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The 2022 “New Hallmarks of Ageing” Research Symposium

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

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

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

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

The “New Hallmarks of Ageing” 2022 Symposium

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

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

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

The Meeting Report

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

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

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

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

Conclusion

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

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

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

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

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

For media inquiries, please contact [email protected]

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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.

YOU MAY ALSO LIKE: MORE AGING VIDEOS ON LABTUBE

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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 [email protected].

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Complex Drug Screenings Show Anti-Aging Potential in Natural Compounds

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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.

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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.

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

For media inquiries, please contact [email protected].

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