive tests (handler questionnaires, β-amyloid plaques, brain atrophy, neuron loss, and etc.). Their performance and scores are measured and compared to their previous scores. The researchers also regularly collect blood samples to assess the dogs for somatic cell genome modifications (accumulation of DNA damage) and immune system status (immunosenescence).

“In general, the canine immune system undergoes similar age-related changes to that of humans [85]. However, since completed canine studies are generally less comprehensive and predominantly cross-sectional, the reliability and relative significance of various immune parameters in aging have yet to be characterized.”

CONCLUSION

This research is still ongoing, and the researchers believe the infrastructure they established in this sled dog study is an important advancement in aging research. In the future, this animal model may be used to test anti-aging therapies and translate into advancing human healthspan and lifespan.

“We expect that these analyses will allow us to (i) characterize the mechanism(s) and regulation of canine aging, (ii) identify parameters and biomarkers suitable for assessment of biological age, and (iii) define factors that may act as aging accelerators or decelerators.”

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

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Aging (Aging-US) is an open-access journal that publishes research papers twice a month—in all fields of aging research and other biomedical topics. 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.

For media inquiries, please contact media@impactjournals.com.

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Trending With Impact: Alzheimer’s Disease as a Systems Network Disorder

By Kathryn Atkins October 8, 2021 October 15, 2021 Blog

In 2020, researchers conducted an analysis of multimodal data on Alzheimer’s disease (AD). Their research concluded that AD may not begin with amyloid-β.

Figure 2. The network of genetic polymorphisms associated with Alzheimer’s disease.

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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The root cause of Alzheimer’s disease (AD) is still unknown. For the past decades, the dominant paradigm many scientists have based their AD therapeutic solutions on has been the amyloid cascade hypothesis. The amyloid cascade hypothesis proposes that AD begins with the overproduction and accumulation of amyloid-β, followed by a number of other cascading symptoms. However, over 200 drug candidates based on this model have failed to prove clinical benefits in trial phases.

“The unsettlingly consistent failure of clinical trials led to questioning of the amyloid cascade hypothesis, stimulating a search for alternative AD paradigms [10–13].”

Researchers Alexei Kurakin and Dale E. Bredesen, from the Uni v ersity of California Los Angeles and the Buck Institute for Research on Aging, conducted detailed analyses of early-stage AD patient data and concluded their study by offering an alternative AD hypothesis. Their paper, published by Aging (Aging-US) in 2020, was entitled, “Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics.”

“In this report, we outline an alternative perspective on AD as a systems network disorder and discuss biochemical and genetic evidence suggesting the central role of chronic tissue injury/dyshomeostasis, innate immune reactivity, and inflammation in the etiopathobiology of Alzheimer’s disease.”

THE STUDY

The researchers attempted to conduct an unbiased analysis of clinical profiles of early-stage Alzheimer’s disease patients and accumulated research data. Their search algorithms were hypothesis-independent and they used “expert assistance” to synthesize multimodal data. A list of AD plasma biomarkers were compared with classical acute-phase response reactants. A network of genetic polymorphisms associated with AD were aggregated in addition to a quick reference guide for select AD susceptibility factors. In totality, their expansive research and organization of accumulated data has led them to conclude that Alzheimer’s disease may be a system-level network disorder.

“Reconciling multimodal clinical profiles of early-stage AD patients and research knowledge accumulated in diverse expert domains suggests that sporadic Alzheimer’s disease may not be a homogenous CNS disease, but a heterogeneous, system-level, network disorder, which is driven by chronic network stress and dyshomeostasis.”

CONCLUSION

Key structures and circuits of the central nervous system may be preferential targets of AD symptoms, including chronic systemic stress, toxicity and inflammation. The researchers believe this is mainly due to the central nervous system’s centric positions and functions. In AD, symptoms are initially highly heterogeneous until the disease reaches its “endpoint,” which is recognized as Alzheimer’s disease. This may be the reason that treating AD with monotherapies has not yet yielded effective results.

Given this new model of viewing Alzheimer’s disease as a system-level network disorder, the researchers propose that patients should be treated using precision medicine tactics. Dr. Bredesen has developed a novel therapeutic approach designed to treat each individual patient for their unique symptoms of cognitive decline and Alzheimer’s disease. Using the Bredeson Protocol, many patients have reported years of improved, and even reversed, cognitive decline. Dr. Bredesen also notes in a recent Aging Interview that it is important to treat early signs of AD, just as it is important to detect other diseases in early stages.

“The promising results of an integrative, systemic, precision medicine approach to treating Alzheimer’s disease suggests that evaluating and addressing the individual organism as a whole rather than focusing exclusively on an apparently failing part may represent a promising strategy to approach other complex chronic multifactorial disorders, which warrants further exploration and development.”

Click here to read the full research paper, published by Aging.

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Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. 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.

For media inquiries, please contact media@impactjournals.com.

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Trending With Impact: New Drug Combinations Inhibit Stress Proteins

By Kathryn Atkins August 19, 2021 August 20, 2021 Misha Blagosklonny

Researchers tested antiviral, anticancer, and immunosuppressive drug combinations that may aid in treating neurodegenerative disorders, including Alzheimer’s disease.

Figure 5. Neratinib and AR12 combine to reduce the expression of HSP90, HSP70, GRP78 and HSP27 via autophagy.

The Trending with Impact series highlights Aging 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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Heat shock proteins (HSPs), also known today as stress proteins, were first observed in fruit flies in the 1960s. After Dr. Ferruccio Ritossa inadvertently subjected a preparation of fruit fly salivary glands to a non-lethal increase in temperature, he discovered a new pattern of chromosomal “puffing.” In 1974, researchers identified the proteins that were encoded by the “puffs” recorded by Dr. Ritossa, and named them heat shock proteins.

These newfound proteins appeared to only become detectable when the cells were heated. Researchers later learned that HSPs can also be induced by oxidants, toxins, heavy metals, free radicals, viruses, and other stressors. Since its discovery, variations of this genetic system have been found in all bacteria, plants, and animals—including humans. HSPs have been well-studied since this revelation, and researchers now believe these molecular chaperones play important roles in protein refolding, aging-related diseases, and overall longevity.

“Toxic misfolded proteins are key drivers of AD [Alzheimer’s disease], ALS [Amyotrophic lateral sclerosis], HC [Huntington’s Chorea] and other neurodegenerative diseases.”

Researchers from Virginia Commonwealth University, Translational Genomics Research Institute, and the Banner Alzheimer’s Institute took part in a research study experimenting with combinations of therapeutic agents that may improve neurodegenerative diseases. In 2021, their paper was published in Aging’s Volume 13, Issue 13, and entitled, “Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43.”

“In this paper we examined using isogenic colon cancer cells [with] several existing drugs that function by increasing autophagy and degrading misfolded proteins.”

THE STUDY

“Aberrant expression of chaperone proteins is found in many human pathologies including cancer, in virology and in AD, ALS and HC.”

In this study, researchers tested drugs that have been used preclinically and clinically in several anticancer studies. The drugs used were: AR12, an antiviral chaperone ATPase inhibitor; Neratinib, a tyrosine kinase inhibitor; a combination of AR12 and Neratinib; Fingolimod, an immunosuppressive sphingosine l-phosphate receptor modulator; MMF, monomethyl fumarate; and a combination of Fingolimod and MMF.

The cells they tested these drug combinations on in vitro included Vero cells (African Green Monkey kidney cells), isogenic HCT116 colon cancer cells (genetically manipulated colon cancer cells), and GB6 cells (glioblastoma cancer stem cells). They also used plasmids, antibodies, and siRNAs. Researchers acknowledged that the use of non-neuronal cells may be a limitation of this study.

“Our present studies were performed in non-neuronal cells and as a caveat, it is possible that our data in HCT116 and Vero cells will not be reflective of the same processes in neuronal cells.”

Despite this caveat, results from their research were promising. Some combinations of these drugs were capable of knocking down many disease specific proteins that form toxic aggregates inside cells and in extracellular environments via autophagy.

CONCLUSION

“As the mechanism of drug-action became clearer it was apparent that these agents should also be tested in neurodegenerative diseases. The entire neurodegenerative field needs rapid translational methods that target the underlying cause of disease, toxic misfolded protein. The findings from this work warrant further testing with a focus on clinical utility.”

Click here to read the full research paper, published by Aging.

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Trending With Impact: Circulating Mitochondria and Inflamm-Aging

By Kathryn Atkins August 5, 2021 August 6, 2021 Misha Blagosklonny

Authors from the National Institute on Aging wrote a trending editorial paper on mitochondria extracellular vesicles and aging.

**Figure 1. Mitochondrial DNA in extracellular vesicles and association with human aging.**

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The Trending With Impact series highlights Aging 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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Some structures inside cells play elusive, yet important roles in human aging. Researchers believe structures classified as extracellular vesicles (EVs), released outside of cell walls, may also play key components in the aging process—specifically related to chronic inflammation.

“EVs are lipid-bound nano-sized vesicles that are secreted outside of cells into the circulation (Figure 1A).”

Two researchers from the National Institutes of Health‘s National Institute on Aging wrote a trending editorial paper, published by Aging in 2021, and entitled, “Mitochondria as extracellular vesicle cargo in aging.”

Inflammation and Aging

The term “inflamm-aging” has been coined to describe the common state of chronic low-grade inflammation associated with aging. Researchers believe that inflammation contributes to many age-related diseases, including cardiovascular disease, diabetes, cancer, and even dementia.

“In fact, inflammation-related diseases account for more than 50% of worldwide deaths, stressing the importance of inflammation in driving age-related disease and mortality [1,2].”

In the elderly, cellular damage and stress (among other causes) may contribute to chronic inflammation, which can initiate a release of mitochondrial damage-associated molecular patterns. This process can initiate cells to release mitochondrial DNA (mtDNA) into the space outside of the cell as circulating cell-free mitochondria DNA (ccf-mtDNA).

“Due to the similarities between mtDNA and bacterial DNA, this release can in turn elicit a sterile inflammatory response through activation of the innate immune system.”

Circulating Cell-Free Mitochondria DNA

Authors of this editorial believe that ccf-mtDNA may contribute to systemic chronic inflammation. In a previous study, researchers found, in general, that higher plasma/serum levels of ccf-mtDNA were reported in patients with inflammatory-related diseases and after acute injury or infection. However, ccf-mtDNA’s role in aging is complex, as one study showed that ccf-mtDNA levels initially decline into middle-age, and then gradually increase after age 50.

The molecular details of how ccf-mtDNA exists within blood circulation has yet to be elucidated. Questions still linger surrounding whether or not components in the blood bind to ccf-mtDNA. If components do bind to ccf-mtDNA, are they capable of protecting ccf-mtDNA from destruction in circulation?

Extracellular Vesicles and mtDNA

“Given these gaps in the field, we recently explored whether plasma mtDNA can be encapsulated in extracellular vesicles (EVs) [5].”

The researchers evaluated multiple studies to find that mtDNA can be encapsulated in EVs isolated from plasma—both in cells that have been grown in vitro and in plasma EVs from patients with breast cancer. The next question the researchers addressed was: How do levels of mtDNA in plasma EVs fair in normal conditions and with age?

“To address this need, we isolated plasma EVs and analyzed mtDNA levels with human age. Individuals in this aging cohort had donated plasma at two different time points approximately 5 years apart, which enabled us to examine both crosssectional and longitudinal changes.”

Conclusion

“In both our cross-sectional and longitudinal analyses, EV mtDNA levels decreased with advancing age [5] (Figure 1B).”

The researchers concluded by reporting EV mtDNA levels decreased over a span of five years in the longitudinal cohort. Mitochondrial components, including mtDNA, may be important EV cargo. They emphasized that further research is needed and that it is important for researchers to consider age when using EVs as diagnostic or prognostic markers of disease.

Click here to read the full editorial paper, published by Aging.

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Trending With Impact: A New Marker of Aging and Cellular Senescence

By Kathryn Atkins July 29, 2021 August 2, 2021 Uncategorized

Researchers from the Campisi Lab discovered new insights while investigating Cdkn1a transcript variants 1 and 2.

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The phenomenon in which cells are still metabolically active but can no longer proliferate is known as cellular senescence. Cellular senescence is a normal mechanism in development and tissue homeostasis—and a hallmark of aging.

“Most of my lab works on a process called cellular senescence, which is a cellular response to stresses and damage, many of which increase with age,” Dr. Judy Campisi, Professor at the Buck Institute for Research on Aging and Senior Scientist at the Lawrence Berkeley National Lab, said in a recent Aging interview.

An international team of researchers from Dr. Campisi’s lab are in search of new biological markers of cellular senescence and aging. Understanding mechanisms of aging such as senescence is key for developing new, safe interventions that may extend human life—with compounding socioeconomic and cultural impacts. Researchers from this lab come from institutions including the Buck Institute, the University of California, Berkeley’s Lawrence Berkeley National Lab, Universidad de Córdoba, Universidad Mayor, Geroscience Center for Brain Health and Metabolism, and Unity Biotechnology. The team published a trending 2021 paper in Aging‘s Volume 13, Issue 10, entitled, “Cdkn1a transcript variant 2 is a marker of aging and cellular senescence.”

“Our results are, to our knowledge, the first to study Ckdn1a transcript variants in the context of aging.”

THE STUDY

There are a number of mechanisms that drive cellular senescence. Previously, mRNA and protein coding gene Cdkn1a transcript variant 1 (p21var1) has been better-studied compared to Cdkn1a transcript variant 2 (p21var2). The authors of this paper explain that this is likely because the encoded protein is identical to that encoded by variant 1, and both variants are regulated by p53. However, neither variants have ever before been studied in the context of aging. In this study, the researchers explored the expression levels of both Cdkn1a transcript variants 1 and 2 in the context of cellular senescence using several tissues from aged mice and a cell culture model of mouse cells.

“The stringent cell growth arrest associated with cellular senescence is determined, among other mechanisms, by activities of cyclin-dependent kinase inhibitor proteins p16Ink4a and p21Cip1/Waf1, encoded by the Cdkn2a and Cdkn1a loci, respectively [1].”

Study results showed that both variants are induced during cellular senescence. They showed that p21var1 and p21var2 are equally sensitive to transcriptional upregulation after p53 stabilization. The in vitro models also found that p21var2 is preferentially induced with age.

“In sum, p21var2 expression is consistently elevated with age, in contrast with an absence of age-related change in p21var1 levels.”

The researchers conducted further tests in vivo to examine the expression pattern of p21var2 and their results suggested that the circadian regulation of p21Cip1/Waf1 is driven solely by expression of Cdkn1a transcript variant 1. The team also induced cellular senescence in vivo with doxorubicin and ABT-263 (navitoclax) and evaluated the variants’ expression. These results confirmed their in vitro findings that p21var2 is more prone to cellular senescence than p21var1, thus making it a better marker for assessing the presence of senescent cells in vivo.

CONCLUSION

“We show that, although tissue-specific exceptions may arise, p21var2 but not p21var1 is a better candidate marker of aging and senescence in mice.”

Click here to read the full research paper, published by Aging.

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Trending With Impact: Epigenetic Shifts, Aging, and Disease

By Kathryn Atkins July 23, 2021 July 23, 2021 Uncategorized

Researchers from Harvard University and the Broad Institute wrote a theory article, published by Aging in 2021, and entitled, “Shifting epigenetic contexts influence regulatory variation and disease risk.”

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From birth to advanced age, chemical changes occur which affect the genetic material in human cells comprising chromosomes—known as chromatin. These nongenetic changes, otherwise referred to as epigenetic aging, accumulate with age and impact transcriptional programs. From growth and development to adulthood, these changes can denote shifting epigenetic contexts.

“Shifting epigenetic contexts influence regulatory variation and disease risk”

There is a considerable amount of evidence that suggests a causal relationship between changes in epigenetic state and cell aging. Curiously, researchers have repeatedly observed similar epigenetic changes occurring across different cell and tissue types, throughout different stages of life. These potentially synchronized changes may implicate mechanisms of the aging process.

“Together, these findings suggest that a central trajectory for epigenetic state that reflects innate aging processes may exist [20], upon which extrinsic and cell-type effects are layered.”

In 2021, researchers from Harvard University and the Broad Institute wrote a theory article that was published in Aging’s Volume 13, Issue 12, and entitled, “Shifting epigenetic contexts influence regulatory variation and disease risk.” The authors described common epigenetic trends throughout human growth, development, and aging. They also aimed to show how changing epigenetic contexts may influence the behavior of evolutionary forces and risk of genetic disease.

FETAL TO ADULT EPIGENETIC SHIFTS

The researchers point out that in order to better understand the contribution of epigenetic changes to disease and aging, it is important to understand the developmental changes that occur between fetal and adult tissues, and their interaction with epigenetic aging.

“Furthermore, these fetal to adult epigenetic shifts can be compounded by additional modifications through aging-associated epigenetic changes.”

Characterizing these epigenetic trends and examining their potential interaction with later-in-life epigenetic aging were main goals of this study. In order to do this, the researchers defined genomic regions where, over the course of development and aging, chromatin accessibility consistently shifts. Chromatin can be broadly classified in either of two epigenetic states: activating or repressing modifications. These states refer to chromatin accessibility and the increased or decreased ability of DNA to access gene-regulatory machinery, such as transcription factors. The authors note that they used an accessibility-based definition of epigenetic context, and that there are other marks of epigenetic changes (e.g. methylation, and etc.) that are not captured by this definition.

“Epigenetic marks established during development can persist into adulthood [9], but they do so in the context of shifts in epigenetic states (see below) as tissues transition into their adult forms and functions.”

CONCLUSION

The researchers utilized genome-wide association study (GWAS) datasets to find that gene variants in adult tissues gaining nearby accessibility have stronger associations across a number of aging-related diseases, including neoplasms, arthritis, and atherosclerosis.

“In other words, it is the change in epigenetic context that modifies the regulatory potential of these variants, and this has direct impacts on individual associations with multiple diseases.”

Among their many findings, the researchers explain that the regulatory sequences which are most active during development are subject to strong negative selection later in life.

“We utilize our findings to propose a model for how evolutionary forces may have acted at these loci in humans, and how these forces in turn influence the distribution of mutations conferring heritable disease risk across a number of age-associated pathologies.”

Click here to read the full theory article, published by Aging.

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