Trending With Impact: Worms Reveal Early Event in Neurodegeneration

Researchers examined roundworms to determine the role of mitochondrial dysfunction in progressive neurodegenerative disorders, such as Alzheimer’s disease.

From Figure 2. Altered mitochondrial morphology and activity in tauwt-expressing larvae. (truncated)
From Figure 2. Altered mitochondrial morphology and activity in tauwt-expressing larvae. (truncated)

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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Many aging-associated neurodegenerative disorders, including Alzheimer’s disease, involve the aggregation of abnormal tau in nerve cells (neurons). Normally, tau proteins function to stabilize microtubules in the brain. Tauopathy occurs when tau proteins become misfolded and misshapen (which turns tau into toxic tau). They then continue to proliferate and bind to each other, forming tau oligomers. These tau oligomers are more toxic and have a greater potential to spread tau pathology. Before the tau pathology snowballs into neurodegenerative disorders, the events that lead up to abnormal tau have remained elusive to researchers. 

“While the association between tau levels and energy metabolism is established, it is not clear whether mitochondrial dysfunction is an early pathological feature of high levels of tau or a consequence of its excessive formation of protein aggregates.”

Previous studies have demonstrated an association between tau levels and mitochondrial metabolism, however, determining which one proceeds the other has yet to be fully illuminated. Shedding light on this subject, researchers—from the University of CopenhagenNational and Kapodistrian University of Athens and the National Institutes of Health’s National Institute on Aging—used a Caenorhabditis elegans (C. elegans; roundworm/nematode) model of tau to examine mitochondrial changes over time. Their paper was chosen as the cover of Aging (Aging-US) Volume 13, Issue 21, published in November of 2021 and entitled, “Alteration of mitochondrial homeostasis is an early event in a C. elegans model of human tauopathy”.  

The Study

“Here, we utilized transgenic nematodes expressing the full length of wild type tau in neuronal cells and monitored mitochondrial morphology alterations over time.”

To investigate the impact of tau on mitochondrial activity, neuronal function and organismal physiology, the researchers selected and cultured an already characterized nematode strain that expresses the full length of wild type human tau protein. They compared wild type nematodes with tau-expressing nematodes (at various ages) over time using a thrashing assay, mitochondrial imaging, worm tracking software, and western blot analysis. Calcium deregulation was also examined to determine whether or not it is implicated in the impairment of mitochondrial activity in the tau-expressing nematodes. They found that chelating calcium led to restored mitochondrial activity and suggested a link between mitochondrial damage, calcium homeostasis and neuronal impairment in this nematode model.

Figure 2. Altered mitochondrial morphology and activity in tauwt-expressing larvae.
Figure 2. Altered mitochondrial morphology and activity in tauwt-expressing larvae.

Conclusion

“Our findings suggest that defective mitochondrial function is an early pathogenic event of tauopathies, taking place before tau aggregation and undermining neuronal homeostasis and organismal fitness.”

The researchers were forthcoming about limitations in their study, given the differences between human and nematode biology and pathology. Nevertheless, they found evidence that, in this nematode tauopathy model, neurotoxicity depends on protein alterations and mitochondrial dysfunction. Mitochondrial dysfunction takes place before high levels of tau are detected. Tau mutations may also modulate calcium homeostasis by influencing the main cellular storage sites—the endoplasmic reticulum and mitochondria.

“Investigating the tight interplay between tau oligomers and energy metabolism will enlighten new avenues for therapeutic strategies to slow or halt the progression of dementia-related diseases such as AD [Alzheimer’s disease].”

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.

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Trending With Impact: Can Singing Improve Aging?

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

Couple singing

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 SingaporeSingapore Institute for Clinical SciencesNational University Health SystemUniversity of CambridgeUniversity of LondonSingapore Immunology NetworkMaurine Tsakok IncVoices of Singapore Choral SocietyPresbyterian Community ServicesNTUC Health Co-operative Limited, Beijing Chui Yang Liu Hospital, Fudan UniversityMassachusetts General HospitalHarvard Medical SchoolNanyang Technological UniversityImperial 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.

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

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

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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 [1013].”

Researchers Alexei Kurakin and Dale E. Bredesen, from the University 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.

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Protocol Reverses Symptoms of Alzheimer’s Disease in Small Cohort

The MEND (Bredesen) protocol to treat neurodegeneration associated with Alzheimer’s disease was tested in a small cohort. In 2016, researchers followed up with objective results.

Blue synapse and neuron on a blue background. 3D rendering
Blue synapse and neuron. 3D rendering

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Precursors to the onset of early Alzheimer’s disease (AD) include mild cognitive impairment (MCI) and subjective cognitive impairment (SCI). Many have viewed this looming neurodegeneration as an unavoidable fate that accompanies aging. However, in a 2014 study, a novel precision medicine treatment approach, termed the metabolic enhancement for neurodegeneration (MEND) protocol, yielded unprecedented results. Nine out of 10 participants with memory loss associated with AD, amnestic MCI, and SCI, were treated using the MEND protocol. Participants displayed subjective improvement in cognition within 3-6 months of this protocol. The study claims their only failure was one patient with very late stage AD.

In 2016, researchers—from the University of CaliforniaBuck Institute for Research on AgingPacific Medical Center, and Brainreader—followed up on the anecdotal results from the 10 patients in this study. They provided objective results from quantitative magnetic resonance imaging (MRI) and neuropsychological testing. The researchers authored another paper on results of the MEND protocol, which was published by Aging and entitled, “Reversal of cognitive decline in Alzheimer’s disease.” To date, this paper has generated an Altmetric Attention score of 263. The original 2014 paper on the MEND study has also generated an impressive Altmetric Attention score of 470.

“In each of these cases, obvious subjective improvement, noted by the patient, his/her significant other, and his/her co-workers, was accompanied by clear, quantitated, objective improvement.”

THE MEND PROTOCOL

The MEND protocol, also known as the Bredesen Protocol (named after the creator of the protocol, Dr. Dale Bredesen), consists of a multifaceted, tailored approach to treating each AD patient for their individual symptoms of cognitive decline—and not only a few symptoms. This strategy uses a combination of diet, lifestyle, and therapeutic interventions. Treatment is based on the hypothesis that AD occurs due to an imbalance in an extensive plasticity network in the brain. The authors note that the MEND protocol is an iterative process and designed to improve with continued patient visits. 

“The therapeutic system described in this report derives from basic studies of the role of APP signaling and proteolysis in plasticity, and the imbalance in this receptor proteolysis that reproducibly occurs in Alzheimer’s disease.”

Upon clinical assessment and lab testing, the patients’ physical and cognitive health were evaluated. Based on this assessment, patients were prescribed a lengthy personalized therapeutic system. Among other objectives, the MEND protocol recommends treating diabetes; improving sleep and digestive health; reducing stress, inflammation, and blood sugar; increasing physical exercise, intellectual stimulation, antioxidants, and vitamins; and optimizing hormone balance, synthesis of acetylcholine, nerve growth factors and mitochondrial function.

ANECDOTAL AND OBJECTIVE RESULTS

“The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective.”

Before participating in the MEND protocol, most of the 10 participants reported a family history of AD, confusion, difficulty with word finding, following instructions, remembering, reading, concentrating, driving, completing work related tasks, and other cognitive struggles. Over the course of between five and 24 months on the MEND, nine of 10 patients and their families or caregivers reported improved cognitive function. Some patients were able to go back to work, play games, and even babysit their grandchildren. One spouse of a patient mentioned that her husband had stopped following the protocol for a period of time, which resulted in him leaving the car in the driveway idling with the keys in the ignition. After he resumed the protocol, no such instances were reported.

Bearing in mind that this study used an extremely small cohort to test this very expensive protocol, the objective results observed by the researchers were still considerably significant. Quantitative neuropsychological testing showed improvements of up to three standard deviations. One patient showed an increase in hippocampal volume from 17th percentile to 75th percentile. These results must be verified in a larger sample size to validate efficacy.

CONCLUSION

“The initial results for these patients show greater improvements than have been reported for other patients treated for Alzheimer’s disease. The results provide further support for the suggestion that such a comprehensive approach [3] to treat early Alzheimer’s disease and its precursors, MCI and SCI, is effective. The results also support the need for a large-scale, personalized clinical trial using this protocol.”

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.

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Hyperbaric Oxygen: A Therapy for Normal Aging?

Hyperbaric oxygen therapy (HBOT) provides significant benefits for patients who have suffered brain damage. In this 2020 study, researchers assessed the effects of HBOT among healthy aging participants.

Figure 4. Brain regions with significant post hyperbaric oxygen therapy changes in cerebral blood flow.

The Top-Performer series highlights papers published by Aging that have generated a high Altmetric attention score. Altmetric scores, located at the top-left of trending Aging papers, provide an at-a-glance indication of the volume and type of online attention the research has received.

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Cognitive decline among elderly populations 60 years of age and older is common. At least 50% of all community-dwelling individuals in this demographic express concern about declining cognitive abilities. Interventions such as exercise, healthy diets, and cognitive training (if maintained habitually) have shown positive effects on cognitive function. Another intervention with potential cognitive benefits—dating as far back as 1662 (before the discovery of oxygen)—in short, is the ingestion of pure pressurized oxygen, or hyperbaric oxygen therapy (HBOT). 

Hyperoxic exposures increase the amount of oxygen dissolved in the body’s tissues and induce hypoxia-like physiological effects, including stem cell proliferation and angiogenesis. Previous studies have shown that repeated intermittent HBOT to improve cognitive functions in post-stroketraumatic brain injury, and anoxic brain damaged patients, even years after an incident. While a number of studies have demonstrated that this therapy induces neurotherapeutic effects in injured patients, the effects of HBOT in normal aging populations had previously not been evaluated. 

In 2020, researchers from Shamir (Assaf-Harofeh) Medical CenterTel-Aviv University, and Bar Ilan University conducted the first published study examining the neurocognitive effects of hyperbaric oxygen therapy in normal aging populations. Their paper was published in Aging’s Volume 12, Issue 13, and entitled: “Cognitive enhancement of healthy older adults using hyperbaric oxygen: a randomized controlled trial.” To date, this research paper has received an impressive Altmetric Attention score of 111

THE STUDY

“The aim of the current study was to evaluate whether HBOT affects cognitive function and brain perfusion in normal, non-pathological, aging adults.”

A total of 63 patients were admitted into this study. The participants’ age, gender, right/left hand dominance, education, employment, medical conditions, medications, and other characteristics were collected at the start of the study. The median age was approximately 69 years old. Cognitive function of each participant was evaluated at baseline in terms of memory, attention, information processing speed, motor skills, and a number of other measures of neurocognitive function.

The participants were then assigned either the HBOT arm or the control arm of the study. Both groups had similar characteristics and cognitive function at baseline. Half of the participants received 60 daily sessions of HBOT over the course of three months. All post-intervention measurements were taken at least one week after the last hyperbaric session. The assessors were blind to the assignment each participant was given when reevaluating for cognitive function after HBOT intervention.

“Our protocol included 60 sessions of 100% oxygen at 2 ATA including 3 air breaks during each session in order to utilize the hyperoxic hypoxic paradox and minimize the risk for oxygen toxicity.”

RESULTS & CONCLUSION

“In summary, the study indicates that HBOT can induce cognitive enhancement in healthy aging populations.”

While the researchers are forthcoming about limitations of this study, results show that 60 sessions of hyperbaric oxygen therapy improved attention, information processing speed, executive function, and global cognitive functions. Importantly, HBOT also significantly improved cerebral blood flow in certain cortical regions of the brain.

“Moreover, the HBOT group had a significantly enhanced brain perfusion in the superior and middle frontal gyri, supplementary motor area and superior parietal lobule.” 

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

Aging is an open-access journal that publishes high-quality research papers bi-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 communities from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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