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Behind the Study: Cdkn1a Transcript and Aging

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Dr. Judith Campisi discusses her priority research paper published in 2021 by Aging, entitled, “Cdkn1a transcript variant 2 is a marker of aging and cellular senescence.”

Researchers explain their studies that were published in Aging

Behind the Study is a series of transcribed videos from researchers elaborating on their recent oncology-focused studies published by Aging. A new Behind the Study is released each Monday. Visit the Aging YouTube channel for more insights from outstanding authors.

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Hello, my name is Judy Campisi. I am a Professor at the Buck Institute for Research on Aging and also a Senior Scientist at the Lawrence Berkeley National Lab. And my laboratory, which is a pretty international laboratory with people from Asia and Europe, published a paper in aging, “Cdkn1a transcript variant 2 is a marker of aging and cellular senescence.”

So why do we care about this?

Well, most of my lab works on a process called cellular senescence, which is a cellular response to stresses and damage, many of which increase with age. And it’s now clear from mouse models that if you eliminate senescent cells, which increase with age, you can increase the health span of a mouse – not necessarily the lifespan, but the health span. So it becomes kind of important to have ways of identifying senescent cells in detail, and we have not been able to do that so far with absolute certainty because there frankly are no senescent-specific markers. So there are markers that are commonly expressed by senescent cells, but none of them are absolutely specific.

Figure 1. The Cdkn1a variant 2 transcript is preferentially induced during aging.
Figure 1. The Cdkn1a variant 2 transcript is preferentially induced during aging.

And so what we have done is we have looked at one of those markers, which is a gene called Cdkn1a and it codes for approaching, called P21. So everyone knows that P21 is one of those common biomarkers of aging, but it also is not necessarily strictly limited to aging. And what we’ve found is that there are two mRNAs that are made from that gene, that had been known before. We looked at these two mRNAs separately and found that one of them, which is called the variant 2, is a better marker of senescence and aging than the other mRNA. And that gives us a little bit of a edge in trying to unambiguously identify senescent cells in vivo and even in culture.

So the importance of this work is that it helps refine our ways of identifying these cells. We now know that these cells are important in aging, certainly in mice, probably in humans as well. So with this group of mine, many of which come from Spain or France or Russia, many of them contributed to refining this marker and allowing us to be able to have a better way of having some confidence that a senescent cell is indeed senescence.

And I can stop here.

Click here to read the full study published by Aging.

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Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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Trending With Impact: Epigenetic Shifts, Aging, and Disease

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

Figure 1. Cross-tissue accessibility.
Figure 1. Cross-tissue accessibility.

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

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

“Shifting epigenetic contexts influence regulatory variation and disease risk”

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

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

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

FETAL TO ADULT EPIGENETIC SHIFTS

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

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

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

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

CONCLUSION

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

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

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

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

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

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Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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Behind the Study: COVID-19 and Chronological Aging

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Dr. Michael P. Lisanti from The University of Salford describes his 2020 paper published by Aging, entitled, “COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection?“

Researchers explain their studies that were published in Aging

Behind the Study is a series of transcribed videos from researchers elaborating on their recent oncology-focused studies published by Aging. A new Behind the Study is released each Monday. Visit the Aging YouTube channel for more insights from outstanding authors.

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Hi, I’m professor Michael Lisanti and I’m the Chair of Translational Medicine at the University of Salford, and today I want to talk about our new prospective article, which links COVID-19 and chronological aging, and is focused on potential treatments and prevention strategies. I got interested in this topic because there seems to be an association between COVID-19 fatalities and aging, especially in patients with advanced chronological age. Patients over 65, and their 70s and 80s, are more likely to have increased morbidity and mortality. And so, I thought there may be a link there, between aging and senescence and the viral replication, as well as the potential therapy.

What I’d like to highlight about this particular article is that it proposes potential treatment strategies as well as prevention strategies. The reason is because it appears that this disease, the virus itself, may target senescent cells and senescent cells have been rewired to increase protein synthesis and also to increase the secretion of inflammatory mediators, which is known as the SASP, the senescence-associated secretory phenotype.

And so, one idea would be to use drugs that are senolytics. Senolytics are drugs that target and lyse senescent cells, but also to use protein synthesis inhibitors. The reason is because proteins synthesis inhibitors and senolytic drugs would prevent viral replication, which would reduce viral transmission. And so this could be used as a preventative strategy. I’ll just give you a couple of examples. If you have a drug which is an FDA-approved protein synthesis inhibitor, it should inhibit the secretion of inflammatory mediators, like IL-6. It should inhibit the fibrosis by preventing the secretion and production of collagen. And most importantly, the virus is also made of protein, so if you have a protein synthesis inhibitor, it will also inhibit viral replication.

Figure 1. What is the relationship between COVID-19 and advanced chronological age?
Figure 1. What is the relationship between COVID-19 and advanced chronological age?

There are three drugs I’d like to mention in particular. One is azithromycin, which is a senolytic. The others are also protein synthesis inhibitors, like doxycycline and rapamycin. All three have been shown to reduce IL-6 production because of their inhibition of protein synthesis activity. And also, all three of them have been shown to inhibit viral replication, not specifically of COVID 19, but since this effect on protein synthesis is a generalized effect, it should work for any virus. For example, azithromycin has been shown to inhibit the replication of Zika virus and Ebola virus, doxycycline has been shown to inhibit the replication of dengue virus, and rapamycin, which is another protein synthesis inhibitor with anti-aging properties, has been shown to inhibit replication of the HIV virus.

So, it seems to me that it’s a no-brainer that we should be repurposing FDA-approved drugs that are protein synthesis inhibitors, both for prevention, to prevent the inflammation fibrosis that’s occurring that’s killing people with COVID-19, and also to prevent the contagion by inhibiting viral replication. So I think this could provide a very inexpensive way forward because drugs like doxycyclin are only less than 10 cents a day, and could be used, as I said, for both prophylaxis and treatment. But, I think we need to use it early in the disease to prevent the fibrosis and inflammation, which makes them long, very inflexible and unable to expand and contract, and leads them to a fibrotic lung disease, which prevents patient recovery and could explain lethality of the disease.

I would like to directly engage with people to pick this up, to bring this forward as potential clinical trials. These clinical trials could be done directly in healthcare workers because they are the most vulnerable. In addition, they could be done in patients with advanced chronological age, or even with patients that are asymptomatic, that have been identified as the virus-positive. And it would be like a window trial where you would do viral titers first, and then you would give the drug and then you could also look at the viral titers after administering the drugs. So this would be a very easy, straightforward trial.

All the diagnostic tools for COVID-19 have already been identified and perfected, so all we need to do is interject FDA-approved drugs, which are protein synthesis inhibitors, to look at the eradication, the virus. So this would also be a very inexpensive clinical trial. But I would like to engage with infectious disease experts and virologists to help facilitate. Thank you.

Of course, I would like to thank two foundations which have supported our work: The Fox Point Foundation in Canada and The Healthy Life Foundation in the UK for providing the equipment and infrastructure at the University of Salford.

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

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Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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Aging Is Easily Treatable

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In 2018, Dr. Mikhail Blagosklonny wrote a thought provoking theory article, entitled: “Disease or not, aging is easily treatable.”

Figure 1. Relationship between aging and diseases. When growth is completed, growth-promoting pathways increase cellular and systemic functions and thus drive aging. This is a pre-pre-disease stage, slowly progressing to a pre-disease stage. Eventually, alterations reach clinical disease definition, associated with organ damage, loss of functions (functional decline), rapid deterioration and death.
Figure 1. Relationship between aging and diseases. When growth is completed, growth-promoting pathways increase cellular and systemic functions and thus drive aging. This is a pre-pre-disease stage, slowly progressing to a pre-disease stage. Eventually, alterations reach clinical disease definition, associated with organ damage, loss of functions (functional decline), rapid deterioration and death.

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

Read Aging’s Top 100 Altmetric papers.

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Would re-classifying aging as an official disease help fuel the anti-aging drug industry? While many sufficient arguments can place aging in this category, Dr. Mikhail Blagosklonny—Editor-in-Chief at Aging, Oncotarget, Oncoscience, and Cell Cycle, and adjunct faculty member at the Roswell Park Comprehensive Cancer Center—believes that classifying aging as a disease is unnecessary and counterproductive.

“It is commonly argued that aging should be defined as a disease so as to accelerate development of anti-aging therapies. This attitude is self-defeating because it allows us to postpone development of anti-aging therapies until aging is pronounced a disease by regulatory bodies, which will not happen soon.”

In 2018, Dr. Blagosklonny wrote a theory article that was published in Aging’s Volume 10, Issue 11, and entitled, “Disease or not, aging is easily treatable.” To date, this top-performing paper has generated an Altmetric Attention score of 54.

“HEALTHY” AGING

In this article, Dr. Blagosklonny emphasizes his theory that human aging is the quasi-programmed continuation of growth and development. He explains that progressive aging later in life results in aberrant systematic hyperfunction, which leads to disease and, eventually, death. 

“Aging is a normal continuation of the normal developmental program, so it is NOT a program but a purposeless, unintended quasi-program [10–16].”

Beginning after the growth process, Dr. Blagosklonny segments the aging process into four stages: pre-pre-disease, pre-disease, clinical disease, and death (see Figure 1). In the early stages of aging, the unseen asymptomatic abnormalities which arise have not yet reached the currently agreed upon clinical definitions of disease. Dr. Blagosklonny explains that “healthy” aging can be interchangeable with “pre-pre-disease” and “pre-disease.”

“‘Healthy’ aging has been called subclinical aging [33], slow aging [18,34] or decelerated aging [35], during which diseases are at the pre-disease or even pre-pre-disease stage.”

TREATING AGING

“Aging is easily treatable.”

Dr. Blagosklonny justifies this instinctually debatable claim simply by pointing out the ways in which humans are already defying aging. Calorie restriction, intermittent fasting, and the ketogenic diet have all been proven to slow aging and extend healthy lifespan. Certain nutrients, conventional drugs, and pharmacological therapies which have shown anti-aging properties include metformin, aspirin, statins, beta-blockers, ACE inhibitors, Angiotensin II receptor blockers (ARB), and (the anti-aging therapy Dr. Blagosklonny is most intrigued by) rapamycin, and other rapalogs. 

“Rapamycin (Rapamune/Sirolimus), an allosteric inhibitor of mTOR complex 1 [63,66], is a natural rapalog as well as the most potent and best studied rapalog.”

Dr. Blagosklonny chronicles numerous studies over the years verifying rapamycin’s life- and health-extending effects in microorganisms, mice, humans, (non-human) primates, and even canines. Read more about the origin and applications of rapamycin.

PREVENTATIVE MEDICINE IS ANTI-AGING

“Gerontologists think of metformin as an anti-aging drug [121–130], and metformin can be combined with rapamycin [131].”

In addition to the use of rapamycin and other anti-aging drugs, current preventative medicine strategies can be seen as anti-aging therapies, and vice versa. Dr. Blagosklonny discusses examples of preventative medicine and anti-aging therapy. In one example, patients who present with pre-diabetic symptoms may be treated with metformin to decrease insulin-resistance in advance, in order to prevent diabetes in the future. This is an example of preventative medicine as an anti-aging therapy.

“Physicians generally do not think of metformin as an anti-aging drug, simply because it is expected that life will be extended, if diseases are prevented.”

CONCLUSION

“Aging does not need to be defined as a disease to be treated.”

In conclusion, Dr. Blagosklonny proposes that “aging can be treated as a pre-disease to prevent its progression to diseases.” He suggests that, to preventatively combat disease brought on by aging, rapamycin and conventional life-extending drugs can be combined with “modestly low-calorie/carbohydrates diet, physical exercise, and stress avoidance.”

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

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Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.


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Deep Learning Technology Consolidates Wearable Sensor Data

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Smart watch / Smartphone

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

Read Aging’s Top 100 Altmetric papers.

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Wearable sensors (smartwatches, smartphones, and other devices) allow users to monitor some biomarkers of their own health with mobile biofeedback technology. In 2019, one-in-five adults in the United States reported regularly using a wearable fitness tracker or smartwatch. Since the COVID-19 pandemic, mobile downloads of health and home fitness apps have increased by 46%—in addition to a boom in wearable sensor use.

“Wearable device motion data have already been used for monitoring acute illnesses including detection of early signs of the outbreak of influenza-like illnesses [28] and COVID-19 [30, 34].” 

Large quantities of these data are being collected consistently from individual users. This potentially useful information is also being collected from large populations of people living in different countries, working in different occupations, with unique health statuses, and across multiple environmental seasons and stages of life. Wearable sensor data provides an opportunity to conduct large-scale studies that could lead to new global discoveries in aging and disease research.

“In fact, only mobile technology can support large-scale studies involving monitoring of early signs of a disease or measuring recovery rates, all requiring sampling more often than once per week.”

However, there are a number of different manufacturers of wearable sensors, smartwatches, and mobile devices. In addition to the inevitable inaccuracies, such as missing data, outliers, and even seasonal variation of physical activity, there are also varying measurements between devices of different manufacturers. These inaccuracies and variations create inconsistencies when comparing large-scale data from wearable sensors.

“We applied deep learning technology to systematically address these challenges.”

In 2021, researchers from Singapore’s Gero AI and Russia’s Moscow Institute of Physics and Technology authored a paper, published in Aging’s Volume 13, Issue 6, and entitled, “Deep longitudinal phenotyping of wearable sensor data reveals independent markers of longevity, stress, and resilience.” To date, this top-performing research paper has generated an Altmetric attention score of 43. 

The Study

“We trained and characterized a simple model that learns physical activity patterns from wearable devices, which are directly associated with morbidity risks on the population level.”

Three wearable sensor manufacturers were assessed in this study: UK Biobank, NHANES, and Healthkit. Researchers collected wearable sensor data for physical activity (steps per minute) from 103,830 users over the course of one week and, among 2,599 users, up to two years of data were collected. The team trained and validated a deep learning neural network technology—the GeroSense Biological Age Acceleration (BAA) system—to extract health-associated features from the physical activity recordings.  

“GeroSense BAA model employs additional neural network components to address this domain shift problem to ensure learning device-independent representations of the input signal.”

Conclusion

“We demonstrate that deep neural networks trained to predict morbidity risk from wearable sensor data can provide a high-quality and cheap alternative for BAA determination.”

The researchers explained that the application and wide deployment of their GeroSense BAA system may provide the means to accurately monitor stress and resilience in response to environmental conditions and interventions among people in different populations, countries, and socio-economic groups. 

“We hope that future developments will lead to further applications of AI in geroscience research, public health, and policy decision-making.”

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

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Aging is an open-access journal that publishes high-quality research papers bi-monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our communities from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

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Trending With Impact: When Aging Switches On Alzheimer’s

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In a trending Aging editorial paper, researchers explain that switches in the aging process may be a window of opportunity for patients with Alzheimer’s disease and potential epigenetic treatments.

Figure 1. The EORS downward spiral of aging and Alzheimer’s (Epigenetic Oxidative Redox Shift) [2].
Figure 1. The EORS downward spiral of aging and Alzheimer’s (Epigenetic Oxidative Redox Shift) [2].

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

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Alzheimer’s disease (AD) develops at different times for different people due to known and unknown variables. AD and aging share a number of features in common, such as oxidative stress, mitochondrial impairment, and bioenergetic and metabolic shifts. Aging is an unmistakable risk factor for Alzheimer’s disease, but what causes aging to switch it on? Do these “switches” present opportunities for intervention?

In 2021, researchers from the University of California and the University of South Carolina wrote an editorial article about the onset of AD—propagated by switches that take place during the aging process. Their trending paper, published in Aging’s Volume 13, Issue 10, was entitled: “When aging switches on Alzheimer’s.”

“[…] the complex mechanisms of switching on so many AD pathologies remain underexplored.”

Oxidative Shifts

“Age-related redox stress, often measured as oxidative stress in aging and AD launches a global switch in the epigenetic landscape, widely affecting methylation, histone modification, and noncoding RNA regulation [5], to further drive downstream metabolic and energetic shifts.”

The authors begin this editorial paper by prefacing readers with the epigenetic oxidative redox shift theory of aging. They explain that the sedentary lifestyle often accompanied by old age resets epigenetic marks to prepare for low mitochondrial capacity and minimal energy production. In order to maintain this setting (resting redox energy levels), the body switches to require more oxygen and energy when performing physical activities and increases the conversion of glucose to lactose (the Warburg Effect). In turn, these metabolic shifts (now enforced by the epigenome) reinforce sedentary behavior—forming a vicious cycle.

“Our environment, lifestyle, stress, physical activity, and habits all modulate epigenetic control of gene expression for continuous environmental tracking.”

Conclusion

Oxidative shifts alter the activity of numerous redox-sensitive transcription factors, enzymes, and signaling proteins. The researchers explain that these oxidative switches taking place in patients with Alzheimer’s disease are potential targets for epigenetic treatments.

“While studies on these ‘switches’ enable elucidation of the underlying mechanisms for when aging switches on Alzheimer’s degeneration, more importantly, these ‘switches’ of redox, epigenetics and neuroinflammation encourage early interventions to decelerate AD pathology and retain functional memory.”

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

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Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

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Hyperbaric Oxygen: A Therapy for Normal Aging?

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

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

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

Read Aging’s Top 100 Altmetric papers.

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

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

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

THE STUDY

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

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

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

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

RESULTS & CONCLUSION

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

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

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

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

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Aging is an open-access journal that publishes high-quality research papers bi-monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our communities from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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Behind the Study: Interview with Dr. Gil Atzmon

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Dr. Gil Atzmon from the Albert Einstein College of Medicine discusses his 2017 study published by Aging, entitled, “The complex genetics of gait speed: genome-wide meta-analysis approach.”

Researchers explain their studies that were published in Aging
Researchers explain their studies that were published in Aging

Speaker

Welcome to the Aging YouTube channel. This interview is with Dr. Gil Atzmon in the department of medicine and genetics at the Albert Einstein College of Medicine in the Bronx, New York. (He is) also in the department of human biology and a faculty member of the Department of Natural Science at the University of Haifa in Haifa, Israel. (He is) talking about a manuscript published in Volume 9, Issue 1 of Aging titled, “The complex genetics of gait speed, genome-wide meta analysis approach.”

Dr. Gil Atzmon

So the paper that I’m talking about is, “The complex genetic of gait speed: genome-wide meta analysis approach.” And what we did here is to combine 21 studies around the world and try to figure out what is the genetic predisposition for gait speed. The idea was that if we are going by number, then we will find something because the size is a matter of the resolution that you can pinpoint the genetic variant that might have an effect on the phenotype that, in our case, is gait speed. So when you’re talking about challenges, think of do you have 21 people or 21 groups that you need to combine together and figure out how you harmonize the data that they provide you with and try to figure out what’s going on there. This is a challenge because it lasted for almost four years until we had the paper done and published.

But eventually what we found was great. Although what we expected to find once we started this endeavor, we thought we’d have variants that have genomic significance. Meaning, if you have this variant either you have a lower gait speed or you have higher gait speed or normal gait speed. And we’re talking about elderly people. That’s what we tried to figure out. We found out that we didn’t find such a variant, but we find other alternatives.

We try to use protein analysis, group analysis, pathway analysis on all kinds of stuff. And every time that we put the finger on such a different analysis, we found something, some other interesting views. As I said, for genetic variant we didn’t find any, meaning the closest that we have was 10 to the -7 when the threshold was 10 to the -8.

Figure 1. Manhattan plot of meta-analysis of genome wide association studies of gait speed for ~2.5 million genotype and imputed SNPs

But when you look at these genes, we found that there are a couple of them that have higher prevalence among the top hit. Again, they didn’t reach a significance, but the minute you have such a number in the top hits, you think it might be relevant. We have a HLA-DPB1, we have the POM121-L2, and so forth and so forth. And you can see in the paper to look at those variants.

The interesting idea I’m seeing of the observation was that there was a couple of hits that we saw only once, but they are hits such as the [inaudible 00:03:36] 12I02 with a peak, meaning there is aggregation of a couple of hits around this gene or inside this gene. Again, it tells us that this gene might be relevant to what we are looking for. When we did the pathway analysis we found a couple of them that are associated with diabetes, which if you think about it, that really can cause people to either have slow gait speed or higher gait speed. It depends on the disease that you have. We have a couple of hits in the pathway, and a lot of this link us to cancer. And again, the same thing. If you think about it, the minute you have a disease, your performance, in this case it’s gait speed, is either declined or increased.

So we can see in both cases, though we didn’t find the right hit, still what we found has some biological explanation. It also does expression analysis or expression QTL. QTL means that those genes that are associated with the expression of the genes didn’t code in the phenotype, we found a couple of them that were higher significance. Again, another example of what is the predisposition of those genes to the phenotype that we had.

So, all in all, we concluded that we found some relevant genetic predisposition for this phenotype. And although we didn’t find the exact variant that can say “if you have it, you have low speed, and if you don’t have it, you have a higher speed,” we think that if we’re looking at the story that we crafted, we think that we’ve found some ideas, some biological explanation which is what is inside this paper.

Speaker

Aging was launched in 2009 and is currently a traditional peer reviewed journal with free access which publishes in monthly issues. Topics include high impact research papers of general interest and biological significance in all fields of aging research, as well as topics beyond traditional gerontology. You can click on the link in the description below to order a reprint or read the manuscript that was discussed in this interview on aging-us.com. Please feel free to subscribe to our YouTube channel and connect with us on Facebook, Twitter, or LinkedIn. Thank you.

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

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Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

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Trending with Impact: Aging and Lung Function Decline

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Is there an association between biomarkers of aging and lung function? Researchers conducted a study which aimed to find out.

Human Respiratory System Lungs Anatomy

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

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Listen to an audio version of this article

By 2050, the United States Census Bureau estimates that 83.7 million people aged 65 years and older will be living in the U.S.—a number that will nearly double the 2012 estimated population. As the scale of the elderly population magnifies, additional aging research will continue to be increasingly relevant. 

“According to the American Lung Association, the lung matures by age 20-25 years, and its function declines gradually after the age of 35 [30].”

Among the elderly population, lung function has been found to vary, even between those who have never smoked, are the same height, and of the same chronological age. This has led researchers to wonder if lung function decline is part of the underlying biological aging processes. No published studies had investigated the associations between epigenetic aging biomarkers and lung function, until 2020.

In 2020, a team of researchers—from Harvard T.H. Chan School of Public Health, Icahn School of Medicine at Mount Sinai, Northwestern University Feinberg School of Medicine, VA Boston Healthcare System, Boston University School of Medicine, and Columbia University—aimed to begin answering this question. The researchers conducted a study with participants from the longitudinal Normative Aging Study (1963 – present) to determine whether or not there is an association between seven biomarkers of aging (BoA) and three measures of lung function. Their paper was published by Aging and entitled: “Biomarkers of aging and lung function in the normative aging study.”

“In this present study, we hypothesized that some of these BoA are associated with lower lung function.”

The Study

From 1961 to 1970, healthy U.S. males between the ages of 21 and 81 enrolled in the ongoing Veterans Affairs Normative Aging Study. One of the objectives of the study is to characterize the biomedical and psychosocial parameters of normal aging (distinct from the development of disease). There are a total of 2,280 participants in the Normative Aging Study (NAS). In the current Aging study, researchers included 696 elderly men from the NAS.

“The present study included 696 elderly men with 1,070 visits during years of 1999-2013.”

In search of associations between biomarkers of aging and lung function, the researchers first collected the study participants’ personal characteristics, including age, smoking history, height, weight, BMI, education, blood work, and other measures. They then analyzed lung function using three tests: forced expiratory volume in one second (FEV1), forced expiratory volume in one second / forced vital capacity (FEV1/FVC), and maximum mid-expiratory flow (MMEF).

Next, the team analyzed the participants’ epigenetic biomarkers of age; including GrimAgeAccel, PhenoAgeAccel, intrinsic epigenetic age acceleration (IEAA), extrinsic epigenetic age acceleration (EEAA), and Zhang’s DNAmRiskScore; as well as non-epigenetic biomarkers of age, including telomere length and mitochondrial DNA copy number (mtDNA-CN). They then assessed for associations between these biomarkers and the three measures of lung function.

Conclusion

“In this longitudinal cohort of 696 elderly males, we found that GrimAgeAccel and Zhang’s DNAmRiskScore were associated with lower lung function, including FEV1, FEV1/FVC, and MMEF.”

The researchers found that the GrimAgeAccel and Zhang’s DNAmRiskScore were both associated with lower lung function in all three measures of lung function. They found no correlation between non-epigenetic aging biomarkers and lung function, but the researchers mention several limitations of their study. Their results suggest that epigenomic variation could help illuminate the pathogenesis of the reduced lung function that comes with age.

“Epigenetic mechanisms such as DNAm may provide further explanation for decreases in lung function as individual age.”

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

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Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

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Behind the Study: Interview with Dr. Marina P. Antoch

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Dr. Marina Antoch of Roswell Park Comprehensive Cancer Center discusses her 2017 study published by Aging entitled, “Physiological frailty index (PFI): quantitative in-life estimate of individual biological age in mice.”

Researchers explain their studies that were published in Aging
Researchers explain their studies that were published in Aging

My name is Marina Antoch, and I am a member of Department of Pharmacology and Therapeutics for Roswell Park Cancer Institute. And actually working here at Roswell for 10 years now. Recently my group, in collaboration with few other laboratories and the local biotech startup company, Everon Biosciences, summarize the recent research in the paper that was published in the journal, Aging. This paper is related to working out a novel approach that will allow us to assess the overall health in the preclinical animal model organelle.

Working with the company that’s really interested in developing some therapeutics that could combat aging, slow down the aging, we really need to get some quantitative tools that we can use to assess the efficacy of those molecules of those potential drugs that they identify in their preclinical studies. There were few works that would suggest some approaches how we can do that, but none of these really satisfy the goals that we have.

So we have to think of some other approaches that we may use, and there were several requirements that we really need for developing the successful protocols. First of all, we wanted this protocol to be absolutely non-invasive for our preclinical animal models, so it could be repeated on the same subject for several times. We can actually look through the lifespan of the subject, how these parameters and overall health is changed with age. They have to be really quantitative. So we didn’t really want to rely on some observational things like the hair grain, for example, that’s been considered the hallmark of aging for many years. Many of these observations, they really require coring by several individual observers and then they are compared, and they’re very subjective. (We) really wanted to get something more objective that we could put in numbers.

This manuscript that was published actually summarized almost three-year work that was dedicated to this problem. We tried many different approaches and finally came up with a protocol that we called determining physiological frailty index. And this frailty index is just the cumulative estimate of many, many physiological parameters that are related to the health of the animal. And they’re very relevant to human studies since these such parameters as body weight or physical strength that we could measure, usually using special equipment or blood pressure that we can measure in animal models-very similar to how we do it in humans, blood cell parameters, and a few others that can really give us the quantitative assessment of each parameter. Then we compare how much it is in older animals – or in animals that don’t feel well. How much of these parameters differ from when compared to the younger animals, and that gave us a certain quantitative estimate. So why is that important? It’s important for the reason of testing, as I mentioned already, various potential biologicals that would be developed as anti-aging drugs.

Figure 1. Assessment of individual biological age of NIH Swiss mice. 

This protocol will now allow us to assess, quantitatively, the health status of animals then treat them with potential therapeutics, and then down the road, repeat this measurement to see if this frailty index, brought any improvement or not, and that would be indicative of the efficacy of the therapy. So this is one of the major goals of our research and why we developed this protocol. But for all future studies, we have actually another thought in mind, how we may use this particular approach. We’re now related to cancer research as you may know, due to the really successful development of many anti-cancer drugs, and many anti-cancer therapies. There are more and more cancer survivors. Actually in 2016, the American Cancer Society published statistics saying that there’s about 15 million people that went through the very harsh chemotherapeutic and radiation therapies. They are cancer-free. They never had relapsed cancer, but these therapies definitely affect a lot of other aspects of their health. And one of those aspects, besides any specific diseases, that they may develop is the accelerated aging.

With the development of more and more therapeutics, the expectation is that in 2026, there’ll be more than 20 million of cancer survivors. We’ll really need to be thinking about developing novel cancer therapeutics. We really should think not to make them more efficient and less toxic, but also to be able to diminish their damaging effect down the road at the latest stages of the life of basically to improve the quality of life of cancer survivors by adjusting the treatments at the time that we treat cancer. So we have less problems later on. To do that first, we have to test this in our preclinical models and for success of those tests, we really needed some quantitative assay that we can apply.

We think that our protocol of physiological frailty index would serve this purpose very well. So, basically, testing the efficacy and the therapeutic efficacy of different chemotherapeutic drugs. We may also look on a long-term effects to see how that affects animals health and adjust treatments based on the preclinical evaluation. This is why we think it’s really an important tool that could be very useful in many aspects of preclinical studies, and maybe sometimes applied then as many of preclinical studies translated into the clinical applications.

I’m also thinking that it may be very relevant for treatment of childhood cancers. Childhood cancers are very specific type of cancers. First of all, the regiments are actually the same as are worked out for adult people. Although young people and adult people are very different physiologically. They’re just adjusted by the weight, the age a little bit. But in principle, they are about the same.

The rate of cure for some types of childhood cancers nowadays is also pretty sufficient. So there is a large population of kids that went through chemotherapy and radiation that was applied to a very critical moment in their development. So they are effective. It’s really very significant. Actually the longevity of those childhood cancer survivors is statistically lower and they will premature age and develop a lot of different complications. So I think that that could be particularly important for treating various types of childhood cancers, and that can really affect the way we are treating childhood malignancies.

If we are able to reach our goal and adjust the treatment so we’re focusing not only on immediate therapeutic effect, but take into account these long-term complications that would inevitably arise after the treatment, we can significantly improve the quality of life of cancer survivors. That would be a very significant impact on the overall health of the population, I would say.

Click here to read the full study published by Aging.

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Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

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