Can microRNAs in the Bloodstream Signal Cognitive Decline?

In a cohort of pre-diagnosed, cognitively “normal” men, a recent Aging study compares expression levels of circulating miRNAs and their association with cognitive function and decline.

miRNAs, microRNAs, RNA illustration
Listen to an audio version of this article

Can factors in our bloodstream tell us about our cognitive abilities or predict cognitive decline later in life? Among individuals with dementias, including Alzheimer’s disease (AD), studies have identified extracellular microRNAs (miRNAs) as potential biomarkers of cognitive impairment. In cognitively normal individuals, however, this association has not yet been fully investigated. 

“Understanding the functions of miRNAs in the earliest stages of cognitive decline will expand our knowledge on the biology of prodromal AD and the roles of circulating miRNAs in neurodegenerative diseases and could result in identification of therapeutic targets to guide drug development [17].”

In a new research paper, published on the cover of Volume 14, Issue 17, of Aging (listed as “Aging (Albany NY)” by Medline/PubMed and “Aging-US” by Web of Science), researchers Nicole Comfort, Haotian Wu, Peter De Hoff, Aishwarya Vuppala, Pantel S. Vokonas, Avron Spiro, Marc Weisskopf, Brent A. Coull, Louise C. Laurent, Andrea A. Baccarelli, and Joel Schwartz from Columbia University Mailman School of Public Health, University of California San Diego, VA Boston Healthcare System, Boston University School of Medicine, and Harvard TH Chan School of Public Health assessed the expression levels of extracellular miRNAs circulating in blood plasma taken from 530 cognitively normal men and investigated the association between these miRNAs and cognitive function. Their secondary goal was to investigate the genes and biological pathways associated with miRNAs linked to cognitive function or decline. The research paper was published on September 6, 2022, and entitled, “Extracellular microRNA and cognitive function in a prospective cohort of older men: The Veterans Affairs Normative Aging Study.”

The NAS Cohort

The Normative Aging Study (NAS) is a large longitudinal study that was established by the United States Department of Veterans Affairs in 1963. Since this study began, researchers have been diligently following-up with a cohort of 2,280 men from Massachusetts, United States. (Most of these men served in World War II and the Korean War.) Participants in NAS have comprehensive baseline examinations every three to five years to record their aging patterns, including global cognitive function assessments using the Mini-Mental State Examination (MMSE). The average age of this veteran cohort is currently 72 years old.

The Study

In the present study, blood samples were collected from 530 NAS participants between the years 1996 and 2013—totaling 1,331 in-person visits; equal to 2,471 years of follow-up. Plasma miRNAs were profiled using small RNA sequencing (RNA-seq). Linear regression and linear mixed models were used to assess the expression of 381 miRNAs and their association with current cognitive function and rate of change in cognitive function.

Of the 381 plasma miRNAs detected in at least 70% of the samples collected, two miRNAs were associated with higher baseline MMSE scores. Thirty-three miRNAs were associated with the rate of change in MMSE over time. KEGG enrichment analysis and repeated measures analyses were used to explore potential regulatory targets of the significant plasma miRNAs. The genes targeted by the significant miRNAs were primarily associated with prion diseases, fatty acid biosynthesis, Hippo signaling, ECM-receptor interactions, and TGF-β signaling pathways. 

“Taken together, our results suggest that various plasma extracellular miRNAs are associated with global cognitive function among cognitively ‘normal’ men. If they were to play a causal role in cognitive decline, it would likely be through pathways that regulate synaptic plasticity, cell death, the response to injury, and energy homeostasis. Extracellular miRNAs may also contribute to greater rates of cognitive decline possibly through involvement in the prion-like propagation of AD lesions or in hindering their neuroprotective role of curbing AD-like pathology.”

Conclusion

These findings suggest that plasma miRNA levels are associated both with global cognition and the rate of change in global cognition among cognitively normal older men. The researchers were forthcoming about the limitations of this study, especially in regard to the study population and the MMSE scoring.  Still, this study highlights the potential of miRNAs as biomarkers for cognitive function and decline in older men and underscores the importance of elucidating the mechanisms by which extracellular miRNAs influence cognition.

“Additional research is needed to identify the biological pathways influenced by expression of these extracellular miRNAs, investigate relationships with CNS miRNA expression, and examine the potential impacts of circulating miRNAs on other neurological outcomes.”

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

AGING (AGING-US) VIDEOS: YouTube | LabTube | Aging-US.com

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

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

The 2022 “New Hallmarks of Ageing” Research Symposium

Figure 1. New hallmarks of ageing.
Figure 1. New hallmarks of ageing.

Humans battle a number of biological processes with age that lead to the gradual deterioration of cells and tissues. Frailty, disability, disease, and death are all costly fates of aging. Researchers who study aging aim to change this fate, however, the mechanisms of aging are still all but fully understood.

In 2013, López-Otín and colleagues attempted to identify these biological processes and proposed the original nine hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication. These hallmarks of aging have helped to provide a framework for thought about the causes and consequences of aging, as well as potential targets for therapeutic interventions. Now, nine years later, the hallmarks of aging have been updated in light of recent discoveries.

“In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones.”

The “New Hallmarks of Ageing” 2022 Symposium

This update was presented on March 22, 2022, at the “New Hallmarks of Ageing” research symposium in Copenhagen, Denmark. On August 29, 2022, a review paper summarizing the symposium was published in Aging (Aging-US), entitled, “New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary.” The authors of this review are researchers Tomas Schmauck-Medina, Adrian Molière, Sofie Lautrup, Jianying Zhang, Stefan Chlopicki, Helena Borland Madsen, Shuqin Cao, Casper Soendenbroe, Els Mansell, Mark Bitsch Vestergaard, Zhiquan Li, Yosef Shiloh, Patricia L. Opresko, Jean-Marc Egly, Thomas Kirkwood, Eric Verdin, Vilhelm A. Bohr, Lynne S. Cox, Tinna Stevnsner, Lene Juel Rasmussen, and Evandro F. Fang from University of Oslo, Akershus University Hospital, Jagiellonian University, University of Copenhagen, Copenhagen University Hospital Rigshospitalet, Bispebjerg and Frederiksberg, Lund University, University College London, Tel Aviv University, University of Pittsburgh, University of Strasbourg, National Taiwan University, Newcastle University, Buck Institute for Research on Aging, National Institute on Aging, University of Oxford, Aarhus University, The Norwegian Centre on Healthy Ageing (NO-Age), and UPMC Hillman Cancer Center.

Among the keynote speakers who presented at this symposium was Vilhelm A. Bohr, M.D., Ph.D., Chief of the Laboratory of Molecular Gerontology at The National Institute on Aging and a distinguished member of the Aging Editorial Board. Dr. Bohr presented new data on the DNA damage response enzyme poly ADP-ribose polymerase 1 (PARP1)-related pathways. He suggested that PARP1 might be present and functional in mitochondria. Dr. Bohr also presented on the short-term use of NAD+ supplementation in age-related hearing loss.

“Here, Professor Bohr’s group showed that the treatment of mice with NR [nicotinamide riboside] was capable of restoring NAD+ in the cochlea of aged mice to the levels found in young mice. Even more strikingly, NR treatment limited the progression of hearing loss in ageing mice while stopping the progression of hearing loss in old mice.”

The Meeting Report

The authors’ review summarized all the work presented in this symposium, consisting of some of the latest findings in the field and contextualized by the updated hallmarks of aging. Their summaries of presentations were grouped by theme, including theories of aging and cellular senescence, new insights into telomeres and cellular senescence, inflammation, NAD+ and aging, mitochondrial dysfunction, premature aging and DNA repair, and cardiovascular, cerebrovascular and muscular pathologies of aging.

“The presented data showcased novel research at the forefront of the field, with a focus on a possible increase in healthspan and the amelioration of age-related diseases. Here, both the possible clearance or delay of senescent cells as well as possible interventions in the NAD+ system were discussed. While both of these approaches are promising, they are not without limitations.”

A panel discussion took place at the end of the symposium which was moderated by Eric Verdin, M.D., President and CEO of the Buck Institute for Research on Aging and also a distinguished member of the Aging Editorial Board. In sum, the symposium hosted several established researchers and young scientists who presented and discussed the latest findings in age-related research. They discussed new aging research in concert with how it connects to the old and new hallmarks of aging.

“Amalgamation of the ‘old’ and ‘new’ hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.”

Conclusion

The goal of the “New Hallmarks of Ageing” symposium was to provide a platform for researchers to discuss the latest findings in aging research and to update the hallmarks of aging in light of new discoveries. While many promising discoveries have been made in the last decade, the authors cautioned that more work is needed to better understand aging and how these findings can be translated into therapies that improve human healthspan and quality of life. Discussions and research shared at this symposium have the potential to lead to new insights and breakthroughs in the field of aging research.

“At this point, tremendous progress has occurred, but a unified theory of ageing that can fully explain the process is still missing, and many open questions remain, both on a cellular and organismal level. Whether it is possible to target the ageing process at its core, or whether a combination of approaches is needed to target the aspects encompassing ageing, remains to be solved in the future.”

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

AGING (AGING-US) VIDEOS: YouTube | LabTube | Aging-US.com

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

For media inquiries, please contact media@impactjournals.com

Stroke Outcomes Mediated by These 2 Mechanisms

In a trending new research paper published in Aging, researchers investigated the effects of microglial activity on post-stroke inflammation and outcomes.

Stroke Outcomes Mediated by These 2 Mechanisms

The Trending With Impact series highlights Aging publications (listed as “Aging (Albany NY)” by Medline/PubMed 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

When the blood supply in and around the brain becomes interrupted, a stroke can occur. A hemorrhagic stroke is when a blood vessel bursts in or near the brain. An ischemic stroke is caused when a blood vessel carrying oxygen and nutrients to the brain is obstructed—usually by a clot. The most common type of stroke is ischemic, which accounts for approximately 87% of all strokes in humans. A major risk factor for an ischemic stroke is aging.

Inflammation (a chronic condition among the elderly) is a key contributing factor to strokes, and microglia are the primary immune cells in the brain. Researchers recently identified a role for the microglial IRF5-IRF4 regulatory axis in mediating responses after stroke. However, whether or not aged microglia also undergo the same regulatory mechanisms after a stroke had previously not been determined.

“Microglial activation plays a central role in initiating and perpetuating the post-stroke inflammation, and acts as a ‘double-edged’ sword to confer both detrimental and beneficial effects [9].”

In a recent study, researchers Conelius Ngwa, Abdullah Al Mamun, Shaohua Qi, Romana Sharmeen, Yan Xu, and Fudong Liu from The University of Texas Health Science Center at Houston investigated aged mice and the role of the microglial IRF5-IRF4 regulatory axis after a stroke. On August 12, 2022, their research paper was published in Aging’s Volume 14, Issue 15, and entitled, “Regulation of microglial activation in stroke in aged mice: a translational study.

The Study

“We have previously found IRF4 signaling is anti-inflammatory and IRF5 is pro-inflammatory in young ischemic microglia [11]. In the present study, we hypothesized IRF4 CKO [conditional knockout] worsens while IRF5 CKO improves stroke outcomes.” 

To better understand how microglia responds to stroke in aged individuals, the researchers first investigated microglial IRF5 and IRF4 expression in young and aged mice. A well-established mouse model of ischemic stroke was used in this study. Next, the researchers performed conditional knockout (CKO) of IRF5 or IRF4 in young and aged mice. The study arm mice underwent a 60-minute middle cerebral artery occlusion (MCAO). Stroke outcomes were quantified three days after MCAO.

To evaluate microglial activation and immune responses (surface and intracellular inflammatory markers) post-stroke, the researchers performed flow cytometry and enzyme-linked immunosorbent assay (ELISA). IRF5 CKO aged microglia had significantly lower levels of IL-1β and CD68 compared to controls. IRF4 CKO had significantly higher levels of IL-1β and TNF-α compared to control microglia. Levels of anti-inflammatory cytokines IL-4 and IL-10 were higher in IRF5 CKO, and lower in IRF4 CKO aged mice. 

“Plasma levels of TNF-α and MIP-1α were decreased in IRF5 CKO vs. flox aged mice, and IL-1β/IL-6 levels were increased in IRF4 CKO vs. controls.”

Results & Conclusion

Since IRF5 signaling drives microglial pro-inflammatory responses, the researchers hypothesized that microglial IRF5 is detrimental for aged mice in stroke. They also suggested that IRF4 signaling drives anti-inflammatory responses and its expression is protective in aged mice in stroke. Indeed, IRF5 CKO aged mice demonstrated improved stroke outcomes; whereas worse outcomes were seen in IRF4 CKO mice compared to their control counterparts. Furthermore, the results of this study demonstrated that aged microglia express higher levels of IRF5 and lower levels of IRF4 compared to young microglia after stroke.

This study provides valuable insights into how microglial activation is regulated post-stroke, and highlights the importance of the IRF5-IRF4 axis in stroke outcomes. The researchers conclude that the IRF5-IRF4 axis is a promising target for developing novel strategies to treat ischemic stroke. Further research is warranted to determine how these findings can be translated into clinical practice to improve stroke outcomes in the elderly.

“By using the aged IRF4/IRF5 microglial CKO mouse models, the study aimed to selectively suppress microglial pro-inflammatory activation and promote its anti-inflammatory response, and will potentially help develop new, effective therapeutic strategies against stroke.”

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

AGING (AGING-US) VIDEOS: YouTube | LabTube | Aging-US.com

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

For media inquiries, please contact media@impactjournals.com

3 Domains of Well-Being Extend Elderly Mobility and Longevity

In Aging’s Volume 14, Issue 15, cover paper, researchers hypothesized that multidimensional well-being may prolong mobility-limitation-free survival and longevity among older adults.

3 Domains of Well-Being Extend Elderly Mobility and Longevity
Listen to an audio version of this article

The Trending With Impact series highlights Aging publications (listed as “Aging (Albany NY)” by Medline/PubMed 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.

The word “well-being” is commonly used in workplace environments, therapy sessions, doctor’s offices, books, online, and elsewhere. However, the definition of this word seems to differ across varying contexts, cultures, traditions, values, and even biological sexes. Below are four definitions of well-being:

  • “noun: [Well-being is] the state of being comfortable, healthy, or happy.” — Oxford English Dictionary
  • “In simple terms, well-being can be described as judging life positively and feeling good.” — Centers for Disease Control and Prevention
  • “The meaning of WELL-BEING is the state of being happy, healthy, or prosperous : welfare.” — Merriam-Webster Dictionary
  • “Well-being, or wellbeing, also known as wellness, prudential value or quality of life, refers to what is intrinsically valuable relative to someone. So the well-being of a person is what is ultimately good for this person, what is in the self-interest of this person.” — Wikipedia

Based on these definitions, one could argue the root meaning of well-being may be distilled down to individual happiness and prosperity that contributes to healthy aging. However, this prosperity and happiness is not anchored to only one domain of well-being. There are three domains of being well, which include behavioralsocial and psychological well-being.

Aging & Well-Being

“Successful aging is a multidimensional construct covering behavioral, social, and psychological domains of well-being, all amenable to individual actions and public health interventions [14].”

Successful, or healthy, aging may be the result of adherence to several protective factors simultaneously within all three of the well-being domains. Previously, the majority of research on healthy aging has been limited to a single domain per study. In a new study, researchers Marguerita Saadeh, Xiaonan Hu, Serhiy Dekhtyar, Anna-Karin Welmer, Davide L. Vetrano, Weili Xu, Laura Fratiglioni, and Amaia Calderón-Larrañaga (from Karolinska InstitutetKarolinska University HospitalStockholm UniversityLund University, and Stockholm Gerontology Research Center) believe that the vast heterogeneity in aging phenotypes cannot be explained by one domain of well-being alone. On July 18, 2022, their research paper was published on the cover of Aging’s Volume 14, Issue 15, and entitled, “Profiles of behavioral, social and psychological well-being in old age and their association with mobility-limitation-free survival.”

“Despite the rising evidence supporting a multidimensional construct of successful aging, most longitudinal studies still fail to cover well-being indicators belonging to different domains, as shown by the disproportionate amount of literature focusing exclusively on lifestyle factors [4548].”

Three Domains of Well-Being: 10 Indicators

In their current study, the researchers selected 10 indicators of behavioral, social and psychological well-being: 1) Behavioral: Mediterranean diet, smoking, physical leisure activities, and mental leisure activities; 2) Social: Social leisure activities (i.e., social participation), social connections and social support; 3) Psychological: life satisfaction, negative affect and positive affect.

Blue zones” are areas around the world with high concentrations of centenarians, or people who live to be over 100 years old. A prevalent diet among people living in blue zones is the Mediterranean diet. The Mediterranean diet consists of fruits, vegetables, whole grains, beans, nuts/seeds, lean poultry, fish, seafood, dairy, eggs, and extra virgin olive oil. This diet has been closely studied as a protective factor of healthy aging.

The psychological well-being indicator listed as “negative affect” refers to the degree to which a person feels guilt, anger and fear, and the following features are considered: distressed, upset, scared, nervous, and afraid. “Positive affect” considers the extent to which a person is active, inspired, determined, alert, and enthusiastic. For additional explanations, the remaining indicators of well-being used in this study are expounded in thorough detail within the research paper itself.

Aging & Mobility

“Mobility decline precedes disability and premature death, and is therefore considered an optimal early indicator of physical function decay among older adults [34].”

The simple ability to exercise, complete day-to-day chores and maintain personal hygiene all rely on a minimum range of physical mobility. A sedentary lifestyle is a well-recognized risk factor for chronic diseases, such as obesity, type 2 diabetes, cardiovascular disease, and some forms of cancer. Furthermore, mobility limitations are associated with social isolation, depression and cognitive decline. The researchers in this study aimed to identify well-being profiles and their association with mobility-limitation-free survival.

“The specific aims of this study were: 1) to identify distinct well-being profiles among men and women separately, by using latent class analysis; 2) to determine which of these profiles are associated with the greatest benefit in terms of mobility-limitation-free survival; and 3) to quantify these potential benefits in absolute terms by calculating differences in median age at onset of mobility limitation or death across profiles.”

The Study

The study population consisted of 1488 functionally healthy individuals (after all exclusion criteria were applied to the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) population-based study). In addition to collecting self-reported data on the 10 indicators of behavioral, social and psychological well-being listed above, the researchers included data on the participants’ covariates. Covariates included age, education, number of chronic diseases, mini-Mental State Examination score (MMSE), and NEO Five-Factor Inventory (NEO-FFI) questionnaire. At the beginning of the study (baseline), the average age in the cohort was 69 years old (with a standard deviation of +/- 8.3 years). Ninety-one percent of participants had at least a high-school-level of education. Females (59%) composed the majority of the cohort.

“In this study, we used latent class analysis to detect data-driven subgroups of people with similar well-being profiles according to behavioral (diet, smoking, and physical and mental leisure activities), social (social participation, connections, and support) and psychological (life satisfaction, positive and negative affect) well-being indicators, as defined by the Centers for Disease Control and Prevention (CDC) [25].”

Since men and women tend to behave differently when it comes to multiple factors of well-being, the researchers stratified their analyses by sex. They scheduled regular followed-ups with these participants over the course of 15 years. Well-being profiles were derived from the 10 well-being indicators using latent class analysis. Endpoints were defined as mobility-limitation-free survival, limited mobility or death. Limited mobility was defined as having a walking speed below 0.8 meters per second.

“A composite endpoint, considered to be an indicator of mobility-limitation-free survival, was operationalized by taking into account the time from study entry until the development of mobility limitation (i.e., walking speed <0.8m/s) or death, whichever occurred first.”

Results

At baseline, the researchers identified three well-being profiles among both men and women that followed a clear gradient in all behavioral, social and psychological indicators throughout the study. Participants categorized in the best well-being profile had high adherence to the Mediterranean diet, the lowest proportion of current smokers, high engagement with leisure activities, and the highest levels of social and psychological well-being. Those in the intermediate well-being profile had low/moderate adherence to the Mediterranean diet, a higher proportion of former/never smokers, and moderate levels of social and psychological well-being. (Men in the  intermediate well-being profile had a low/moderate engagement in leisure activities, while women had moderate/high engagement levels.) Participants in the worst well-being profile had low adherence to the Mediterranean diet, a higher proportion of former/never smokers, the lowest levels of leisure activity engagement, and the lowest levels of social and psychological well-being.

To examine the association between these well-being profiles and the incidence of mobility limitation or death, the researchers used Cox and Laplace regression models and applied sensitivity analyses to the data.

“In agreement with the Cox regressions, results from Laplace regressions showed that men in the intermediate and best profiles survived 1 and 3 years longer without mobility limitations, respectively, compared to those in the worst profile after adjustment for potential confounders (Figure 2). Women in the intermediate and best profiles lived 2 and 3 years longer without mobility limitations, respectively, compared to those in the worst profile.”

Conclusion

The well-being profiles of older adults are associated with their risk of developing mobility limitations and death. Those in the best well-being profile had the lowest risk, while those in the worst well-being profile had the highest risk. These findings suggest that interventions to improve multi-domain well-being in older adults may improve longevity and help reduce the incidence of mobility limitations in old age. Although this study has many strengths, the researchers were forthcoming about its limitations. Future studies are recommended to confirm these findings.

“While theoretical insights into different models of successful aging are on the rise, empirical evidence from population-based longitudinal data on the complex interplay among the distinct well-being domains and their association with person-centered outcomes, such as mobility-limitation-free survival, is currently lacking. This study addresses such an important gap and provides further evidence to better understand and promote functional independence in community-dwelling older adults through primary prevention multi-domain interventions.”

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

AGING (AGING-US) VIDEOS: YouTube | LabTube | Aging-US.com

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

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

Osteoporosis Linked to Age-Related Changes in Circadian Rhythm

Researchers published a new editorial paper on restoring the circadian rhythm to minimize the risk of aging-related osteoporotic fractures.

The Trending With Impact series highlights Aging publications (listed as “Aging (Albany NY)” by Medline/PubMed 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 circadian rhythm is a daily cycle (24 hours) of biological activity that is driven by an internal biological clock. A regular circadian rhythm is important for maintaining numerous facets of human life. Aging-related changes to this delicate rhythm have demonstrated negative consequences in many aspects of health, including bone health.

“Among the many risk factors for osteoporosis, a new kid on the block is disruption of the biological clock.”

On July 19, 2022, an editorial paper was published in Aging‘s Volume 14, Issue 14, entitled, “Restoring rhythm to prevent age-related fractures.” In this editorial, Annelies E. Smit, Maaike Schilperoort and Elizabeth M. Winter from Leiden University Medical Center discuss the treatment of osteoporosis by way of restoring circadian rhythm. The researchers review the use of both medical and lifestyle interventions that aim to restore circadian rhythm to minimize the risk of aging-related osteoporotic fractures.

Osteoporosis & Cortisol

Osteoporosis is a condition characterized by decreased bone mass and an increased risk of bone fracture. Age-related osteoporosis is a major public health concern, particularly in postmenopausal women. Cortisol, a stress hormone and the most important endogenous glucocorticoid (GC), plays a key role in the regulation of circadian rhythm. Circulating cortisol levels are naturally highest in the morning and gradually decline throughout the day. (This high peak in cortisol is responsible for initiating the waking cycle each morning.)

“Rhythm in circulating cortisol levels is regulated by the ‘master clock’, the suprachiasmatic nucleus (SCN) in the hypothalamus.”

Unfortunately, as humans age, SCN rhythmicity frequently becomes decoupled from environmental rhythms. Changes in circadian rhythm can result from aging-related lifestyle changes, such as changes in light exposure (which can occur from decreasing visual capabilities), the sleep-wake cycle, eating habits, and exercise patterns. Over time, cortisol begins to peak earlier in the morning, and average circulating cortisol levels increase. The researchers argue that circadian rhythm-related changes in cortisol secretion result in a loss of bone mass and age-related osteoporosis.

“Since both SCN [5] and cortisol [6] rhythm amplitude decline with age, and because we demonstrated in a preclinical model that flat endogenous GC levels result in osteoporosis, we argue that flattened circadian rhythmicity in the elderly population is causally related to the high incidence of osteoporosis at older age [4].”

Restoring Circadian Rhythm

Glucocorticoid (GC) therapy is a common treatment for osteoporosis. Unfortunately, administering glucocorticoids at an improper time can disrupt the natural circadian rhythm of cortisol secretion, leading to an increased risk of osteoporotic fractures. The researchers suggest that restoring the circadian rhythm is critical for restoring healthy patterns of cortisol secretion, especially in patients receiving glucocorticoid therapy.

“In elderly, physical inactivity and irregular eating patterns are common, and both have been demonstrated to dysregulate bone rhythm [8].”

In addition to lifestyle changes, such as timed exercise and timed feeding, the researchers note that chronotherapy may contribute to reinforcing circadian rhythmicity. Chronotherapy is a promising new field of circadian medicine that aims to optimize the timing of drug administration to match the natural circadian rhythm. The researchers suggest glucocorticoids, and any other bone formation-promoting therapeutic, should be administered in the morning (to mimic the behavior of a healthy circadian rhythm). Chronotherapy can also incorporate lifestyle interventions, such as changes in sleeping patterns, sleep hygiene and light exposure therapy.

“Thus, restoring normal sleep/wake cycles by psychological and behavioural measures, such as strict bedtime routines, may strengthen SCN rhythm.”

Conclusion

Circadian rhythms are important for bone health and preventing age-related osteoporosis. Glucocorticoid therapy can disrupt circadian rhythms, but this disruption can be minimized by administering glucocorticoids in the morning. In addition, lifestyle changes and chronotherapy can help reinforce circadian rhythms.

“In conclusion, the multifaceted origin of age-related fractures asks for a full toolbox of intervention strategies, to which restoring circadian rhythm may provide a valuable addition. Lifestyle and medical interventions may improve sleep quality and decrease risk for osteoporotic fractures (Figure 1). Furthermore, respecting circadian timing through chronotherapy could optimize current and new therapeutic outcomes.”

Figure 1. Bone health depends on diurnal variation in bone turnover, which is regulated by the circadian timing system
Figure 1. Bone health depends on diurnal variation in bone turnover, which is regulated by the circadian timing system

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

AGING (AGING-US) VIDEOS: YouTube | LabTube | Aging-US.com

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

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

Trending With Impact: Humanin G Treatment in AMD Reduces Inflammation

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

Trending With Impact: Humanin G Treatment in AMD Reduces Inflammation

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

Listen to an audio version of this article

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

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

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

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

The Study

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

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

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

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

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

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

Conclusion

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

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

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

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

AGING (AGING-US) VIDEOS: YouTube | LabTube | Aging-US.com

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

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

Trending With Impact: Neuromodulation in Alzheimer’s Disease Treatment

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

Neuromodulation in Alzheimer’s Disease Treatment

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.

Listen to an audio version of this article

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

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

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

Neuromodulation

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

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

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

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

Conclusion

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

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

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

AGING (AGING-US) VIDEOS: YouTube | LabTube | Aging-US.com

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

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

Aging-US: Hallmarks of Cancer and Hallmarks of Aging

“Hyperfunctional signaling directly drives age-related diseases.”

— Mikhail Blagosklonny, M.D., Ph.D.

Listen to an audio version of this press release

BUFFALO, NY- May 18, 2022 – Dr. Mikhail Blagosklonny published his new review paper in Aging (Aging-US) Volume 14, Issue 9, entitled, “Hallmarks of cancer and hallmarks of aging.”

In this review, Dr. Blagosklonny expands on Gems and de Magalhães’ notion that canonic hallmarks of aging are superficial imitations of the hallmarks of cancer. He takes their work a step further and proposes the hallmarks of cancer and aging based on a hierarchical principle and the hyperfunction theory.

“Here I present the hallmarks of cancer, depicted as a circle by Hanahan and Weinberg [1], not as the circle but hierarchically, from molecular levels to the organism (Figure 1).”

Figure 1. Hierarchical representation (from molecular to organismal levels) of the original hallmarks of cancer based on Hanahan and Weinberg. See text for explanation.

Next, Dr. Blagosklonny depicts the hallmarks of aging suggested by López-Otín et al. based on the hierarchical principle. 

“This representation renders hallmarks tangible but reveals three shortcomings (Figure 2).”

Figure 2. Hierarchical representation of the hallmarks of aging based on López-Otín et al. See text for explanation.

The first shortcoming that Dr. Blagosklonny notes is the lack of hallmarks on the organismal level. The second is that the relationship between hallmarks on different levels is unclear. The third is that the inclusion of genetic instability as a hallmark is based on the theory that aging is caused by the accumulation of molecular damage. 

“The molecular damage theory was refuted by key experiments, as discussed in detail [44–51].” 

Dr. Blagosklonny then uses the hyperfunction theory to arrange the hierarchical hallmarks of aging.

“Let us depict hallmarks of aging, according to the hyperfunction theory of aging (Figure 3).”

Figure 3. Hierarchical hallmarks of aging based on hyperfunction theory, applicable to humans. Non-life-limiting hallmarks are shown in brown color. See text for explanation.

Dr. Blagosklonny continues by discussing the key to understanding aging and aging as a selective force for cancer. He concludes this review by discussing the common hallmarks of cancer, aging and cell senescence.

“In organismal aging, cancer and cellular senescence, the same key signaling pathways, such as mTOR, are involved. This is why the same drugs, such as rapamycin, can suppress all of them.”

DOI: https://doi.org/10.18632/aging.204082 

Correspondence to: Mikhail V. Blagosklonny 

Email: Blagosklonny@oncotarget.comBlagosklonny@rapalogs.com 

Keywords: oncology, carcinogenesis, geroscience, mTOR, rapamycin, hyperfunction theory

Follow Dr. Blagosklonny on Twitter: https://twitter.com/Blagosklonny

AGING (AGING-US) VIDEOS: YouTube | LabTube | Aging-US.com

About Aging-US:

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Follow Aging on social media: 

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

Aging (Aging-US) Journal Office

6666 E. Quaker Str., Suite 1B

Orchard Park, NY 14127

Phone: 1-800-922-0957, option 1

###

Dr. Blagosklonny’s Rapamycin-Based Recommendation for Altos Labs

Listen to an audio version of this article

After the January 2022 launch of Altos Labs, a new anti-aging biotechnology company, Mikhail (Misha) Blagosklonny, M.D., Ph.D., joined this exciting public conversation with a recommendation. Dr. Blagosklonny is a prominent scientist in the fields of cancer and aging research. He is well-known for his experimental research articles and theoretical papers on the hyperfunction theory of aging and the pursuit of longevity with rapamycin. On April 22, 2022, his latest research perspective was published in Oncoscience, and entitled, “Altos Labs and the quest for immortality: but can we live longer right now?” 

“Here I discuss how combining rapamycin with other modalities may let us live long enough to benefit from future discoveries in cellular reprogramming and what needs to be done at Altos Labs to make this happen.” (Source: Blagosklonny, 2022)

Altos Labs

Funded by multiple billionaire investors, including Jeff Bezos and Yuri Milner, Altos Labs has announced that their primary focus is on reprogramming cells in the pursuit of reversing the trajectory of many diseases, and thus, reversing aging.

“Altos Labs is a new biotechnology company focused on cellular rejuvenation programming to restore cell health and resilience, with the goal of reversing disease to transform medicine.” (Source: AltosLabs.com)

Altos Labs researchers are aiming to turn back the human aging process by resetting epigenetic clocks within our cells. Cellular rejuvenation programming is a process by which the aging of cells may be reversed, potentially leading to the prevention or reversal of age-related diseases, such as cancer. In animal studies, cellular rejuvenation programming has been shown to lead to improved healthspan and increased lifespan. Researchers at Altos Labs intend to investigate its effects in humans with further research. The process will potentially involve the use of the Yamanaka factors, specialized proteins known as sirtuins and artificial intelligence or machine learning. Implications of successfully developing this technology would be vast, and it could one day lead to a significant extension of the human lifespan.

Dr. Blagosklonny’s Recommendation

Following the public unveiling of this new and highly-funded quest to reverse aging through cellular reprogramming, Dr. Blagosklonny openly chimed in with a perceptive recommendation in his latest research perspective. Given that potential revelations learned from studies at Altos Labs may take years to be brought safely to public markets, Dr. Blagosklonny suggests that research at Altos Labs should also include a deep investigation into rapamycin, a clinically approved mTOR inhibitor. Rapamycin is a promising anti-aging agent that was first clinically approved as an immunosuppressive drug to prevent organ rejection after a kidney transplant. 

“Rapamycin treatment is rapidly becoming a mainstream anti-aging intervention.” (Source: Blagosklonny, 2022)

Dr. Blagosklonny writes that potential life-extension with rapamycin may allow us to slow aging while we await future discoveries that may reverse aging altogether. However, he also writes that treatment with rapamycin alone is unlikely to extend lifespan sufficiently enough to benefit from Altos Labs’ future discoveries within our lifetime. Dr. Blagosklonny urges that discovering efficacious combinations of rapamycin with other therapeutic agents may enable humans today to live long enough to benefit from Altos Labs’ future discoveries in cellular reprogramming.

“If Altos Labs would allocate a small percentage of its funding to develop rapamycin based drug combinations, then additional decades of life extension may be available 3–5 years from now.”

“The number of potential combinations with rapamycin is enormous.” (Source: Blagosklonny, 2022)

Click here to read Dr. Blagosklonny’s full research perspective, published in Oncoscience.

Press release: Altos Labs and the Quest for Immortality: Dr. Blagosklonny’s Perspective.

AGING (AGING-US) VIDEOS: YouTube | LabTube | Aging-US.com

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

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

Trending With Impact: Tobacco PEBP Increases Lifespan in Fruit Flies

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

Fruit flies

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.

Listen to an audio version of this article

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

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

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

The Study

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

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

Conclusion

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

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

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

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

AGING (AGING-US) VIDEOS: YouTube | LabTube | Aging-US.com

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

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

  • Follow Us