“In January 2023, diagnosed with numerous metastases of lung cancer in my brain, I felt that I must accomplish a mission. If everything happens for a reason, my cancer, in particular, I must find out how metastatic cancer can be treated with curative intent. This is my mission now, and the reason I was ever born. In January 2023, I understood the meaning of life, of my life. I was born to write this article. In this article, I argue that monotherapy with targeted drugs, even when used in sequence, cannot cure metastatic cancer. However, preemptive combinations of targeted drugs may, in theory, cure incurable cancer. Also, I share insights on various topics, including rapamycin, an anti-aging drug that can delay but not prevent cancer, through my personal journey.”
Keywords: lung cancer, brain metastases, capmatinib, resistance, MET
AboutOncoscience:
Oncoscience is a peer-reviewed, open-access, traditional journal covering the rapidly growing field of cancer research, especially emergent topics not currently covered by other journals. This journal has a special mission: Freeing oncology from publication cost. It is free for the readers and the authors.
To learn more about Oncoscience, visit Oncoscience.us and connect with us on social media:
Dr. Mikhail Blagosklonny joins “Master One Thing” host Krister Kauppi to discuss the impact of his rapamycin research and hyperfunciton theory of aging.
The world’s leading Rapamycin researcher, Dr. Mikhail Blagosklonny, has a long background in cancer research and one important discovery he made around 2000 was that Rapamycin slowed down senescent cancer cells in different ways. After that step-by-step, his interest in the longevity field increased and he developed the very interesting hyperfunction theory of aging.
He has made a huge contribution in moving the Rapamycin longevity field forward and his research papers have impacted many people. For example, the Rapamycin physician Alan Green who – thanks to these papers – took the decision in 2017 to start prescribing Rapamycin off label. Today, Alan Green has the biggest clinical experience in the area with more than 1,200 patients. A lot of other physicians have after that also taken these steps and one of those, for example, is physician Peter Attia.
The podcast is for general information and educational purposes only and is not medical advice for you or others. The use of information and materials linked to the podcast is at the users own risk. Always consult your physician with anything you do regarding your health or medical condition.
In his recent paper, Dr. Mikhail Blagosklonny explains his perspective on the current landscape of anti-aging drug studies, a key differentiation between healthspan and lifespan variables, and the next steps for human use of anti-aging drugs—beyond clinical trials.
Aging in humans seems as natural as aging in leaves—but is it necessary?
Listen to an audio version of this article
The process of human aging is a fascinating mystery. Despite all that we do not know, a handful of researchers have dedicated recent decades to the exciting beginnings of solving this biological riddle. One such researcher is Dr. Mikhail Blagosklonny. As a professor of oncology at the Roswell Park Cancer Institute in Buffalo, New York, and Editor-in-Chief at the AgingandOncotarget journals, Dr. Blagosklonny’s mission is to prevent cancer (and other age-related diseases) by inhibiting the aging process—preventing cancer by maintaining youth.
The cover paper chosen for Oncotarget’s Volume 12, Issue #3, is titled, “The goal of geroscience is life extension;” a research perspective written by Dr. Blagosklonny. In this compelling paper, he reflects on the history of anti-aging studies, the differences between drugs that enhance healthspan versus lifespan, and next steps in the human application of anti-aging drugs.
Hyperfunction Theory of Aging
“According to the geroscience hypothesis, aging is a risk factor for diseases [127]. According to hyperfunction theory, in contrast, aging is a sum of all age-related diseases, not their risk factors.”
Dr. Blagosklonny defines aging as a continuation of human development, driven partially by growth-promoting pathways which drive age-related diseases—he has coined this as the hyperfunction theory.
“Hyperfunction (inappropriate activation) of these signaling pathways directly drive all age-related diseases, which are manifestations of aging. We just need clinically available inhibitors (drugs) of these signaling pathways to extend both healthspan and lifespan, by slowing aging.”
Increasing Lifespan via Increasing Healthspan
Before beginning his interpretation of data from previous anti-aging research studies, Dr. Blagosklonny emphasises the importance of correctly measuring healthspan and lifespan. As indicated in his paper title, the goal of geroscience is to extend lifespan by way of extending overall healthspan.
“Healthspan is a period of life without age-related diseases [27]. It is disease-free survival.”
Healthspan can be difficult to measure due to the nature and hidden course of many diseases. If one particular disease is subdued by treatment in a study and healthspan appears to be increased (through one marker of health or another), this does not guarantee that other age-related diseases have been nullified by this treatment. Dr. Blagosklonny explains that accurate measurements of healthspan are important because, based on the hyperfunction theory, aging is the sum of all age-related diseases.
“After all, aging is an exponential increase of death with age and should be measured by deadly diseases.”
Another point he makes is that many anti-aging drug trials have presented results finding increased healthspan in mice without demonstrating an increase in lifespan. Given that increased healthspan should always lead to increased lifespan, it is not sufficient to only measure healthspan without measuring lifespan in animal studies of anti-aging drugs. If lifespan is not increased, the drug does not demonstrate longevity or anti-aging properties.
“So how is it possible that some senolytics, NAD boosters and resveratrol, increase healthspan without lifespan? The simplest explanation is that they do not increase healthspan at all, because such studies use irrelevant or ambiguous markers of health.”
Over the years, numerous initially promising anti-aging drugs have been tested and debunked by researchers. No compound has continued to withstand the many tests, or has delivered consistent results, quite like the unique bacterium, rapamycin.
Anti-aging Properties in Rapamycin
Rapamycin was discovered in 1964 in a test tube sample of dirt taken from Easter Island—a highly remote volcanic island in the Pacific ocean, west of Chile. Initially looking for antibiotics (often uncovered in the dirt) researchers found the rapamycin bacteria unexpectedly. To their surprise, this new bacteria created a defensive chemical with the ability to affect the activity of a protein and homeostatic ATP sensor called the mammalian target of rapamycin, or mTOR. mTOR is now known to function in regulatory pathways that are responsible for governing cell growth.
“It was predicted that rapamycin must extend lifespan before it was shown in any animal [105].”
In 1999, rapamycin was FDA approved to regulate hyperimmunity in transplant patients to help enable their immune system to accept a new organ. Since then, rapamycin’s ability to slow cell growth and proliferation has been widely accepted as an anticancer agent and the focus of anti-aging studies in a number of mouse-modeled trials.
“Since 2009, dozens of studies have shown that rapamycin extends medium and maximum lifespan in both males and females in all strains of normal mice tested, as well as in some cancer-prone and short-lived mice [36, 40–70].
Other Drugs With and Without Anti-aging Potential
In this paper, Dr. Blagosklonny categorizes a list of seemingly debunked anti-aging drugs with little or no results, including antioxidants, resveratrol, curcumin, quercetin (used alone), and spermidine. He explains that some of these drugs may have potential when used in combination with other drugs in future studies.
He acknowledges potential in berberine (one study found promising initial results), fisetin (clinically available and safe for human use), 17-alpha-estradiol (only results in male mice thus far), acarbose (blocks digestion of complex carbs), enalapril (decreases oxidative damage), losartan (angiotensin receptor blocker), quercetin with dasatinib (clinically available and safe for human use), and metformin.
“Some life-extending drugs are already approved for human use: supplements (fisetin, vitamin B3 and its analogs), over-the-counter medicine (aspirin) and prescription drugs (rapamycin, metformin, dasatinib, enilopril).”
Dr. Blagosklonny recalls a famous study of metformin where, at a low doses, it increased lifespan in male mice and, at high doses, it ironically decreased lifespan. Metformin was also tested with rapamycin in this study and demonstrated improved results in extending lifespan.
“Yet, a combination of metformin and rapamycin should be re-tested to include a rapamycin-alone group.”
Conclusion
“I expect that a combination of low doses of pan-mTOR and MEK inhibitors with high doses of rapamycin would extend life further compared with rapamycin alone. That could be the next important advance in the anti-aging field since the discovery of anti-aging properties of rapamycin.”
Dr. Blagosklonny believes that researchers should not wait for the lifespan results of clinical trials in humans to begin widespread application of these drugs, since studies already safely display increased lifespan and longevity in mouse models. He is so convinced by rapamycin that Dr. Blagosklonny is currently taking 10 milligrams of rapamycin per week along with his personalized treatment plan, a ketogenic diet, and exercise to jumpstart the next phase of human anti-aging trials within our lifetime. He notes that medical doctors interested in this topic may email Blagosklonny@rapalogs.com or follow him on Twitter @Blagosklonny.
“This article does not represent medical advice or recommendations to patients. The media should exercise caution and seek expert medical advice for interpretation when referring to this article.”
Oncotargetis a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues, and other researchers, far and wide.
As you may know, Oncotarget is a scientific journal that publishes oncology-focused review and research papers every week on its open access platform — available at no cost to readers. Recently, a new Special Collections series debuted, and the first collection launched in honor of breast cancer awareness.
What makes our collections special?
Oncotarget carefully selects the most credible and insightful studies to publish on Oncotarget.com, while also choosing papers that link different fields of oncology, cancer research, and biomedical sciences together to eliminate borders between specialties. The term “oncotarget” encompasses all molecules, pathways, cellular functions, cell types, and tissues that can be viewed as targets relevant to cancer, as well as other diseases. This journal is a resource for oncology researchers and the larger scientific community.
Before a study is published in Oncotarget, selected papers are meticulously peer-reviewed by an editorial board of award-winning scientific editors from academic universities and institutions well-known for their excellence and precision. Click here for a complete list of Oncotarget Editorial Board members.
Breast cancer research
Each year, over 40,000 women and men lose the fight against breast cancer in the United States. After skin cancer, breast cancer is the most commonly diagnosed cancer in women. The spread of breast cancer awareness and increase in research funding has helped develop advances and discoveries in the diagnosis and treatment of this proliferous cancer.
The new Special Collections by Oncotarget are yet another tool researchers and science readers alike may use as a resource to learn more about breast cancer. The creators of these collections also hope that they may be used by scientists to discover new biomarkers, mechanisms, and therapies to improve our quality of life and better treat cancer and diseases.
Click here to explore the Special Collection on breast cancer.
A recent breakthrough medical study has revealed that exercise has been proven to combat breast cancer. The paper, entitled “Anticancer effect of physical activity is mediated by modulation of extracellular microRNA in blood,” was recently published in a June 2020 issue of the free online open-access medical journal Oncotarget. It was authored by an international team of medical researchers, headed by Dr. Alessandra Pulliero of the University of Genoa in Italy, and included Doctors Ming You, Pradeep Chaluvally-Raghavan, Barbara Marengo, Cinzia Domenicotti, Barbara Banelli, Paolo Degan, Luigi Molfetta, Fabio Gianiorio, and Alberto Izzotti.
While previous
medical studies have shown that physical activity reduces the risk of cancer,
particularly breast cancer, it’s been a mystery up to now exactly how this
happens. Medical researchers have long suspected that this healing process is
triggered by microRNAs, cellular fragments of RNA (ribonucleic acid) also known
as miRNAs.
What’s RNA?
Like DNA (deoxyribonucleic acid), RNA is one of the building blocks of life. It
acts as a messenger transmitting instructions that control the synthesis of
proteins. MicroRNAs stop a particular protein from being produced by binding
to, and then destroying, the messenger RNA that would have produced this
protein.
It is known
that miRNAs are incredibly important when it comes to carcinogenesis (the
creation of cancer) and cancer outcomes. In addition, MiRNAs regulate the creation
of muscle tissueand muscle mass,
and it’s been learned that structured exercise controls the creation of miRNA,
especially in skeletal muscle.
The research
team endeavored to test how exercise in breast cancer patients changed the
production of miRNA in their bodies. To begin, 30 women from northern Italy
between 54 and 78 years old walked for 45 minutes on the treadmill under
identical conditions. Blood samples were taken from them both before and after
the exercise sessions.
THE RESULTS
A technique
known as microarray analysis revealed that structured exercise modified 14
different extracellular miRNAs related to cancer. Structured exercise caused
all these miRNAs to decrease, except for a miRNA called miR-206, which
increased. The researchers discovered that the most striking effects induced by
exercise were changes in two miRNAs involved in breast cancer progression.
When the
researchers investigated the biological effects of these two miRNAs on human
breast cancer cells, they conclusively learned that working together, the
changes in these two microRNAs activated by a physical exercise program
suppressed breast cancer cells. Since too many miRNAs are linked to triggering
inflammation and the creation of lymphocytes (white blood cells in the lymph
system, which can influence breast cancer), the researchers also believe that
structured exercise might reduce inflammation by modulating miRNA in the blood.
They also found
that structured exercise improved blood pressure and glucose levels (cancerous
tumors feed on glucose) among participants. The doctors discovered that these
improvements in blood pressure and glucose levels helped regulate the miRNAs
being studied, and in turn helped the miRNAs combat cancer.
This
international team of researchers is confident that by testing for the levels
of these miRNAs in patients’ blood, they’ve achieved a non-invasive way of
establishing biomarkers (a measurable sign of whether a disease is present or
how severe it is) to prevent breast cancer. This is potentially a significant
breakthrough in breast cancer prevention and treatment.
As a result of
this study, the medical community now knows that structured exercise fights
breast cancer, and it’s been given a non-invasive way to diagnose and battle breast
cancer—and possibly other forms of cancers as well.
ABOUT ONCOTARGET
This important study was able to be published, and noticed so quickly, because it was made available by Impact Journals’ free, open-access cancer research journal Oncotarget. Currently, over 20,000 Oncotarget papers are also searchable on PubMed, a widely used free search engine for life sciences and biomedical research.
Because Oncotargetis open-access, it is free for everyone in the world to read. Most medical journals charge authors for publishing their work, and then in turn charge readers to access what could be all-important, life-saving information. With its revolutionary publishing model, Impact Journals, through publications like Oncotarget, makes it easy for anyone with important medical discoveries to communicate them to the public in the fastest and most effective way possible—possibly saving, prolonging, and improving many people’s lives in the process.
With the goal
of a life without disease, Impact Journals allows scientists to share their
exceptional discoveries, offers services that enable rapid dissemination of
results, and presents vital findings from the many fields of biomedical
science. It shares scientific findings through a comprehensive publication
process entailing peer review, manuscript preparation, and publication
promotion.
In addition, Oncotarget is well-known for publishing papers by Nobel Prize winners. The 2019 Nobel Prize in Physiology or Medicine was awarded jointly to Oncotarget Editorial Board members William G. Kaelin Jr., and Gregg L. Semenza for their discoveries of “how cells sense and adapt to oxygen availability,” which can help us understand and potentially treat a range of conditions like cancer, heart attack, stroke, and anemia. (They shared the Prize with UK physician-scientist Sir Peter J. Ratcliffe.) Both William G. Kaelin and Gregg L. Semenza are founding members of Oncotarget, where Gregg L. Semenza has published eight papers.
Another notable Oncotarget Nobel Prize winner is endocrinologist Andrew V. Schally, a member of Oncotarget’s Editorial Board who won the Nobel Prize in Physiology or Medicine in 1977 and who has published 12 papers in Oncotarget. Of Oncotarget’s work, he remarked: “Oncotarget is an outstanding and most important journal in the field of oncology and cancer research. Oncotarget is performing an extremely useful function for those of us working not only in cancer research, but also on other important topics in the field of medicine. Oncotarget deserves strong support from investigators working in the area of oncology as well as from the National Institutes of Health (NIH).”
If you would like to be first to learn about some of the most exciting new discoveries in medical science, consider investigating the groundbreaking work being published by Impact Journals, including its flagship publication, Oncotarget.
