How Menopause Changes Brain Structure and Connectivity

In this study, researchers use neuroimaging to see how menopause alters brain structure and connectivity in postmenopausal women.

Menopause marks the beginning of the next biological chapter in a woman’s life. Characterized by the natural ebb of reproductive hormones (particularly estrogen), menopause ushers in a new season of aging. This hormonal shift not only signifies a transition in fertility but also influences systemic health. The menopause-associated decline in estrogen has been associated with various health issues, including alterations in brain structure and function. However, the mechanics of this phenomenon are still poorly understood. A greater understanding of how menopause alters the brain could aid in the early detection, and possible prevention, of neurodegenerative disease.

In a new study, researchers Gwang-Won Kim, Kwangsung Park, Yun-Hyeon Kim, and Gwang-Woo Jeong from Chonnam National University used neuroimaging to shed light on how menopause alters brain morphology and functional connectivity in postmenopausal women. On March 23, 2024, their research paper was published as the cover of Aging’s Volume 16, Issue 6, entitled, “Altered brain morphology and functional connectivity in postmenopausal women: automatic segmentation of whole-brain and thalamic subnuclei and resting-state fMRI.” 

“To the best of our knowledge, no comparative neuroimaging study on alterations in the brain volume and functional connectivity, especially focusing on the thalamic subnuclei in premenopausal vs. postmenopausal women has been reported.”

The Study

The decline in estrogen levels during menopause has been linked to an elevated risk of neurodegenerative diseases, notably Alzheimer’s disease (AD). Estrogen plays a pivotal role in modulating neurotransmitter systems, neurotrophins, and brain cytoarchitecture, and there is evidence that these interactions also affect mood, memory, and cognition. The biological mechanisms underlying the increased AD risk in postmenopausal women are not fully understood.

In this study, 21 premenopausal women and 21 postmenopausal women were subjected to magnetic resonance imaging (MRI). The researchers utilized T1-weighted MRI and resting-state functional MRI data to assess differences in brain volume and seed-based functional connectivity. For statistical analysis, they employed multivariate analysis of variance, factoring in age and whole brain volume as covariates, to compare the surface areas and subcortical volumes between the two groups.

Results

Postmenopausal women showed significantly smaller cortical surface, especially in the left medial orbitofrontal cortex (mOFC), right superior temporal cortex (STC), and right lateral orbitofrontal cortex, compared to premenopausal women. These findings suggest that diminished brain volume may be linked to menopause-related symptoms caused by lower sex hormone levels.

In addition to structural changes, the functional connectivity between the brain regions also showed changes. The study found significantly decreased functional connectivity between the left mOFC and the right thalamus in postmenopausal women — reinforcing the hypothesis that the left orbitofrontal-bilateral thalamus connectivity is associated with cognitive impairment. Although postmenopausal women did not show volume atrophy in the right thalamus, the volume of the right pulvinar anterior (PuA), a significant thalamic subnuclei, was significantly decreased. Decreased PuA volume in postmenopausal women is closely related to decreases in female sex hormone levels following menopause.

Expectedly, the study found a significant difference in age and sex hormone levels between premenopausal and postmenopausal women. Postmenopausal women had lower total estrogen and estradiol (E2) levels and higher follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels than premenopausal women. Estrogen levels were positively correlated with the surface area of the left mOFC, right STC, and right lOFC, as well as the volume of the right PuA.

“Concerning the close connection between the estrogen level and STC volume, our findings support a potential role of decreases in sex hormones following menopause due to the correspondent brain structural atrophy. However, further study is needed to elucidate the specific cognitive and emotional implications in connection with these structural changes.”

Conclusions & Future Directions

Postmenopausal women showed significantly lower left mOFC, right lOFC, and right STC surface areas, reduced right PuA volume, and decreased left mOFC-right thalamus functional connectivity compared to premenopausal women. These findings provide novel insight into the structural and functional changes in the brain associated with menopause. However, further research is needed to validate these findings in a larger cohort and to understand the potential cognitive implications of these changes.

“Our findings provide novel insight into the structural and functional changes in the brain associated with menopause.”

Click here to read the full research paper published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that publishes high-impact papers in all fields of aging research. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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Aging’s Top 10 Papers in 2023 (Crossref Data)

Crossref is a non-profit organization that logs and updates citations for scientific publications. Each month, Crossref identifies a list of the most popular Aging (Aging-US) papers based on the number of times a DOI is successfully resolved. 

Below are Crossref’s Top 10 Aging DOIs in 2023.


#10: Old-age-induced obesity reversed by a methionine-deficient diet or oral administration of recombinant methioninase-producing Escherichia coli in C57BL/6 mice

DOI: https://doi.org/10.18632/aging.204783

Authors: Yutaro Kubota, Qinghong Han, Jose Reynoso, Yusuke Aoki, Noriyuki Masaki, Koya Obara, Kazuyuki Hamada, Michael Bouvet, Takuya Tsunoda, and Robert M. Hoffman

Institutions: AntiCancer Inc., University of California San Diego and Showa University School of Medicine 

Quote: “This is the first report that showed the efficacy of methionine restriction to reverse old-age-induced obesity.”


#9: Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity

DOI: https://doi.org/10.18632/aging.204498 

Authors: Pedro S. Marra, Takehiko Yamanashi, Kaitlyn J. Crutchley, Nadia E. Wahba, Zoe-Ella M. Anderson, Manisha Modukuri, Gloria Chang, Tammy Tran, Masaaki Iwata, Hyunkeun Ryan Cho, and Gen Shinozaki

Institutions: Stanford University School of Medicine, University of Iowa, Tottori University Faculty of Medicine, University of Nebraska Medical Center College of Medicine, and Oregon Health and Science University School of Medicine 

Quote: “In this study, we compared genome-wide DNA methylation rates among metformin users and nonusers […]”


#8: Age prediction from human blood plasma using proteomic and small RNA data: a comparative analysis

DOI: https://doi.org/10.18632/aging.204787 

Authors: Jérôme Salignon, Omid R. Faridani, Tasso Miliotis, Georges E. Janssens, Ping Chen, Bader Zarrouki, Rickard Sandberg, Pia Davidsson, and Christian G. Riedel

Institutions: Karolinska Institutet, University of New South Wales, Garvan Institute of Medical Research, and AstraZeneca

Quote: “[…] we see our work as an indication that combining different molecular data types could be a general strategy to improve future aging clocks.”


#7: Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic

DOI: https://doi.org/10.18632/aging.204616 

Authors: Fares Al-Mansour, Abdullah Alraddadi, Buwei He, Anes Saleh, Marta Poblocka, Wael Alzahrani, Shaun Cowley, and Salvador Macip

Institutions: University of Leicester, Najran University and Universitat Oberta de Catalunya

Quote: “The mechanisms of induction of senescent cell death by CUDC-907 remain to be fully elucidated.”


#6: Potential reversal of biological age in women following an 8-week methylation-supportive diet and lifestyle program: a case series

DOI: https://doi.org/10.18632/aging.204602 

Authors: Kara N. Fitzgerald, Tish Campbell, Suzanne Makarem, and Romilly Hodges

Institutions: Institute for Functional Medicine, Virginia Commonwealth University and the American Nutrition Association

Quote: “[…] these data suggest that a methylation-supportive diet and lifestyle intervention may favorably influence biological age in both sexes during middle age and older.”


#5: Leukocyte telomere length, T cell composition and DNA methylation age

DOI: https://doi.org/10.18632/aging.101293 

Authors: Brian H. Chen, Cara L. Carty, Masayuki Kimura, Jeremy D. Kark, Wei Chen, Shengxu Li, Tao Zhang, Charles Kooperberg, Daniel Levy, Themistocles Assimes, Devin Absher, Steve Horvath, Alexander P. Reiner, and Abraham Aviv

Institutions: National Institute on Aging, National Heart, Lung and Blood Institute, George Washington University, Children’s National Medical Center, Rutgers State University of New Jersey, Hebrew University-Hadassah School of Public Health and Community Medicine, Tulane University, Fred Hutchinson Cancer Research Center, Stanford University School of Medicine, HudsonAlpha Institute for Biotechnology, University of California LA, and University of Washington

Quote: “The two key observations of this study are: (a) LTL is inversely correlated with EEAA; and (b) the LTL-EEAA correlation largely reflects the proportions of imputed naïve and memory CD8+ T cell populations in the leukocytes from which DNA was extracted.”


#4: DNA methylation GrimAge strongly predicts lifespan and healthspan

DOI: https://doi.org/10.18632/aging.101684 

Authors: Ake T. Lu, Austin Quach, James G. Wilson, Alex P. Reiner, Abraham Aviv, Kenneth Raj, Lifang Hou, Andrea A. Baccarelli, Yun Li, James D. Stewart, Eric A. Whitsel, Themistocles L. Assimes, Luigi Ferrucci, and Steve Horvath

Institutions: University of California LA, University of Mississippi Medical Center, Fred Hutchinson Cancer Research Center, Rutgers State University of New Jersey, Public Health England, Northwestern University Feinberg School of Medicine, Columbia University Mailman School of Public Health, University of North Carolina, Chapel Hill, Stanford University School of Medicine, VA Palo Alto Health Care System, and National Institutes of Health 

Quote: “We coin this DNAm-based biomarker of mortality “DNAm GrimAge” because high values are grim news, with regards to mortality/morbidity risk. Our comprehensive studies demonstrate that DNAm GrimAge stands out when it comes to associations with age-related conditions, clinical biomarkers, and computed tomography data.”


#3: Deep biomarkers of aging and longevity: from research to applications

DOI: https://doi.org/10.18632/aging.102475 

Authors: Alex Zhavoronkov, Ricky Li, Candice Ma, and Polina Mamoshina

Institutions: Insilico Medicine, The Buck Institute for Research on Aging, The Biogerontology Research Foundation, Sinovation Ventures, Sinovation AI Institute, and Deep Longevity, Ltd

Quote: “Here we present the current state of development of the deep aging clocks in the context of the pharmaceutical research and development and clinical applications.”


#2: An epigenetic biomarker of aging for lifespan and healthspan

DOI: https://doi.org/10.18632/aging.101414 

Authors: Morgan E. Levine, Ake T. Lu, Austin Quach, Brian H. Chen, Themistocles L. Assimes, Stefania Bandinelli, Lifang Hou, Andrea A. Baccarelli, James D. Stewart, Yun Li, Eric A. Whitsel, James G Wilson, Alex P Reiner, Abraham Aviv, Kurt Lohman, Yongmei Liu, Luigi Ferrucci, and Steve Horvath

Institutions: University of California LA, National Institute on Aging, Stanford University School of Medicine, Azienda Toscana Centro, Northwestern University Feinberg School of Medicine, Columbia University Mailman School of Public Health, University of North Carolina, Chapel Hill, University of Mississippi Medical Center, Fred Hutchinson Cancer Research Center, Rutgers State University of New Jersey, and Wake Forest School of Medicine

Quote: “Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.”


#1: Chemically induced reprogramming to reverse cellular aging

DOI: https://doi.org/10.18632/aging.204896

Authors: Jae-Hyun Yang, Christopher A. Petty, Thomas Dixon-McDougall, Maria Vina Lopez, Alexander Tyshkovskiy, Sun Maybury-Lewis, Xiao Tian, Nabilah Ibrahim, Zhili Chen, Patrick T. Griffin, Matthew Arnold, Jien Li, Oswaldo A. Martinez, Alexander Behn, Ryan Rogers-Hammond, Suzanne Angeli, Vadim N. Gladyshev, and David A. Sinclair

Institutions: Harvard Medical School, University of Maine and Massachusetts Institute of Technology (MIT) 

Quote: “We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.”

Click here to read the latest papers published by Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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Understanding the Mechanisms of Brain Aging and Longevity in Neurons

In a new editorial, researchers discuss interconnected mechanisms of neuronal functionality and available tools to investigate neuronal aging and longevity. 

Neurons, the building blocks of the nervous system, play a vital role in our body’s function and longevity. Unlike other cells, neurons do not undergo replicative aging. However, they are still susceptible to various sources of damage throughout life, leading to neuronal death. Understanding the mechanisms behind aging and neuronal death is crucial for uncovering the secrets of brain longevity and developing potential interventions to promote healthy aging.

In a new editorial, researchers Fang Fang, Robert Usselman and Renee Reijo Pera from University of Science and Technology of China, Florida Institute of Technology and McLaughlin Research Institute discussed new interconnected mechanisms of neuronal functionality and available tools to investigate neuronal aging and longevity. On December 13, 2023, their editorial was published in Aging’s Volume 15, Issue 23, entitled, “Aging and neuronal death.”

Neuronal Durability, Differentiation & Maintenance

Neurons, born during embryonic development, must function in the body for the entire lifespan of the organism. They are incredibly durable cells, but they are not immune to damage. Neurons require a significant amount of oxygen and glucose to carry out their activities, making them vulnerable to ischemia. Ischemia occurs when the blood supply to a particular tissue is restricted, leading to oxygen and nutrient deprivation. 

Neurons can accumulate damage over time, which may result in cell death linked to reactive oxygen species (ROS). Neurons may also die due to ion overload and swelling caused by the malfunction of voltage-gated ion channels on their membranes. High concentrations of neurotransmitters and the accumulation of misfolded proteins are also implicated in neuronal death, observed in various neurodegenerative diseases.

To gain insights into the factors that promote neuron differentiation and maintenance, researchers have developed innovative screening methods. For example, Cui and colleagues described a high-throughput screening method using a luciferase reporter construct inserted downstream of the endogenous tyrosine hydroxylase (TH) gene. They differentiated neurons from human pluripotent stem cells and monitored their activity over time. This approach allows for the modeling of cell survival and demise, providing valuable information about the factors that influence neuronal longevity.

The Role of ROS in Survival & Death

Reactive oxygen species (ROS) are molecules produced during normal cellular metabolism. They play a crucial role in various biological processes but can also lead to oxidative stress when their levels exceed normal functional levels. Recent research has shed light on the distinction between global and local ROS balances and imbalances in cell phenotyping and mitochondrial energy management.

While global ROS homeostasis is essential for overall cellular health, ROS signaling pathways are driven locally by cellular microdomain-specific ROS production and degradation. Neurons have developed mechanisms to control ROS production and combat oxidative stress. For example, they express neurotrophic proteins that enhance mitochondrial activity, promoting the overall health of neurons.

“A sustained disruption of ROS balance can result in desirable enhanced cell signaling or undesirable oxidative stress, which can either improve function or diminish performance, respectively.”

Mechanisms for Longevity

Neurons have evolutionarily developed intricate mechanisms to maintain their longevity. They possess a distinct transcriptome signature that represses genes related to neural excitation and synaptic function. By preventing neurons from experiencing ion overload, this mechanism contributes to their long-term survival.

These brain cells have also developed specific DNA repair mechanisms to correct errors induced by active transcription. Neurons can turn off pro-apoptotic genes through alternative splicing, avoiding apoptosis and promoting long-term survival. These interconnected mechanisms work together to reduce the accumulation of aging-related damage in neurons. Understanding the fundamental mechanisms that enable the longevity of neurons is crucial for developing interventions that promote healthy brain aging. Researchers can use novel tools, including cell-based models, imaging techniques and animal studies, to investigate these mechanisms.

Conclusions

Neurons, although durable cells, are susceptible to various forms of damage that can lead to their demise. By studying the interplay between ROS, neuronal excitation, DNA repair, and apoptosis, researchers aim to uncover the secrets of brain longevity and develop strategies to mitigate the effects of aging on neurons. By understanding these mechanisms, researchers aim to develop interventions that promote healthy brain aging and enhance our overall understanding of brain health.

“Together, these findings suggest that neurons have evolved a set of intrinsically interconnected mechanisms to reduce long-term accumulations of aging-related damages. Disruption in these mechanisms may tip the neuron homeostasis off-balance and drive the neurons into the path of degeneration. We have a plethora of tools to probe the fundamental mechanisms with hopes of translation to clinical applications.”

Click here to read the full editorial published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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How Cognitive Reserve Can Help You Sleep Better and Think Sharper

In a new study, researchers investigated the association between sleep, cognitive reserve and cognition in older adults.

Sleep is vital for our health and well-being, but as we age, we tend to experience less and less of it. In particular, we lose some of the deep sleep stages, known as slow wave sleep (SWS), that are crucial for memory consolidation and brain maintenance. This can affect cognitive performance and increase our risk of developing dementia.

Not everyone is equally vulnerable to the negative effects of poor sleep quality. Some people seem to be more resilient and able to cope with less SWS without compromising their mental abilities. What makes them different? One possible factor is cognitive reserve (CR).

CR is a concept that refers to the brain’s ability to adapt and compensate for age-related changes or brain damage. It is influenced by various aspects of our life experiences, such as education, occupation, leisure activities, social interactions, and mental stimulation. People with higher CR are thought to have more efficient brain networks, more cognitive strategies, and more brain reserve (i.e., more neurons and connections) that can buffer the impact of aging or pathology on cognition.

In a new study, researchers Valentin Ourry, Stéphane Rehel, Claire André, Alison Mary, Léo Paly, Marion Delarue, Florence Requier, Anne Hendy, Fabienne Collette, Natalie L. Marchant, Francesca Felisatti, Cassandre Palix, Denis Vivien, Vincent de la Sayette, Gaël Chételat, Julie Gonneaud, and Géraldine Rauchs from Normandie University, UNI – ULB Neuroscience Institute, University of Liege, University College London, and CHU de Caen aimed to identify individuals in whom sleep disturbances might have greater behavioral consequences. On September 28, 2023, their research paper was published in Aging’s Volume 15, Issue 18, entitled, “Effect of cognitive reserve on the association between slow wave sleep and cognition in community-dwelling older adults.”

The Study

The researchers investigated whether CR could modulate the association between SWS and cognition in older adults. The researchers recruited 135 cognitively intact older adults (mean age: 69.4 years) from the Age-Well randomized controlled trial and measured their sleep quality using polysomnography — a technique that records brain waves, eye movements, muscle activity, and other physiological signals during sleep. They also assessed their cognitive performance using neuropsychological tests that evaluated executive function (i.e., the ability to plan, organize, monitor, and control one’s behavior) and episodic memory (i.e., the ability to remember personal events and experiences).

To estimate CR, the researchers used two measures of cognitive engagement throughout life: a questionnaire that asked about the frequency and diversity of participation in various activities (such as reading, playing games, learning languages, etc.) in different age periods; and a composite score based on the highest level of education attained, the complexity of the main occupation held, and the current cognitive activity level.

The results showed that SWS was positively associated with episodic memory performance, meaning that participants who had more SWS tended to have better memory scores. However, this association was not observed for executive function performance. CR proxies modulated the associations between SWS and both executive and episodic memory performance. Specifically, participants with higher CR were able to maintain cognitive performance despite low amounts of SWS, whereas participants with lower CR showed a steeper decline in performance as SWS decreased.

“This study provides the first evidence that CR may protect against the deleterious effects of age-related sleep changes on cognition.”

Conclusions

The study suggests that engaging in cognitively stimulating activities throughout life may enhance one’s ability to cope with less SWS without compromising one’s mental abilities. It also highlights the importance of considering individual differences in CR when evaluating the impact of sleep quality on cognition in older adults.

The authors were forthcoming about limitations of their study, such as the cross-sectional design that does not allow causal inferences, the relatively small sample size that limits the generalizability of the findings, and the use of proxy measures that may not capture all aspects of CR. They also point out some directions for future research, such as exploring the underlying mechanisms of how CR influences sleep-cognition relationships, examining whether CR can also modulate the effects of other sleep parameters (such as sleep duration or fragmentation) on cognition, and investigating whether interventions that target sleep quality or CR can improve cognitive outcomes in older adults.

In conclusion, this study suggests that CR may be an important factor that can help us sleep better and think sharper as we age. It also encourages us to keep our brains active and challenged throughout our lives, as this may benefit not only our cognitive functioning but also our sleep quality.

“These findings are important to understand the factors promoting successful aging and suggest that the deleterious impact of sleep disturbances could be counteracted by an enriched lifestyle. This will help to design non-pharmacological interventions to promote successful aging and counter age-related sleep changes.”

Click here to read the full study published in Aging.

Interested in reading more about cognitive reserve and aging? Click here.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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The Role of R-loops in Neuronal Aging

In a new editorial, researcher Hana Hall discusses the role of R-loops in neuronal aging and neurodegeneration. 

R-loops are structures that form when the nascent RNA hybridizes with the template DNA strand, displacing the non-template strand. In other words, R-loops are like temporary tangles in our DNA where a new RNA molecule forms by copying one of the DNA strands and pushes aside the other DNA strand. Nascent RNA refers to the newly synthesized RNA molecule that is produced during the process of transcription. In addition to transcription, R-loops are involved in various biological processes, such as splicing, DNA repair and chromatin remodeling. However, when R-loop homeostasis is disrupted, they can also cause transcriptional impairment, genome instability and cellular dysfunction.

“R-loops have been shown and studied in a wide range of organisms and while they have important regulatory roles, persistent R-loops can be detrimental to cell function and survival, having been closely linked to both gene expression dysregulation and increased genome instability.”

In a new editorial paper, researcher Hana Hall from the Purdue Institute for Integrative Neuroscience at Purdue University discusses the role of R-loops in neuronal aging and neurodegeneration. On September 13, 2023, her editorial was published in Aging’s Volume 15, Issue 17, and entitled, “R-loops in neuronal aging.” Hall summarizes her recent study and the current knowledge on how R-loop levels change during aging, how they affect gene expression and neuronal function, and how they are regulated by different factors.

“In our recent study, we demonstrated that R-loops accumulate in fly PR [photoreceptor] neurons by middle age and significantly increase into late-life stages [5].”

The Editorial

According to Hall, R-loop levels increase with age in different organisms and tissues, including neurons. This could be due to several reasons, such as reduced expression or activity of R-loop resolving enzymes (e.g., Top3β, RNase H1), increased transcriptional activity or stress, or impaired DNA repair mechanisms. Hall also highlighted that R-loop accumulation is associated with decreased expression of long and highly expressed genes, which are enriched for neuronal functions. This could lead to impaired neuronal activity and communication, as well as increased vulnerability to neurodegenerative diseases.

“Our study provides first evidence of R-loop accumulation in aging neurons and a contributing role in loss of neuronal function during aging.”

Hall further discussed how R-loop homeostasis is modulated by various factors, such as chromatin structure, epigenetic modifications, RNA-binding proteins, and non-coding RNAs. She also mentioned some potential therapeutic strategies to restore R-loop balance in aging neurons, such as overexpressing or delivering R-loop resolving enzymes, modulating chromatin accessibility or targeting specific R-loop forming genes.

Conclusions

Hall concluded that R-loops are important players in neuronal aging and neurodegeneration, and that more studies are needed to understand their molecular mechanisms and functional consequences. She also suggested that R-loop mapping could be used as a biomarker to monitor neuronal health and disease progression. This editorial provides a comprehensive overview of the current knowledge of R-loops in neuronal aging, and highlights the challenges and opportunities for future research. 

“Undoubtedly, R-loops are at the crossroads of several hallmarks of aging, namely transcriptional stress, genome instability, and chronic immune response. Targeting R-loop levels thus may help restore these pathways to a normal/healthy state and slow down or prevent the onset of age-dependent neurodegenerative diseases.”

Click here to read the full editorial published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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Exploring the Impact of Cognitive Reserve on Cognitive Resilience

In a new editorial, researchers discuss their recent study investigating the effect that cognitive reserve has on brain integrity and cognitive resilience.

Why do some individuals maintain cognitive abilities throughout their lifespan and others do not? The better question may be: How can certain individuals preserve their cognitive abilities and delay the onset of dementia despite the presence of significant neuropathologies that would otherwise suggest cognitive decline? This question remains unanswered.

“What contributes to this ‘resilience’ [3], that is why some successfully cope with progressive neuropathology while others cannot tolerate the same level of neurodegeneration, is not fully understood.”

This unanswered question has driven researchers to consider the idea of “cognitive reserve.” The rather new concept of cognitive reserve suggests that certain factors, such as engaging in education, mental stimulation and challenging activities, can create a buffer against cognitive decline and delay the onset of cognitive impairment or dementia. Researchers continue to study cognitive reserve to better understand its mechanisms and potential implications for maintaining brain health and designing effective interventions.

In a new editorial paper, researchers Monica E. Nelson, Ross Andel and Jakub Hort from the University of South Florida’s​​ School of Aging Studies discussed the outcomes, lessons and future implications of their previous 2022 study. The team examined the influence of cognitive reserve proxies on the relationship between brain integrity and cognition. On July 14, 2023, their editorial was published in Aging’s Volume 15, Issue 13, entitled, “Cognitive reserve, neuropathology, and progression towards Alzheimer’s disease.”

Cognitive Reserve’s Effect on Brain Integrity and Cognitive Performance

In their 2022 study, a total 570 older adult participants were assessed from the Czech Brain Aging Study (a longitudinal cohort study from two memory clinics in the Czech Republic). Most of the participants (n = 457) were without dementia (including those with subjective cognitive decline and amnestic mild cognitive impairment) and the remaining participants were with dementia syndrome (n = 113). The researchers examined the influence of education and occupational position (cognitive reserve proxies) on the relationship between the participants’ hippocampal or total gray matter volume and cognitive performance. Measurements included brain volume, executive control, language, memory, attention/working memory, and visuospatial skills.

“[…] we assessed the inter-link between cognitive reserve, neuropathology, and cognitive functioning among participants with subjective cognitive decline, mild cognitive impairment, and dementia.”

The team found that the association between brain volume and cognitive performance varies based on cognitive reserve. Findings showed that a higher education and occupational position magnified the associations between brain volume and cognitive performance in participants without dementia. In participants with dementia, higher education decreased the associations between brain volume and visuospatial skills. Overall, the results showed that cognitive reserve affects the relationship between brain volume and cognitive performance, with greater cognitive reserve related to a stronger link before dementia diagnosis and a weaker link after.

Future Directions 

In their subsequent editorial, the researchers were forthcoming about limitations of this study and addressed key opportunities for future studies. Limitations were identified as the use of a relatively homogeneous sample population, the absence of the use of biomarkers in diagnosis and the cross sectional design. Cross-sectional studies may not fully capture disease-related changes in neuropathology and could present a distorted view of the linkages between cognitive reserve, neuropathology and cognitive outcomes. The authors advocate for conducting longitudinal studies to track how cognitive reserve operates in individuals as they progress from normal to dementia. 

Additionally, the team wrote that future studies would be improved by investigating a range of Alzheimer’s disease biomarkers, such as beta-amyloid and tau, individually and together, to understand how they influence the associations between cognitive reserve, brain health and cognition. Different biomarkers may lead to varied results in how cognitive reserve moderates these associations. And finally, future studies should also assess older adults across the cognitive spectrum to determine when cognitive reserve is protective against brain health decline and neuropathology, and when its effectiveness diminishes. Some researchers have suggested a U-shaped relationship to explain mixed findings in different studies.

“Even though our study represents one of the first to come from Eastern Europe [4], future work should be conducted in additional populations, representing geographic, racial, and socioeconomic diversity.”

Implications

The potential impact of this research may be important, as it could lead to the development of effective interventions and strategies to preserve cognitive abilities and delay the onset of dementia. By gaining a deeper understanding of cognitive reserve and its mechanisms, we can take steps to promote brain health throughout life, potentially reducing the burden of dementia on individuals, communities and society overall.

As research continues in this field, it is clear that cognitive reserve holds great promise for unlocking the secrets of cognitive resilience and paving the way for healthier aging and improved quality of life for older adults. By addressing the limitations of current studies and exploring new avenues of investigation, we move closer to finding answers to the vital question of how some individuals maintain their cognitive abilities despite the presence of significant neuropathologies, while others do not.

“By assessing cognitive reserve in distinct populations, a more complete understanding of how cognitive reserve relates to neuropathology and cognition and whether these associations may be affected by distinct macro-level contextual differences among populations can be established. Disentangling these complex relationships may provide a critical step in reducing the impact of dementia on society.”

Click here to read the full editorial published by Aging.

Aging is an open-access, peer-reviewed journal that has been publishing high-impact papers in all fields of aging research since 2009. These papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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Can a Leaky Gut Lead to Alzheimer’s Disease?

In a new editorial, researchers explore how a leaky gut can lead to Alzheimer’s disease using the Seed and Soil Model of Neurocognitive Disorders to explain.

New research continues to illuminate the far-reaching implications of the gut microbiome and its crucial role in our overall health. The term “gut dysbiosis” refers to an imbalance of healthy and unhealthy microbes in the gastrointestinal tract. Repercussions of gut dysbiosis are not only limited to innocuous discomfort—it can lead to immune dysregulation and trigger a cascade of various disease states. 

In a new editorial paper, researchers Chun-Che Hung, Kristi M. Crowe-White and Ian M. McDonough from Chang Gung University and The University of Alabama discuss the relationship between gut dysbiosis and neurocognitive disorders such as Alzheimer’s disease (AD). Their editorial was published in Aging’s Volume 15, Issue 12, on June 19, 2023, entitled, “A seed and soil model of gut dysbiosis in Alzheimer’s disease.”

“[…] recent research has demonstrated a crucial role of gut microbiota in the etiopathogenesis of AD [Alzheimer’s disease] that offers a new window into possible origins and consequences of AD through interactions between gut microbiota and the central nervous system, known as the ‘microbiota-gutbrain axis’ [1].”

The Seed and Soil Model of Neurocognitive Disorders

The “Seed and Soil Model” in biology was first used in an attempt to describe why some individuals who are predisposed to developing neurocognitive disorders do not ever develop them. As the researchers wrote in their editorial, the “seeds” in this analogy represent genetic predispositions or a family history of a particular disease state. The “soil” represents the external environment that either enables or disables the expression of these seeds. This external environment can be influenced by behavioral and/or lifestyle factors. Although this model did not originally include the microbiota-gut-brain axis, the authors of this editorial are now applying it.

Interestingly, the researchers here have related the “leaky gut” phenomenon of gut dysbiosis to Alzheimer’s disease (AD). A leaky gut, plainly described as increased intestinal permeability, is a condition where the lining of the intestine becomes more porous. This allows larger molecules and toxins to pass through into the bloodstream—opening the door to potential inflammation and various health problems. 

Metabolites involved with gut leakiness have previously been linked to increased permeability of the blood-brain barrier (BBB). The opening of the BBB allows bacterial endotoxins to travel from the gut to the brain environment. This can increase inflammation within the system. The authors propose that gut leakiness, through the Seed and Soil Model, may explain why some people predisposed to AD realize the disease, while those without gut dysbiosis may not.

“According to the Seed and Soil Model of Neurocognitive Disorders, this translocation would create a toxic microenvironment in the brain vulnerable to pathogenesis, especially for those with a genetic predisposition to AD.”

Conclusion

“According to the Seed and Soil Model of Neurocognitive Disorders, environmental and behavioral patterns can influence the balance of neuroprotection vs. toxicity of the brain’s micro-environment.”

In sum, emerging research continues to shed light on the significance of the gut microbiome and its connection to our overall health. The editorial by Hung, Crowe-White and McDonough explores the relationship between gut dysbiosis and neurocognitive disorders, particularly Alzheimer’s disease, through the lens of the Seed and Soil Model of Neurocognitive Disorders. By considering the impact of leaky gut and the translocation of bacterial endotoxins on the brain, the authors propose that gut dysbiosis may contribute to the pathogenesis of AD, particularly in individuals with a genetic predisposition. This perspective opens new avenues for understanding the complex interactions within the microbiota-gut-brain axis and provides insights into ways to potentially stave off cognitive decline with diet and lifestyle interventions.

“Here, we extend the model to better understand how the microbiota-gut-brain axis may play a causal role in the development of AD. However, more research is needed to test additional hypotheses of the model.”

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

Aging is an open-access, peer-reviewed journal that has been publishing high-impact papers in all fields of aging research since 2009. These papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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Brain Aging Insights from Individuals Without Neurodegeneration

The Trending With Impact series highlights Aging publications (listed by MEDLINE/PubMed as “Aging (Albany NY)” and “Aging-US” by Web of Science) 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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A healthy brain continuously produces new proteins to support synaptic plasticity, maintain neuronal health, facilitate signaling pathways, produce neurotransmitters, enable neuroplasticity and adaptation, and meet its metabolic demands. These processes are essential for normal brain function, learning, memory, and overall cognitive abilities. Researchers believe that the dysregulation of proteins is at the core of brain aging. However, the exact recipe for protein dysregulation that leads to accelerated brain aging and neurodegenerative disorders has yet to be brought to light. 

Previous brain proteostasis (referring to the maintenance of protein homeostasis in brain cells) studies in individuals with Alzheimer’s disease (AD) pathology and age-related neuropathological changes have shown protein dysregulation leading to a buildup of amyloid plaques and neurofibrillary tangles. While these studies have greatly enhanced our knowledge of brain aging, gaps in our understanding remain. What proteomic characteristics do healthy brain aging individuals—without neurodegenerative disorders—have in common?

“To our knowledge, whole phosphoproteomes centered on the human brain aging without AD pathology are unavailable.”

In a new study, researchers Pol Andrés-Benito, Ignacio Íñigo-Marco, Marta Brullas, Margarita Carmona, José Antonio del Rio, Joaquín Fernández-Irigoyen, Enrique Santamaría, Mónica Povedano, and Isidro Ferrer from Bellvitge Institute for Biomedical Research, Universidad Pública de Navarra, Barcelona Institute for Science and Technology, and University of Barcelona aimed to shed light on the mechanisms underlying brain aging in the absence of AD pathology and age-related neuropathological changes. Their research paper was published on May 13, 2023, in Aging’s Volume 15, Issue 9, and entitled, “Proteostatic modulation in brain aging without associated Alzheimer’s disease-and age-related neuropathological changes.”

The Study

The production of new proteins is crucial for maintaining protein homeostasis in the brain. A post-translational modification used to maintain this homeostasis is protein phosphorylation. In this study, the researchers conducted proteomic and phosphoproteomic analyses of frontal cortex samples from the donor brains of deceased individuals between the ages of 30 and 85. These individuals had passed away due to non-neurological complications and were reported to have had full cognitive function. Individuals were divided into four groups: young group one (30–44), middle-aged group two (45-52), early-elderly group three (64–70), and late-elderly group four (75–85).

“​​We chose the FC [frontal cortex] because of its role in cognition and emotion and the abundant molecular information that permits comparison with other studies.”

Conventional label-free- and SWATH- (sequential window acquisition of all theoretical fragment ion spectra) mass spectrometry were used to assess the (phospho)proteomes of the frontal cortices from individuals in all four age groups. Immunohistochemistry and/or western blotting was/were also used to validate a subgroup of proteins. The researchers categorized deregulated proteins and phosphoproteins into eight clusters based on their age-dependent expression similarity (see paper for clusters). Interestingly, protein and phosphoprotein levels of the larger hierarchical clusters were stable until the age of 70 years. After 70, the late-elderly group showed significant decreased or increased expression of protein clusters one and seven, and major phosphorylation modifications occurred in clusters four and eight.

Results

The team then used multi-comparative analyses to categorize altered proteins and phosphoproteins as neuronal, astroglial, oligodendroglial, microglial, and endothelial. They observed a similar pattern among proteomic and phosphoproteomic alterations: major changes were related to neuronal cell populations across all four groups—and these changes were more pronounced with age. Cytoskeletal and membrane proteins accounted for the largest number of differentially-expressed proteins and phosphoproteins.

“Furthermore, main alterations in the proteome are associated with proteins specific to neuronal populations, rather than those found in other cell types in the brain.”

Their findings also revealed a decline in the expression of P20S α + β with aging, while the expression of P19S and immunoproteasome subunits LMP2 and LMP7 remained preserved. Notably, the expression levels of an autophagy component, ATG5, remained unchanged with age. Some mitochondrial membrane proteins showed altered levels at advanced ages, but key markers of mitochondrial function were preserved. These findings suggest a potential preservation of these pathways in advanced aging, contrasting with observations in neurodegenerative disorders. Additionally, reduced levels of GSK3α/β were observed, and the researchers point out that this decrease in GSK3α/β with age may be understood as protective against different age-related brain diseases.

Summary & Conclusion

“Therefore, our results fill the gap between brain ageing without ADNC [AD neuropathological changes], and cases with early and advanced stages of AD pathology.”

The researchers are forthcoming about limitations of this study. Given it is rare for old-aged individuals not to have neurological deficits, AD or other neuropathological changes, their main limitation was that each of the four groups included merely four individuals. Despite limitations, these findings contribute to our understanding of brain aging in the absence of AD pathology and age-related neuropathological changes. 

The study revealed that major changes in protein expression were primarily associated with neuronal cell populations and became more pronounced with age. The preservation of specific protein pathways, proteasome components, autophagy-related components, and mitochondrial markers in advanced aging individuals without neurodegenerative disorders suggests the presence of resilience mechanisms that protect against protein dysregulation and neurodegeneration. Overall, this research provides valuable insights into the proteomic characteristics of healthy brain aging and highlights potential targets for therapeutic interventions aimed at promoting healthy brain aging and preventing age-related neurodegenerative diseases. Further studies are necessary to elucidate the specific mechanisms underlying these proteomic alterations and their functional implications in brain aging.

“The present observations identify proteostatic changes, including different changes in the phosphoproteome in the human FC in brain aging in the rare subpopulation of old-aged individuals without neurological deficits, and not having ADNC and other neuropathological change in any region of the telencephalon.”

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

Aging is an open-access, peer-reviewed journal that has been publishing high-impact papers in all fields of aging research since 2009. These papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

Click here to subscribe to Aging publication updates.

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

The Brain Age Gap

The Trending With Impact series highlights Aging publications (listed by MEDLINE/PubMed as “Aging (Albany NY)” and “Aging-US” by Web of Science) 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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Aging is a risk factor for many diseases, including Alzheimer’s disease (AD). While scientists have made some progress in understanding the physiology of aging and its relationship to AD and related disorders, our understanding remains incomplete (to say the least). It is possible that civilization is currently in the midst of an artificial intelligence (AI) and machine learning (ML) “boom.” Researchers are now using AI and ML technologies to elevate our comprehension of aging and aging-related diseases.

“Artificial intelligence (AI) and machine learning (ML) technologies can help us better understand these diseases and aging itself by using biological data from the brain or other sources to create a mapping between age and biological data.”

In a new editorial paper, researchers Jeyeon Lee, Leland R. Barnard and David T. Jones from the Mayo Clinic in Rochester, Minnesota, discuss a recent study they conducted and explore the potential of AI to revolutionize the field of geriatrics. Their editorial was published in Aging’s Volume 15, Issue 8, on April 3, 2023, entitled, “Artificial intelligence and the aging mind.”

Their Study

In a recent 2022 study, Lee, Barnard, Jones, and the rest of their team developed convolutional neural network-based brain age prediction models using a large collection of data from brain magnetic resonance imaging (MRI) and brain fluorodeoxyglucose positron-emission tomography (FDG-PET) in people aged from 26 to 98 years old. In a sample of cognitively normal individuals, the AI models showed accurate brain age estimation of which a mean absolute error (MAE; unit, years) was 3.08±0.14 for the FDG-based model and 3.49±0.16 for the MRI-based model. 

The team found that higher brain age gaps (the difference between biological age and chronological age) were estimated in cohorts with neurodegenerative disorders—including mild cognitive impairment (MCI), AD, frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB)—than normal controls. The brain age gap was strongly associated with pathologic tau protein levels and cognitive test scores. This gap also showed longitudinal predictive ability for cognitive decline in AD-related disorders.

“Interestingly, the brain imaging patterns generating brain age gaps in AD showed higher similarity with normal aging than other neurodegenerative syndromes implying that AD might be more like an accelerated representation of biological aging than others.”

Summary & Conclusions

The study conducted by Lee, Barnard, Jones, and their team using neural network-based brain age prediction models has shown promising results in accurately estimating brain age and identifying differences between normal aging and neurodegenerative disorders. However, the authors of this editorial note that variations in data make creating a uniform language used to compare and contrast large sums of data very difficult.

“Although more research and optimization are needed to determine its clinical usefulness, the study of brain age has great potential as a tool for understanding brain aging and age-related diseases.”

In conclusion, aging is a complex process that increases the risk of Alzheimer’s disease and various diseases. Recent advancements in artificial intelligence and machine learning technologies offer new opportunities to better understand the underlying mechanisms of aging and aging-related disorders. This research opens up exciting possibilities for the future of geriatric care and improving the lives of aging populations. As technology continues to advance, it is likely that we will gain further insights into aging through the brain age gap, ultimately leading to better prevention, diagnosis and treatment options.

“The fact that the brain age gap is a comprehensive and intuitive measure of disease severity using biological data that is already being acquired in clinical practice, makes it an attractive biomarker for further development for clinical use [8].”

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

Aging is an open-access, peer-reviewed journal that has been publishing high-impact papers in all fields of aging research since 2009. These papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

Click here to subscribe to Aging publication updates.

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

Fruit Flies Shed New Light on Memory and Aging

In a recent study, researchers from Western University and Indiana University investigated the connection between aging, memory and lactate metabolism in flies.

Fruit Flies Shed New Light on Memory and Aging
Male common fruit fly (Drosophila Melanogaster) doing what fruit flies do best – enjoing its fruit (apple)

The Trending With Impact series highlights Aging publications (listed by MEDLINE/PubMed as “Aging (Albany NY)” and “Aging-US” by Web of Science) 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.

Listen to an audio version of this article

The brain is a complex organ responsible for many critical functions, including the formation and retrieval of our memories. As we age, the brain undergoes changes that can affect cognitive abilities, including our memory. Understanding the mechanisms that underlie these changes is critical for developing therapies for age-related cognitive decline. 

“Over the last two decades there has been growing recognition that lactate, the end product of glycolysis, serves many functions, including acting as a source of energy, a signaling molecule, and even as an epigenetic regulator.”

Lactate & LDH

Lactate is a molecule that is produced during the metabolism of glucose in the body. It is a byproduct of anaerobic metabolism, which occurs when there is insufficient oxygen supply to meet the energy demands of the body. Lactate can be used as an energy source by some cells, such as the heart and skeletal muscles, and it can also be transported to the liver where it can be converted back into glucose.

Lactate dehydrogenase (LDH), on the other hand, is an enzyme that catalyzes the conversion of pyruvate to lactate (the reverse reaction of lactate production) and is also involved in other metabolic processes. This enzyme is found in many tissues of the body, including the heart, liver and skeletal muscles, and is released into the bloodstream when tissues are damaged. LDH is often used as a diagnostic marker for various medical conditions, such as heart attacks, liver disease and certain cancers. High levels of LDH in the blood may indicate tissue damage or cell death, while low levels may indicate a deficiency in the enzyme.

The Study

Recently, researchers investigated the role of LDH in memory formation and aging using Drosophila melanogaster (fruit flies) as a model organism. In a new study, researchers Ariel K. Frame, J. Wesley Robinson, Nader H. Mahmoudzadeh, Jason M. Tennessen, Anne F. Simon, and Robert C. Cumming from Western University and Indiana University used genetic manipulation techniques to alter LDH expression in the neurons or glia of fruit flies to investigate its effects on aging and memory. Their research paper was published in Aging’s Volume 15, Issue 4, and entitled, “Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies.”

“The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory.”

Lactate shuttling is a process in which lactate is transported from one cell or tissue to another for use as an energy source or as a signaling molecule. Previous research has shown that LDH is expressed in both neurons and glia in the brain, and that it may play a role in regulating synaptic plasticity and memory formation. The authors of the current research paper aimed to test the hypothesis that alterations in LDH expression in the brain may contribute to age-related cognitive decline.

D. melanogaster serves as a good model for understanding the role of glia-neuron lactate shuttling in central nervous system (CNS) function and cognitive behaviour.”

To test this hypothesis, the researchers genetically manipulated LDH expression in the neurons or glia of fruit flies (dLDH) and assessed the impact on memory formation and aging. Specifically, they used RNA interference (RNAi) to either knock down or overexpress dLDH in either neurons or glia. They then assessed the effects of these manipulations on two different memory tasks at different ages, courtship memory and aversive olfactory memory, and also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets), and brain metabolites.

Results

Their results showed that dLDH manipulation had differential effects on fruit flies depending on the cell type in which it was altered. In neurons, both upregulation and downregulation of dLDH resulted in memory impairment and decreased survival with age. In contrast, downregulation of dLDH in glial cells caused age-related memory impairment, without altering survival. Upregulating dLDH expression in glial cells lowered survival without disrupting memory. Both neuronal and glial dLDH upregulation increased neutral lipid accumulation.

“We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation.”

The results of this study may provide new insights into the role of LDH in memory formation and aging in humans. The findings suggest that LDH may be a potential target for developing therapies to combat age-related cognitive decline. Additionally, the study highlights the importance of considering cell-type specificity when investigating the role of genes and enzymes in complex biological processes. A limitation of the study is that it was conducted in fruit flies, which may not fully capture the complexity of memory formation and aging in humans. However, fruit flies have been shown to be a valuable model organism for studying many aspects of brain function, and the findings of this study may provide a foundation for future research in mammals.

“Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.”

Conclusion

In conclusion, the study provides new insights into the role of LDH in memory formation and aging. The findings suggest that LDH may play a critical role in regulating energy metabolism in the brain, which in turn affects synaptic plasticity and memory formation. The study also highlights the importance of considering cell-type specificity when investigating the role of genes and enzymes in complex biological processes. Future research in mammals may be needed to further explore the implications of these findings for human health and the potential for developing therapies for age-related cognitive decline. Nonetheless, this study provides an important step forward in understanding the complex interplay between lactate metabolism, memory and aging.

“In this study we demonstrate the importance of maintaining appropriate levels of dLdh in D. melanogaster glia and neurons for maintenance of long-term courtship memory and survival with age (Figure 6). In addition, our results implicate lipid metabolism, 2HG accumulation, and changes in TCA cycle activity as factors underlying the age-related impacts of perturbed dLdh expression, which likely modifies glia-neuron lactate shuttling in the fly brain.”

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

Aging is an open-access, peer-reviewed journal that has been publishing high-impact papers in all fields of aging research since 2009. These papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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

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