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.

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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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 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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Risks for Dementia and Mortality: Sleep Disturbance and Deficiency

Researchers used nationally representative data to examine the relationship between sleep disturbance and deficiency and their risk for incident dementia and all-cause mortality among older adults.

Person sleeping in bed and alarm clock in the foreground
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Are serious health consequences looming for those with trouble sleeping? Based on a large sum of available research, the answer appears to be yes—poor sleep poses an increased risk of dementia and all-cause mortality. But what defines poor sleep? Conflicting results have been reported by researchers regarding the characteristics of sleep when examining incident dementia and all-cause mortality. For instance, one meta-analysis suggests that sleeping fewer than five hours (short sleep) and longer than nine hours (long sleep) per night is associated with greater risk of mortality. Another meta-analysis finds that only longer than nine hours is associated with greater risk of mortality.

“Research on sleep disturbance and deficiency and all-cause mortality therefore has shown conflicting results. Further, few studies have included a comprehensive set of sleep characteristics in a single examination of incident dementia and all-cause mortality.” 

From Brigham and Women’s Hospital, Harvard Medical School, and Boston College, based out of Massachusetts, United States, a team of researchers saw the need to address the gaps in this research and developed a new study. They organized a single examination of the relationships between a comprehensive set of sleep characteristics and incident dementia and all-cause mortality. This paper was entitled, “Examining sleep deficiency and disturbance and their risk for incident dementia and all-cause mortality in older adults across 5 years in the United States,” and published in Aging’s Volume 13, Issue 3 in February 2021.

The Study

The researchers collected baseline data from the National Health and Aging Trends Study (NHATS). The NHATS is a nationally-representative longitudinal study of Medicare beneficiaries (65 years and older) in the United States. The data were collected from a randomly selected subset of 2,812 participants from the NHATS population that were administered sleep questionnaires in 2013 and 2014.

“Participants with dementia at baseline (year 2013) were excluded (n = 202) for a sample of 2,812 with sleep data in either 2013 or 2014.”

The sleep characteristics measured from the questionnaire were: sleep duration, sleep latency, difficulty maintaining alertness, sleep quality, napping frequency, and snoring. First, participants rated their memory and performed a memory-related activity to assess their cognitive capacity and screen for incident dementia. Body weight was reported by participants annually, and diagnosis of heart attack, heart disease, hypertension, arthritis, diabetes, stroke, and cancer were also self-reported. Annual interviews were conducted to record instances of participant mortality. The researchers used Cox proportional hazards modeling and controlled for confounders to examine each sleep characteristic and outcome.


“Overall, our findings show a strong relationship between several sleep disturbance and deficiency variables and incident dementia over time.”

In the results adjusted for confounders, the team found that longer time to fall asleep and shorter sleep duration predicted incident dementia. They also found that short sleep duration, difficulty maintaining alertness, napping, and poor sleep quality predicted all-cause mortality. Given that short sleep duration was a strong predictor for both incident dementia and all-cause mortality, the researchers suggest that this may be the most important sleep characteristic related to adverse outcomes among older adults. 

“The association observed in our study between short sleep (5 hours or less) and incident dementia screening may be understood via the research drawing upon animal models to demonstrate brain toxin removal during sleep [24].”

Another fascinating finding from this study was the difference between unadjusted and adjusted results for long sleep. As mentioned, previous studies have shown that long sleep is associated with both incident dementia and all-cause mortality. However, after the researchers adjusted for confounders, such as age and chronic conditions, the association between long sleep and incident dementia and all-cause mortality disappeared. The relationship between short sleep and both incident dementia and all-cause mortality remained significant even after full adjustment. These findings stand in contrast to the meta-analyses initially mentioned that have found associations between both short and long sleep and all-cause mortality in adults. The researchers suggest the cause may be that long sleep is a reflection of underlying disease.

“The most parsimonious explanation for the disappearance of the effect of long sleep on dementia and mortality in adjusted models is that the deleterious impact of long sleep is a reflection of underlying disease.”


The researchers confirm that addressing the sleep disturbance and deficiency variables in this study may have a positive impact on risk for incident dementia and all-cause mortality among older adults.

“Also, future research may consider the development of novel behavioral interventions to improve sleep among older adults.”

Click here to read the full study, published on

Aging is an online 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 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 [email protected].

Participating in the 2021 AACR Annual Meeting: Aging (by Impact Journals)

As the world continues to account for COVID-19, this year the American Association for Cancer Research (AACR) Annual Meeting will be a virtual event. Aging, by Impact Journals, is proud to be a participant in the conference on April 10-15 and May 17-21, 2021.

As the world continues to account for COVID-19, this year the American Association for Cancer Research (AACR) Annual Meeting will be a virtual event. Aging, by Impact Journals, is proud to be a participant in the conference on April 10-15 and May 17-21, 2021.
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BUFFALO, NY-MARCH 25, 2021 – Aging is indexed by PubMed/Medline abbreviated as “Aging (Albany NY)”, PubMed Central, ISI/Web of Science: Science Citation Index Expanded (abbreviated as Aging‑US and listed in the Cell Biology category; since June 2017 it has also been listed in the Geriatrics & Gerontology category), and Scopus /Rank Q1 (abbreviated as Aging).

Every year, the American Association for Cancer Research (AACR) organizes a conference program that covers the latest discoveries in cancer research. Topics include population science and prevention, cancer biology, translational and clinical studies, survivorship, and advocacy. This conference aims to highlight work from the best minds in research and medicine from institutions all over the world. The journal Aging, by Impact Journals, will be participating at the AACR Annual Meeting this year. 

Impact Journals is an open-access publisher of rigorously peer-reviewed scientific literature, and owns four medical research journals, including Aging. Aging was launched by Impact Journals in 2009 with the goal of spotlighting high-impact papers, authored by scientists who study the process of aging and age-related diseases—including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. 

Aging has published outstanding papers and reviews by highly-cited authors and award winners, including Andrew V. Schally (Nobel Laureate), Shinya Yamanaka (Nobel Laureate), Lawrence Donehower, Toren Finkel, Stephen Helfand, Gerald Shadel, Andre Nussenzweig, Maurice Burg, Karen Vousden, Leonard Guarente, and Dale Bredesen. Importantly, the Aging Editorial Board also comprises numerous prestigious award winners, including Nobel Laureate Elizabeth H. Blackburn, and many other distinguished scientists, including Cynthia Kenyon, Judith Campisi, Leonard Guarente, Michael Hall, Mikhail Blagosklonny, Vera Gorbunova, David Sinclair, Jan Vijg, and Thomas Rando. 

The journal has recently concluded its 12th year of publishing and has become Impact Journals’ featured journal. Learn more about Aging and Impact Journals at the virtual 2021 AACR conference on April 10-15 and May 17-21, 2021. Registration will be open through the beginning of the event.

About Aging

To learn more about Aging, its publication standards, and past or current issues, visit

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About Impact Journals:

Impact Journals is an open-access publisher with four scientific journals: Aging, Oncotarget, Genes & Cancer, and Oncoscience. Our mission to provide scientists with the opportunity to share their exceptional discoveries, offer services that enable rapid dissemination of results, and to present vital findings from the many fields of biomedical science. Our goal is life without disease.

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Pressurized Oxygen Therapy Can Reverse Mechanisms of Aging

For the first time, researchers demonstrate that hyperbaric oxygen therapy can reverse the mechanisms that mark the aging process.

Oxygen molecules and erythrocytes floating in a vessel in the blood stream.
Oxygen molecules and erythrocytes floating in a vessel in the blood stream.
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Aging is the progressive loss of physiological integrity, which results in impaired functionality and increased susceptibility to diseases, and ultimately death. For the first time, researchers collaborated in an in vivo study to observe the effects of hyperbaric oxygen therapy on cellular mechanisms to reverse aging.

Researchers based out of Israel from Shamir Medical Center, Tel-Aviv University, and Bar Ilan University published a groundbreaking new paper titled, “Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells : a prospective trial,” in the open access journal, Aging. The importance of this study hinges on understanding the mechanisms of aging that were evaluated by the researchers.

“At the cellular level, two key hallmarks of the aging process include telomere length (TL) shortening and cellular senescence.”

Telomere Length

Telomeres (TLs) function to protect chromosomes from DNA damage and are located at the end of the chromosome. In each instance of cell division, the telomeres shorten due to an inherent inability to fully replicate the DNA strand. Given that cells can only replicate a finite number of times before they can no longer engage in mitosis, the shortening of telomeres has been shown in adults to lead to increased rates of mortality.

Researchers in this study also provide examples of studies that are finding a number of pharmacological agents capable of reducing the shortening rate of telomeres.

“Shortened TLs can be a direct inherited trait, but several environmental factors have also been associated with shortening TL, including stress, lack of physical endurance activity, excess body mass index, smoking, chronic inflammation, vitamins deficiency, and oxidative stress [2, 8, 9].”

Cellular Senescence

The other hallmark mechanism of the aging process is cellular senescence. Previously, senescent cells have been viewed as mechanisms that protect the body against cancer through cell-cycle arrest, however, recent discoveries have found that they also have a role in processes such as development, tissue repair, aging, and age-related disorders. The phase of senescence can be triggered by telomere shortening and other non-telomeric DNA damage.

“The primary purpose of senescence is to prevent propagation of damaged cells by triggering their elimination via the immune system. The accumulation of senescent cells with aging reflects either an increase in the generation of these cells and/or a decrease in their clearance, which in turn aggravates the damage and contributes to aging [1].”

Oxidative Stress

In this well-written paper, the researchers introduce the topic by citing numerous interventional studies measuring the association between telomere length and lifestyle modifications. Studies include the measuring of diet, supplements, physical activity, stress management, and social support. However, the team found that the most common mechanism associated with telomere shortening is oxidative stress.

“Oxidative stress can occur from imbalances between the production of reactive oxygen species (ROS) and cellular scavengers.”

Previous studies indicate that telomeres are highly sensitive to oxidative DNA damage which occurs due to an excess of reactive oxygen species (ROS), or molecular oxygen by-products. The excess formation of these ROS occurs through the sequential reduction of oxygen via the addition of electrons and a lack of scavenger cells to digest excess microorganisms. This leads to the shortening of telomeres.

Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy (HBOT) has been observed to stimulate brain function and increase cognitive ability in previous studies. HBOT involves patients breathing in 100% oxygen in a pressurized chamber on a repeated basis. Being in this type of environment increases the amount of oxygen that is dissolved in the blood and tissue. Increasing oxygen levels in the body using pure oxygen on a daily basis can induce the hormesis phenomenon. This eustress type of therapy has been shown to have beneficial and positive effects on the body and mind.

“Single exposures [to HBOT] increase ROS generation acutely, triggering the antioxidant response, and with repeated exposures, the response becomes protective [13, 18].”

The Study

This study was designed to evaluate the effects of HBOT on the telomeres and concentrations of senescent cells in aging/healthy adults. Thirty-five participants living independently at 64+ years of age received HBOT exposures daily, over the course of 60 days.

Researchers collected whole blood samples prior to intervention (baseline), at the 30th and 60th session, and 1-2 weeks after the last HBOT session. They assessed the telomere lengths and senescence of peripheral blood mononuclear cells (PBMCs) in each participant’s blood sample.

Figure 3. Senescent cell changes with HBOT.
Figure 3. Senescent cell changes with HBOT.

“In this study, for the first time in humans, it was found that repeated daily HBOT sessions can increase PBMC telomere length by more than 20% in an aging population, with B cells having the most striking change. In addition, HBOT decreased the number of senescent cells by 10-37%, with T helper senescent cells being the most affected.”


Following HBOT, telomere lengths increased by over 20% in T helper, T cytotoxic, natural killer, and B cells. There was also a significant decrease in the number of senescent T cytotoxic and T helper cells observed in the participant blood samples, allowing for new healthy cells to regenerate.

“In conclusion, the study indicates that HBOT may induce significant senolytic effects including significantly increasing telomere length and clearance of senescent cells in the aging populations.”

Click here to read the full scientific paper, published in Aging.

Learn more about Hyperbaric Oxygen Therapy (HBOT)

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 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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