From rapalogs to anti-aging formula

Mikhail V. Blagosklonny

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Abstract

Inhibitors of mTOR, including clinically available rapalogs such as rapamycin (Sirolimus) and Everolimus, are gerosuppressants, which suppress cellular senescence. Rapamycin slows aging and extends life span in a variety of species from worm to mammals. Rapalogs can prevent age-related diseases, including cancer, atherosclerosis, obesity, neurodegeneration and retinopathy and potentially rejuvenate stem cells, immunity and metabolism. Here, I further suggest how rapamycin can be combined with metformin, inhibitors of angiotensin II signaling (Losartan, Lisinopril), statins (simvastatin, atorvastatin), propranolol, aspirin and a PDE5 inhibitor. Rational combinations of these drugs with physical exercise and an anti-aging diet (Koschei formula) can maximize their anti-aging effects and decrease side effects.

Keywords: lifespan, longevity, rejuvenation, health, diseases

At first, the discovery of anti-aging properties of rapamycin was met with skepticism because it challenged the dogma that aging is a decline driven by molecular damage caused by free radicals. By now, rapamycin has been proven to be an anti-aging drug. In contrast, anti-oxidants failed in clinical trials [1–9] and the dogma was shattered [1, 2, 10–18]. In the last decade, anti-aging effects of rapamycin have been confirmed. Anti-aging doses and schedules can be extrapolated from animal studies. Well-tolerated doses with minimal side effects can be deducted based on clinical use of rapalogs. So optimal anti-aging doses/schedules can be suggested. Given that rapamycin consistently extends maximal lifespan in mice, rapamycin will likely allow mankind to beat the current record of human longevity, which is 122 years. Yet, rapamycin will not extend life span as much as we might wish to.

Now is the time for anti-aging drug combinations. For example, metformin is currently undergoing re-purposing as an anti-aging agent. Several other existing drugs can be re-purposed. Now we can design an anti-aging formula, using drugs available for human use. However, we must first discuss the link between growth, aging and age-related diseases.

MTOR: from growth to aging

It was theoretically predicted that stimulation of mitogenic/growth pathways in arrested or quiescent cells must lead to senescence [19]. This conversion from quiescence to senescence is called geroconversion [20–22]. Cellular senescence is a futile growth, a continuation of cellular growth when actual growth is restricted [21, 23, 24]. Growth-stimulation of arrested cells causes their hypertrophy and hyperfunctions (for example, hyper-secretory phenotype or SASP in senescent fibroblasts).

This can be applied to organismal aging. When developmental growth is completed, then mTOR (mammalian Target of Rapamycin) and some other signaling pathways) drives organismal aging [1, 15, 25, 26]. These pathways stimulate cellular functions, leading to hyperfunctions (for example, hypertension). Secondary, hyperfunctions can lead to loss of functions [1, 27]. Hyperfunction theory links growth, aging and age-related diseases [1]. Suppression of aging prevents or delays age-related diseases [17, 28–30].

Age-related diseases are manifestations of advanced aging

Age-related pathologies and conditions include atherosclerosis, hypertension, osteoporosis, obesity, insulin-resistance and type II diabetes, cancer, macular degeneration, Parkinson and Alzheimer's diseases as well as menopause in women, and many changes in the appearance that are not called diseases (baldness, for example) and presbyopia (a condition that resembles nearsightedness). Stroke, myocardial infarction, heart fibrillation, broken hip, renal and other organs failure are consequences of age-related pathology [17, 28, 31].

In brief, age-related diseases are both manifestations of advanced aging and causes of death. Aging is the sum of age-related diseases, syndromes and symptoms ranging from wrinkles and presbyopia to stroke and cancer metastasis. Of course, age-related diseases can occur in young patients with either genetic predisposition or due to environmental hazards. However, each of these diseases will develop in the aging organism, even without any predispositions and hazards, if the organism would live long enough. Since aging is not programmed, these diseases develop at different speeds. For example, menopause (in women) and presbyopia develop fast and strike all aging humans. Whereas, Alzheimer disease develops slowly and an elderly person can die from cancer or stroke before Alzheimer disease takes place [17, 28].

In brief, animals die from age-related diseases, which are manifestations of advanced aging (Figure ​(Figure1).1). If a drug delays ALL age-related diseases, it is a classic anti-aging drug because it will extend life span by delaying causes of death.

Figure 1

Schema of aging and its pharmacological suppression

Aging is an increase in the probability of death. Aging is a continuation of developmental growth, when the development is stopped but signaling pathways (such as mTOR) remain active. Chronic cellular overactivation increases cellular functions (secretion, synthesis, metabolism, contraction, aggregation, lipid accumulation and so on), leading to systemic hyperfuntions such as hypertension and other diseases of aging. Hyperfunction, manifested as age-related diseases, causes organ damage and loss of functions. Aging consists from subclinical hyperfunction, diseases and loss of function/organ failure. Anti-aging drugs inhibit signaling pathways, decreasing hyperfunction, slowing down aging and delaying diseases and death. The most important drugs are shown in larger fonts.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482593/

When people mention today’s medicine, accuracy plays one of the most important roles and human lives are directly dependent on it. Hence, any researches related to medicine are necessary to comply with the highest standards. The issue nowadays is that any results of researches can be posted online and used as a reference without being precisely checked and approved. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this problem and decided to generate an alternative solution. That’s how a weekly oncology-focused research journal named “Oncotarget” has been founded back in 2010. The major principle of this journal is based on Altmetric scores that are used as a quality measure. That allows both readers and authors to quality-check publications with Altmetric Article Reports that provide “real-time feedback containing data summary related to a particular publication.” Oncotarget website provides a complete publications list with respective scores higher than 100 as well as reports mentioned previously. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it provides the required assistance to anybody, who has interest in oncology.
http://www.impactjournals.com/oncoscience/index.php?board
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This article was published back in 2018 by Oncotarget and written by diversified experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study discusses “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The article has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that majority of readers are willing to understand the very meaning of it. Based on the Altmetric website, the score relates to “how many people have been exposed to and engaged with a scholarly output.” Hereby, the publication about melanoma, was used for citations in various news articles 69 times. In addition, it was mentioned in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their news on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study
Another Oncotarget’s study with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This study has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have come across a short overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do receive useful scientific facts. Oncotarget is proud to have the ability to share with online customers this highly appreciated and high-quality information, that is trustworthy and reliable.
https://en.wikipedia.org/wiki/Mikhail_Blagosklonny