Aging Is Easily Treatable

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.

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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 AgingOncotargetOncoscienceand 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 [1016].”

Beginning after the growth process, Dr. Blagosklonny segments the aging process into four stages: pre-pre-diseasepre-diseaseclinical 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 [121130], 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

Smart watch / Smartphone

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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 [3034].” 

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.

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Trending With Impact: When Aging Switches On Alzheimer’s

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.

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Trending with Impact: Aging and Lung Function Decline

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

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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 HealthIcahn School of Medicine at Mount SinaiNorthwestern University Feinberg School of MedicineVA Boston Healthcare SystemBoston 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.

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Can a Daily Dose of Electricity Improve Aging?

Researchers from the University of Leeds and the University of Glasgow conducted a 2019 study on the effects of transcutaneous vagal nerve stimulation (tVNS) among participants 55 years of age and older.

Medical illustration of vagus nerve with brain, lungs, heart, stomach and digestive tract.
Medical illustration of vagus nerve with brain, lungs, heart, stomach and digestive tract.

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Among the cranial nerves, the vagus nerve has the largest distribution in the body. Extending from the brain to the abdomen, its name is derived from the Latin word vagari—which means “to wander.” This wandering nerve serves as part of the involuntary, or autonomic, nervous system. The vagus nerve is responsible for a number of important autonomic bodily functions, including lung function, heart rate, inflammation, brain/gut communication, mood, and even the consolidation of memories. 

Human aging is accompanied by progressive autonomic changes, including increases in sympathetic nervous activity (“fight or flight” responses) and decreases in parasympathetic nervous activity (“rest and digest” responses). These changes can have considerable effects on heart function, emotion, mood, gut function, and overall quality of life, and can often lead to an increase in medication consumption with age. 

TRANSCUTANEOUS VAGAL NERVE STIMULATION (TVNS)

In efforts to boost parasympathetic activity and decrease sympathetic activity, interventions such as vagus nerve stimulation (VNS) and transcutaneous vagal nerve stimulation (tVNS) have been developed. VNS is a highly invasive intervention, which involves surgically implanting an electrode around the cervical vagus nerve and a generator unit in the thoracic wall. Researchers have found that the non-invasive tVNS therapy (an electrical pulse focused on the tragus of the outer ear) is a safer and simpler intervention. Positive effects on autonomic function have been reported in non-patient groups treated with tVNS.

“tVNS is a simple, non-invasive and inexpensive therapy that involves stimulating the auricular branch of the vagus nerve (ABVN) at outer parts of the ear, conferring autonomic benefits in healthy volunteers [10].”

Previous research has shown that tVNS significantly reduces sympathetic nerve activity in healthy participants and boosts measures of parasympathetic activity. However, there are few studies available which detail the effects of tVNS in healthy older participants. 

“Despite this evidence, there is little work examining the autonomic implications of administering tVNS in healthy older individuals who are undergoing age-associated shifts towards sympathetic prevalence.”

THE STUDY

In 2019, researchers from the United Kingdom’s University of Leeds and University of Glasgow reported on the results of the effects of tVNS among participants 55 years of age and older in three studies. Their paper was published in Aging’s Volume 11, Issue 14, and entitled: “Effects of transcutaneous vagus nerve stimulation in individuals aged 55 years or above: potential benefits of daily stimulation.” To date, this research paper has received an impressive Altmetric Attention score of 350.

In the first study, the researchers observed the effects of acute, single-session tVNS on cardiovascular autonomic function compared with the effects of sham (ear lobe/placebo) stimulation among 14 healthy participants 55 years of age and older. They collected baseline values and measured heart rate variability (HVR) and baroreflex sensitivity. 

“Since not all participants responded to tVNS, we examined if it was possible to identify potential tVNS responders from baseline parameters.”

In the second study, the researchers explored the effects of acute, single-session tVNS on autonomic function in the same age group and expanded the sample to 51 participants. The third study examined 26 participants in the same age group when administered tVNS once per day, for 15-minutes, over the course of two weeks. The researchers reported the impacts of daily tVNS in measures of autonomic function, health-related quality of life (QoL), mood, and sleep.

“Transcutaneous vagal nerve stimulation (tVNS) acutely administered to the tragus in healthy volunteers aged ≥ 55 years was associated with improvements in spontaneous cardiac baroreflex sensitivity and HRV.”

CONCLUSION

“For the first time, we have shown that age-related autonomic, QoL, mood and sleep changes may be improved with tVNS administered every day for two weeks.”

Although the researchers note that there are opportunities for improvement in this study design and further research is needed, participants reported improved sleep, depression, tension, vigor, and mood disturbance after two weeks of daily tVNS.

“These findings therefore suggest that daily tVNS may be an effective means of improving aspects of everyday life in this age group.” 

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 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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TRENDING WITH IMPACT: EFFECTS OF EXERCISE ON AGING

Researchers surveyed available literature related to exercise and its association with longevity and aging. This extensive review expands on exercise as a lifestyle intervention and its ability to counteract cellular and tissue aging.

Figure 4. Conceptual overview. Created in BioRender.

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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Regular physical exercise provides benefits for both the body and mind, but how exactly does this healthy habit benefit our cells, signaling pathways, organs, and even bones? Furthermore, how can we employ regular exercise as part of an anti-aging strategy to extend our healthspan and lifespan?

Two researchers from the Beta Cell Aging Lab at Harvard Medical School authored a recent review paper which breaks down the currently available research on this very topic, with a special focus on pancreatic beta-cells and Type 2 diabetes. The authors detailed the recorded effects of exercise at systemic and cellular levels, its effects on each of the hallmarks of aging, and a potential molecular regulatory node that may integrate those effects. This review was published in May of 2021 by Aging, and entitled: “Effects of exercise on cellular and tissue aging.”

THE NINE HALLMARKS OF AGING

With age, cellular functions and systems in the human body progressively decline and destabilize, which eventually leads to disease and all-cause mortality. There are nine hallmarks of aging, which are classified as either primary, secondary, or integrative: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. 

“Exercise is a promising lifestyle intervention that has shown antiaging effects by extending lifespan and healthspan through decreasing the nine hallmarks of aging and age-associated inflammation.” 

The researchers in this review explain that exercise is capable of counteracting each of these hallmarks of aging at systematic and cellular levels. They used publicly available research to cite and discuss the effects of exercise in each hallmark of aging in clear and thorough detail. The purpose of this article is to summarize this review, though readers are highly encouraged to read the full paper for deeper insights. 

“The literature was surveyed on MEDLINE through freely accessible PubMed as a search engine for the terms: ‘exercise’, ‘longevity’ and ‘aging’; the most relevant studies were included as they related to the 9 hallmarks of aging.”

AMPK AS A CENTRAL REGULATOR

“In summary, exercise attenuates all hallmarks of aging through different molecular pathways and effectors that seem independent and disconnected.” 

Given that exercise regulates each of these hallmarks individually, the researchers hypothesize that there must exist some kind of molecular regulatory node(s) capable of coordinating these responses. They propose that the 5’ adenosine monophosphate-activated protein kinase (AMPK) enzyme/protein could play this role.

“In summary, AMPK activation through exercise can impact all the hallmarks of aging through different signaling pathways as summarized in Figure 2 and can act as a signaling node capable of orchestrating many of the effects of exercise on the health span of different tissues and organs.”

EXERCISE AND TYPE 2 DIABETES

The researchers also discuss the effects of exercise on Type 2 diabetes mellitus (T2D). 

“In summary, exercise activates molecular signals that can bypass defects in insulin signaling in skeletal muscle and increase skeletal muscle mitochondria, which are associated with improved insulin sensitivity in skeletal muscle and therefore improve aging-associated effects of T2D.”

Figure 1. Effects of exercise upon the aging process of different organs and systems. Created in BioRender.
Figure 1. Effects of exercise upon the aging process of different organs and systems. Created in BioRender.

CONCLUSION

“We propose that future studies should address the effects of exercise on tissues which are not considered its direct targets but do show accelerated aging in T2D, such as pancreatic β-cells. In these, the role of AMPK and its physiological control will become especially significant as exercise is considered a cellular antiaging strategy.”

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

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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The Epigenetic Clock, Aging, and Rejuvenation

Researchers discuss the role that the epigenetic clock may play in the aging process and in rejuvenation as an approach to set back epigenetic age.

Figure 3. Morphological changes induced by long-term OSKM gene action in human umbilical cord perivascular cells (HUCPVC).
Figure 3. Morphological changes induced by long-term OSKM gene action in human umbilical cord perivascular cells (HUCPVC).

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

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A centenarian is a human that has lived as long or longer than one hundred years. These individuals are marvels to aging researchers and have been studied at length in hopes of uncovering clues about the mechanisms that drive aging. Many researchers have crafted views and theories about the roots of gerontology; these curiosities have preceded the development of modern science.

In an effort to describe different views and theories of aging—leading to the emergent view of the epigenome as the driver of aging—researchers from the National University of La PlataNational University of CordobaWorld Academy of Art and Science, and Betterhumans Inc., authored a research perspective published by Aging in 2021. This well-written paper describes the role that the epigenetic clock may play in both the aging process and in rejuvenation as an approach to set back epigenetic age. The paper was entitled, “Aging and rejuvenation – a modular epigenome model.”

“The hypothesis proposing the epigenome as the driver of aging was significantly strengthened by the converging discovery that DNA methylation at specific CpG sites could be used as a highly accurate biomarker of age defined by the Horvath clock [5].”

THE EPIGENETIC CLOCK

Throughout our lifetime, the rate of change in DNA methylation at age-dependent CpG sites has been found to consistently correlate with our rate of epigenetic aging and organismal aging. In 2013, researcher Stephen Horvath devised a mathematical algorithm using DNA methylation at specific CpG sites that is a highly accurate biomarker of age. 

“In humans, the epigenetic age calculated by the clock algorithm shows a correlation of 0.96 to chronological age and an error margin of 3.6 years, an unprecedented accuracy for a biomarker of age [524].”

In human babies, from birth to one year old, researchers explain that the ticking rate of the epigenetic clock is very high, as is our rate of aging at this point in the lifecycle. Then, from one to 20 years of age, the rate progressively decelerates. After age 20, the ticking rate is much slower. Among individuals with conditions such as cancer, HIV, obesity, Alzheimer’s disease, and even alcohol abuse, the ticking of the epigenetic clock and aging rate is, unsurprisingly, much higher. In another example, the rate of epigenetic aging is slower in supercentenarians and their children compared with non-centenarians. 

“There is compelling evidence that the ticking rate of the clock is significantly correlated with the rate of biological aging in health and disease.”

THE EPIGENETIC CLOCK & AGE REJUVENATION

Even while they continue to proliferate, embryonic cells (ES) may remain indefinitely young—in a type of “suspended animation.” The epigenetic clock does not tick in embryonic cells, until they differentiate.

“In ES cells, the epigenetic clock does not tick [5] nor does the circadian clock oscillate [26]. Only when ES cells differentiate, both clocks become active and cells begin to age.” 

Over the years, there have been clues indicating that it is possible to rejuvenate non-reproductive (somatic) cells back to induced pluripotent stem (iPS) cells, or embryonic-like cells. When somatic cells are reprogrammed to iPS cells, their epigenetic clocks stop ticking, their circadian clocks cease to oscillate, and ultimately, their epigenetic clock is set back to zero (or close to zero). These clues came from the development of animal cloning in the early 60s and, more recently, cell reprogramming.

The authors of this research perspective explain rejuvenation strategies including cell reprogramming, cyclic partial cell reprogramming, and other non-reprogramming strategies.

Two cell rejuvenation studies were described by the authors of this paper which suggest that, even at advanced stages of age, the epigenome continues to be responsive to command signals, including the OSKM genes, also known as the Yamanaka factors. This finding is compatible with the hypothesis that aging is not associated with DNA damage. The researchers explain two additional possible theories: 1.) Aging is preprogrammed in our DNA and due to progressive epigenome disorganization and loss of epigenetic information. 2.) Aging is not a programmed process, but a continuation of developmental growth driven by genetic pathways, such as mTOR.

“What seems to be clear is that epigenetic rejuvenation by cyclic partial reprogramming or alternative non-reprogramming strategies holds the key to both, understanding the mechanism by which the epigenome drives the aging process and arresting or even reversing organismal aging.”

CONCLUSIONS

In summary, the researchers explain that what the few initial study results seem to suggest is that when the epigenetic clock is forced to tick backwards in vivo, it is only able to drag the phenotype to a partially rejuvenated condition. However, the researchers emphasize that no firm conclusions should be drawn from the very few experimental results currently documented.

“Since we now have molecular tools, like the Yamanaka factors, that allow us to make the clock tick backwards, the time is ripe for opening a new dimension in gerontology, moving from aging research to epigenetic rejuvenation research.”

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

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: Method Yields Cell-Type-Specific Brain Data

Researchers used a bioinformatics approach (ESHRD) that leverages gene expression data from brain tissue to derive cell-type specific alterations in Alzheimer’s disease.

Neurons cells from the brain under the microscope.
Neurons cells from the brain under the microscope.

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Cell-to-cell variability in the human brain is significantly heterogeneous. An abundance of differential brain cell types makes it laborious and expensive for researchers to generate single-cell gene expression data. While some studies use laser capture microdissection (LCM) and single-cell RNA sequencing (scRNA-Seq) to directly address the cellular heterogeneity in brain tissue, due to labor and cost, these studies generally have a small sample size and face power concerns. Most gene expression profiling studies of patients with Alzheimer’s disease (AD) are conducted post-mortem using brain tissue homogenates.

“Ultimately, the overall goal of gene expression profiling in AD is to understand the transcriptome changes in all major cell types of the brain in a well-powered approach that would facilitate the exploration of all the variables mentioned above.”

The need existed for a cost-effective bioinformatics approach to leverage expression profiling data from brain homogenate tissue to derive cell type-specific differential expression and pathway analysis results. In 2020, researchers from Columbia University Medical Center, The University of Sydney School of Medicine, University of Miami, and the Banner Sun Health Research Institute described an Enrichment Score Homogenate RNA Deconvolution (ESHRD) method for identifying alterations in the brain. They published a research paper in Aging’s Volume 12, Issue 5, entitled: “ESHRD: deconvolution of brain homogenate RNA expression data to identify cell-type-specific alterations in Alzheimer’s disease.” 

The Study

“We applied our approach to different gene expression datasets derived from brain homogenate profiling from AD patients and Non-Demented controls (ND) from 7 different brain regions.”

Researchers conducted brain region cell-specific pathway analysis and Gene Set Enrichment Analysis (GSEA). The team mapped and measured five different cell types in seven different brain regions. The cell types included: microglia, neuron, endothelial, astrocyte, and oligodendrocyte. Endothelial and oligodendrocyte are two cell types that are not easily examined in the brain and only very little gene expression data previously existed for Alzheimer’s disease.

“We conducted RNA expression profiling from both brain homogenates and oligodendrocytes obtained by LCM from the same donor brains and then calculated differential expression.”

The researchers used a dataset of Multiple System Atrophy (MSA) patients (n = 4) and controls (n = 5) to validate their ESHRD method. Homogenate, LCM, and scRNA-Seq results were compared using the ESHRD method. They also compared their findings to other research studies.

Results

“The ESHRD approach replicates previously published findings in neurons from AD patient brain specimens, and we extended our work to characterize novel AD-related changes in relatively unexplored cell types in AD, oligodendrocytes and endothelial cells.”

Neuronal, endothelial cells, and microglia were found to be the most represented “cell-specific” gene classes in patient brains with Alzheimer’s disease. Neuronal-specific genes were downregulated and enriched for synaptic processes. Endothelial genes were found to be upregulated in AD and enriched for angiogenesis and vascular functional processes.

“Differentially Expressed Genes (DEGs) we labeled as “mixed” represent the most prevalent class (73.4%), followed by DEGs labeled as microglia (6.6%), neuron (5.9%) and endothelial (5.7%). Astrocyte and oligodendrocyte labeled DEGs have a frequency of 3.6% and 3.1%, respectively.” 

Microglia showed different patterns of expression across the brain in multiple regions. They found that astrocyte genes were enriched in SLC transport and immune processes and oligodendrocytes were enriched for the Glycoprotein metabolism in Alzheimer’s disease.

Conclusion

“We demonstrate the ability of this approach to highlight known neuronal-specific changes in the AD brain and utilize it to identify novel changes in endothelial cells and oligodendrocytes, two cell types not easily examined in the brain and for which only minimal gene expression knowledge exists in AD.”

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

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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Complex Drug Screenings Show Anti-Aging Potential in Natural Compounds

In an effort to mimic metformin and rapamycin, researchers used powerful screening methods to analyze over 800 natural compounds to assess their anti-aging potential and safety profile.

Modern Medical Research Laboratory. Scientific Lab, Drug Engineering Center Full of High-Tech Equipment, Computer Screen Showing DNA concept, Technology for Vaccine Development.

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By 2030, one in five Americans will age over 65 years old in the United States. As a society, an even larger aging population is fast on our heels. With age comes wisdom, and unfortunately, so does a number of costly and devastating diseases, including cancer, cardiovascular disease, Alzheimer’s disease, and Type II diabetes.

Researchers are currently working to mitigate the upcoming burden for this expanding population by developing anti-aging and anti-cancer drugs, and other geroprotective interventions that could extend healthspan, lower disease rates, and maintain productivity. However, the slow and expensive process of gaining approval for new potential pharmaceutical and nutraceutical interventions is historically arduous and prone to failure—especially when it comes to anti-aging and longevity research.

“Even if successful, to be used preventatively, anti-aging drugs face extraordinarily high safety and efficacy standards for approval [9].”

In 2017, researchers from the United States’ Insilico Medicine, Inc. and Life Extension, the United Kingdom’s Biogerontology Research Foundation, Canada’s Queen’s University, and Russia’s Russian Academy of Sciences, worked together to test a strategy to accelerate the development of safe, wide-scale anti-aging nutraceuticals. Their study was published in Aging’s Volume 9, Issue 11, and entitled, “Towards natural mimetics of metformin and rapamycin.” To date, this top-performing research paper has generated an Altmetric Attention score of 127.

Metformin and Rapamycin

“One strategy to hasten the process has been the repurposing of existing, FDA-approved drugs that show off-label anti-cancer and anti-aging potential [10,11], and at the top of that list are metformin and rapamycin, two drugs that mimic caloric restriction [12].”

Metformin and rapamycin have already been FDA approved for use in renal transplants, Type II diabetes, and metabolic syndrome. These two drugs are both mTOR inhibitors which, through numerous research studies, have shown pleiotropic effects exhibiting multiple anti-aging, anticancer, and anti-cardiovascular disease benefits. However, some adverse side effects pertaining to extended use have made it so these two interventions (used alone) are unable to move forward for wide-scale preventative use.

“Taken together, rapamycin and metformin are promising candidates for life and healthspan extension; however, concerns of adverse side effects have hampered their widescale adoption for this purpose.”

Although there are some adverse side effects, the chemical structures of metformin and rapamycin should not be ignored. These two drugs can be analyzed, and even mimicked, to develop new, safer interventions to prevent and treat age-related diseases. The researchers in this study initiated an effort to identify nutraceuticals as safe, natural alternatives to metformin and rapamycin drugs. 

“Nutraceuticals have received considerable attention in recent years for potential roles in preventing or treating a number of age-related diseases [88].”

The Study

“Our work is done entirely in silico and entails the use of metformin and rapamycin transcriptional and signaling pathway activation signatures to screen for matches amongst natural compounds.” 

Test compounds were selected based on the natural compounds listed in the UNPD and Library of Integrated Network‐based Cellular Signatures (LINCS) datasets. Gene‐ and pathway‐level signatures of metformin and rapamycin were mapped and screened for matches against the over 800 natural compounds chosen. The team used conventional statistical methods, pathway scoring-based methods, and training of deep neural networks for signature recognition. Researchers applied several bioinformatic approaches and deep learning methods, including the Oncofinder, Geroscope, and in silico Pathway Activation Network Decomposition Analysis (iPANDA). The iPANDA extracts robust, biologically relevant pathway activation signatures from the data. 

“In an application of these methods, we focused on mimicry of metformin and rapamycin, seeking nutraceuticals that could preserve their anti-aging and disease-preventive potential while being better suited for wide-scale prophylactic use.”

Results and Conclusion

“The analysis revealed many novel candidate metformin and rapamycin mimetics, including allantoin and ginsenoside (metformin), epigallocatechin gallate and isoliquiritigenin (rapamycin), and withaferin A (both). Four relatively unexplored compounds also scored well with rapamycin.”  

Their initial list of over 800 natural compounds was condensed to a shortlist of candidate nutraceuticals that showed similarity to metformin and rapamycin and had low adverse effects. 

“This work revealed promising candidates for future experimental validation while demonstrating the applications of powerful screening methods for this and similar endeavors.”

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

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.

Aging is a proud participant in the AACR Annual Meeting 2021 #AACR21

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

Rapamycin Rules out DNA Damage Theory of Aging

Dr. Mikhail Blagosklonny gleans an important new discovery in aging research—deduced from recent studies on short-lived mice and rapamycin.

3D illustration of a mutated or damaged DNA strand

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The exact mechanisms at play in the human aging process are still up for debate. A number of great minds in science have proposed plausible aging mechanisms and theories, such as DNA damage, telomere shortening, and DNA damage theories of aging. DNA damage theories suggest that aging is functional decline, caused by the accumulation of molecular damage. However, some scientists counterclaim that neither DNA damage nor telomere shortening limit lifespan or cause aging.

Dr. Mikhail Blagosklonny—an adjunct faculty member at the Roswell Park Comprehensive Cancer Center and Editor-in-Chief at Aging, Oncotarget, Oncoscience, and Cell Cycle—gleaned an important new perspective from recent aging studies, which could have been overlooked. He expanded on this discovery in a recent research perspective that was published in February 2021 in an issue of Aging, entitled: “DNA- and telomere-damage does not limit lifespan: evidence from rapamycin.” To date, this research paper has generated an Altmetric Attention score of 43.

Rapamycin is a macrolide antibiotic that has immunosuppressive properties, regulates a key cellular growth pathway (mTOR), and has been at the center of numerous studies of aging since its discovery in 1964. Dr. Blagosklonny explains that, based on findings from recent mouse-model studies of rapamycin’s effects on short-lived mice, normal aging is not caused by the accumulation of molecular damage or telomere shortening.

“Here I discussed new evidence that normal aging is not caused by accumulation of molecular damage or telomere shortening: while extending normal lifespan in mice, rapamycin failed to do so in mice dying from molecular damage (Figure 1).”

Evidence From Rapamycin

In the study which Dr. Blagosklonny refers to, researchers genetically modified mice to artificially shorten telomeres, administered rapamycin to normal mice and the telomerase-deficient short-lived mice, and observed the effects. In normal mice, results were congruent with a number of other studies that found lifespan was significantly extended. In the telomerase-deficient mice, lifespan was shortened as a result of rapamycin. 

“While shortening lifespan by 18% in unnatural telomerase-deficient mice, in the same study in natural mice, rapamycin increased lifespan by 39% and healthspan by 58% (measured as tumor-free survival) [3].”

Given that rapamycin prolongs life in normal mice, Dr. Blagosklonny asserts that this study proves that normal lifespan is not constrained by telomere length. Telomeres only become life-limiting when they are artificially shortened to the point where rapamycin can no longer extend lifespan. Furthermore, Dr. Blagosklonny explains that although molecular damage and telomere shortening could be life-limiting, they ultimately do not limit life because quasi-programmed aging occurs at a faster rate.

“Although molecular damage accumulates, this accumulation is not life-limiting because quasi-programmed aging terminates life first (Figure 1A). Quasi-programmed (hyperfunctional) aging is life-limiting, because it is favored by natural selection.”

Quasi-Programmed (Hyperfunctional) Aging

In 2012, Dr. Blagosklonny wrote another widely-read research perspective that explains in great detail what his proposed hyperfunction theory of aging is, entitled, “Answering the ultimate question “What is the Proximal Cause of Aging?

“According to hyperfunction theory, aging is quasi-programmed, a continuation of developmental growth programs, driven in part by hyper-functional signaling pathways including the mTOR pathway [9].”

He explains that hyperfunction is an excessive, yet normal function that occurs later in life. Hyperfunction in this context does not necessarily mean an increase in function and, in some cases, it even means a decrease in function. The same pathways and functions that drive growth and development earlier in life, also drive age-related diseases later in life. Dr. Blagosklonny proposes that quasi-programmed (hyperfunctional) aging is favored by natural selection and is what limits life.

“It is hyperfunctional signaling pathways such as mTOR (one of many) that drive both growth and aging, causing age-related diseases that in turn damage organs, leading to secondary loss of function.”

Many signaling pathways interact with mTOR to drive aging, forming a network, including MEK/MAPK, NF-kB, p63, HIF-1, and many others. Dr. Blagosklonny suggests that, in theory, there could be a number of mTOR-independent factors of quasi-programmed aging that are life-limiting, as well. He goes on to exemplify several lines of evidence concluding that it is not molecular damage that causes normal aging or limits life—it is normal, quasi-programmed (hyperfunctional) aging.

Conclusion

Dr. Blagosklonny mentions a forthcoming review that will be entitled: “When longevity drugs do not increase longevity: Unifying development-driven and damage-induced theories of aging.”

“Once again, damage accumulates and must cause death eventually, but quasi-programmed (hyperfunctional) aging terminates life first. Molecular damage can become life-limiting, when artificially accelerated or, potentially, when quasi-programmed aging is decelerated.” 

Click here to read the full research perspective, published in Aging.

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.

Aging is a proud participant in the AACR Annual Meeting 2021 #AACR21
Aging is a proud participant in the AACR Annual Meeting 2021 #AACR21
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