In a trending new research paper published in Aging, researchers investigated the effects of microglial activity on post-stroke inflammation and outcomes.
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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].”
“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 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.
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.
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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.
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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
“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 behavioral, social 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 [1–4].”
“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 [45–48].”
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 socialsupport; 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.
Agingis 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.
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.
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The circadian rhythm is a daily cycle (24 hours) of biological activity that is driven by an internal biologicalclock. 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‘sVolume 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
Click here to read the full editorial paper published by Aging.
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.
In the cover paperpublished inAging-US Volume 14, Issue 10, researchers investigated a potential therapeutic intervention to reduce chronic inflammation in age-related macular degeneration (AMD).
The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.
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One of the leading causes of vision loss among aging populations in the United States, and worldwide, is age-related macular degeneration (AMD). The progression of this disease is known to be driven by inflammatory processes. However, the exact inflammation-associated proteins and the mechanisms that drive them have not yet been fully elucidated.
“Inflammation plays a crucial role in the etiology and pathogenesis of AMD (Age-related Macular Degeneration).”
“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) 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.
Dr. Fabrizio Vecchio wrote about the potential synergistic effects of neuromodulation combined with cognitive training to treat Alzheimer’s disease.
The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.
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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.
“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) 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.
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).”
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).”
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).”
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.”
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.
“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.
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.
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.
The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.
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The 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.
“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) 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.
Published on the cover of Aging’s Volume 14, Issue 7, researchers conducted a new study investigating the role of IGFBP5 in replicative senescence.
The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.
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In 1961, Leonard Hayflick and Paul Moorhead proposed a theory later named the Hayflick Limit. They discovered that a normal human cell can divide between 50 and 70 times before it can no longer proliferate and eventually dies. Researchers have since continued to explore this phenomenon and, today, this aging process is known as cellular (replicative) senescence.
“There are currently several experimental models of cellular senescence. Hayflick and Moorhead observed that primary human fibroblasts in culture exhibit a limited proliferative capacity [6]. This growth arrest during passages is called replicative senescence.”
This permanent cessation of the cell cycle is universally found in biology due to known and unknown causes, including the shortening of telomeres. While telomere shortening plays an important role, it is not the only event responsible for inducing cellular senescence. Thus, researchers have spent decades under the microscope experimenting with cellular models of replicative senescence.
Cellular senescence is typically characterized by cell growth arrest, an increase of cells positive for SA-β -gal staining, and upregulation of p16 and p19. To begin this study, the team cultured embryonic mouse fibroblasts (MEFs) and conducted cell passages according to the 3T3 method. They found that the MEFs underwent senescence after the 5th passage (P5). The team also found that at P8, the expression of insulin-like growth factor binding protein 5 (IGFBP5) mRNA was significantly reduced when compared with that of P2 MEFs.
Next, the team performed a knockdown of IGFBP5 in the MEF cells. Results showed that IGFBP5 knockdown induced premature cellular senescence in P2 MEFs. Knockdown of IGFBP5 increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) but did not affect expression levels of Akt or p16 repressors. The researchers also found that supplementing the cell culture growth medium with additional exogenous IGFBP5 delayed growth arrest and reduced replicative senescence in the MEF cells.
“To examine whether activated ERK1 and ERK2 by IGFBP5 knockdown are involved in the induction of senescent phenotypes, we examined effects of knockdown of ERK1 and ERK2 using a combination with IGFBP5 siRNA in P2 MEFs.”
Upon further analysis of ERK1/2’s role in IGFBP5-knockdown cells, the team found that the silencing of ERK2, and not ERK1, blocked the increase in the number of SA-β-GAL-positive cells. ERK2 knockdown attenuated the reduction in the cell number and upregulation of p16 and p21 in IGFBP5-knockdown cells. This study provides evidence that downregulation of IGFBP5 contributes to replicative senescence via ERK2 activation in mouse embryonic fibroblasts.
Conclusion
For the first time, the role of IGFBP5 in replicative senescence was demonstrated in MEFs. Their findings suggest that ERK2 underlies cellular senescence induced by IGFBP5 downregulation. Cellular senescence appears to be a complex process with many moving parts. While more research is needed to fully understand the role of IGFBP5 in replicative senescence, this study provides new insights into the underlying mechanisms involved in this complex process.
“In conclusion, the results of the present study demonstrated that downregulation of IGFBP5 during serial passage contributes to replicative senescence via an ERK2-dependent mechanism (Figure 6). The results suggest that IGFBP5 counteracts replicative senescence in MEFs.”
Figure 6. Schematic summary of our findings. MEFs at early passage secrete certain levels of IGFBP5. Secreted IGFBP5 proteins inhibit MEK/ERK2 by attenuating their phosphorylation (P) in the neighboring cell, leading to suppression of cellular senescence. IGFBP5 secretion is decreased during serial passage, causing activation of ERK2 and cellular senescence.
Click here to read the full research paper published by Aging (Aging-US).
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.
Researchers investigated the effects of injecting platelet-rich plasma in women with a poor ovarian response to in vitro fertilization (IVF).
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In a day and age when women and men are beginning families later in the life cycle, women of advanced age (or with some health conditions) often have trouble becoming pregnant. Today, in vitro fertilization (IVF) is a widely-used form of assisted reproductive technology. This manual process of fertilization is achieved first by combining an egg and a sperm outside of the uterus and then helping the fertilized egg become implanted in the uterus.
The world’s first IVF baby was born in Lancashire, England, in 1978. Since then, this technique has solved reproductive issues for millions of women and men around the world. While this procedure has helped build many families, there is a subset of reproductively challenged women who exhibit resistance to IVF. Researchers have observed accelerated ovarian aging in women who demonstrate a poor ovarian response (POR) to IVF.
“These women are labeled ‘poor ovarian response’ (POR) or ‘poor responders’ due to a combination of low parameters of ovarian reserve and previous low oocyte yield after ovarian stimulation.”
This prospective observational study took place in Acibadem Maslak Hospital in Istanbul, Turkey, in 2020. The study’s inclusion criteria admitted women who were diagnosed with POR, between 30 and 45 years old, had at least a one-year history of infertility, and had at least one ovary. After the exclusion criteria were accounted for, 510 women with POR were included in the study. Patients were divided into three groups for subgroup assessment: patients younger than 38 years old, patients between 38 and 42 years old and patients between 42 and 45 years old.
Before IVF, autologous PRP was administered to participants through intra-ovarian injections. (Learn more about PRP and IVF materials and methods in the study.) The team then assessed the effects of PRP on ovarian reserve parameters and IVF outcomes. Ovarian reserve parameters included antral follicle count (AFC), ovarian volume, serum anti-Müllerian hormone (AMH) level, and serum follicle-stimulating hormone (FSH) level. IVF outcomes were defined by the number of oocytes retrieved (an oocyte is an immature ovum, or egg cell) and the number and quality of embryos that developed, including embryos in cleavage and blastocyst stages.
The Results
Compared to baseline measures before treatment, PRP injections resulted in higher AFC, higher serum AMH, lower serum FSH, and a higher number of mature oocytes and cleavage/blastocyst stage embryos. In this cohort of women with POR, the PRP intervention yielded a total pregnancy rate of 20.5% and a sustained implantation/livebirth rate of 12.9%.
“After PRP injection, 22 women (4.3%) conceived spontaneously, 14 (2.7%) were lost to follow up, and 474 (92.9%) attempted IVF. Among women who attempted IVF, 312 (65.8%) generated embryos and underwent embryo transfer, 83 (17.5%) achieved a pregnancy, and 54 (11.4%) achieved sustained implantation/live birth (SI/LB).”
The researchers found that the greatest increase in IVF outcomes was seen in women 38 years old or younger. They also performed a receiver operating characteristic curve analysis and found that the cut-off for patients who would not benefit from PRP was 40 years old. The authors explained that this was due to a lack of ovarian response.
Conclusion
The researchers suggest that PRP may be considered for IVF cycles in women with POR, especially for those younger than 38 years old. However, the authors also caution that PRP should not be recommended as part of routine treatments until further prospective randomized trials test for clinical efficacy in wider clinical applications. Intra-ovarian injection of autologous PRP may someday be the standard of care for women with POR seeking IVF.
“In conclusion, intraovarian injection of autologous PRP might be considered in women with POR. The ideal population that may benefit from this approach can be summarized as patients <40 years old, with an FSH < 21.2 mIU/mL, AMH > 0.23 ng/ml, with at least one antral follicle, and a mean ovarian volume > 4.30 cm3.”
Click hereto read the full research paper published by Aging (Aging-US).
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.
