Why human lifespan is rapidly increasing: solving "longevity riddle" with "revealed-slow-aging" hypothesis. Mikhail V. Blagosklonny
Abstract
Healthy life span is rapidly increasing and human aging seems to be postponed. As recently exclaimed in Nature, these findings are so perplexing that they can be dubbed the 'longevity riddle'. To explain current increase in longevity, I discuss that certain genetic variants such as hyper-active mTOR (mTarget of Rapamycin) may increase survival early in life at the expense of accelerated aging. In other words, robustness and fast aging may be associated and slow-aging individuals died prematurely in the past. Therefore, until recently, mostly fast-aging individuals managed to survive into old age. The progress of civilization (especially 60 years ago) allowed slow-aging individuals to survive until old age, emerging as healthy centenarians now. I discuss why slow aging is manifested as postponed (healthy) aging, why the rate of deterioration is independent from aging and also entertain hypothetical use of rapamycin in different eras as well as the future of human longevity.
Unexpected increase in longevity
Death from aging is technically death from age-related diseases, which are manifestations of advanced aging [1]. But, historically, most people died young and, of course, not from age-related diseases but, rather, from starvation and epidemics (cholera, smallpox, tuberculosis and many currently rare infections) as well as from physical violence. Just three centuries ago, life expectancy was less than 16 years and 75% of people born in London in 1662 died before they reached the age of 26 (Graunt's life table). The progress of civilization eliminated many causes of death that killed young people in the past. This dramatically increased the average lifespan. In addition, modern medicine extended lifespan of old people by treating age-related diseases. But maximal lifespan seemed to be not affected. It was assumed that human life span is close to its upper limits. However, surprising demographists and gerontologists, it was shown that life expectancy continues to increase at an astonishing pace [2,3]. In the countries with the highest life expectancies, the long term increase in life expectancy proceeds at a pace of 2.5 years per 10 years, or six hours per day [4]. A century ago, the chance to become centenarian (a person older than 100 years) was a hundred times lower. Furthermore, as calculated, most babies born since 2000 in countries with long life expectancies will celebrate their 100th birthdays [5]. Most astonishingly, people are reaching very old age in better health. But then they deteriorate fast, seemingly indicating that the rate of aging was not changed but just aging was postponed [3]. "Taken together, these findings are so perplexing that they can be dubbed the ‘longevity riddle': why do the evolutionary forces that shaped human aging provide a license to alter the level of health but not the rate of debilitation?" [3]. So why can aging be delayed but not slowed? Or can aging be slowed? In order to solve the longevity riddle, we should turn gerontology on its head. It has been always assumed that aging is caused by damage. As recently argued, aging is not driven by damage, but, in contrast, leads to damage (organ damage) [6-8]. And aging is driven in part by mTOR (mammalian target of rapamycin).
Morbid phase
When diseases become clinical then deterioration may be fast. For example, high blood pressure, thrombosis and atherosclerosis can culminate in stroke. This will initiate a chain of deteriorations (immobility - pneumonia, etc.) that are TOR-independent. The duration of this morbid (deterioration) phase is almost solely determined by the level of medical care. Furthermore, age-related blindness and Alzheimer's disease are rarely lethal anymore. Medicine may dramatically prolong the morbidity phase, delaying death. Thus, the speed of deterioration is almost independent from the aging process and cannot serve as a marker of aging or the rate of aging. The rate of aging is actually determined by the age of the onset of age-related diseases. Slowing down the aging process (by calorie restriction, rapamycin or genetic manipulation) delays diseases.
"Thought experiment": how would rapamycin affect longevity in 1667 versus 1967
Rapamycin is an anti-aging drug, which is currently used to prevent donor organ rejections [16]. Rapamycin delays cancer in animals and humans (see for review [17]). It also delays other age-related diseases in animal models of accelerated diseases. For example, rapamycin and its analogs delay atherosclerosis [18-23]. mTOR is involved in age-related diseases exactly because it is involved in aging. In fact, rapamycin prolongs life span in mice and flies [24-27]. It is expected that, in adult humans, rapamycin (at correct doses and schedules) will prolong healthy and maximal lifespan [16]. But consider rapamycin administered for life, starting from childhood. Then its effect on longevity will depend on the level of civilization and will be opposite in the 17th and 20th centuries.
Scenario 1. Assume that in 1667, 3 out of 4 newborns were randomly prescribed rapamycin for life. Rapamycin would slow down developmental growth (a disadvantage for survival, especially for orphans). Malnutrition and stresses would be less tolerated, because the nutrient sensing pathway is deactivated by rapamycin. Reduced muscle mass and fat stores would increase chances of death from violence and famine. In infants with natural immunotolerance, rapamycin would further decrease immunity against infections, which were numerous, incurable and non-preventable in 17th century. So, if 3 out of 4 people must die before the age of 26 (1667 in London), they would be those who were treated with rapamycin. The control group would survive and develop diseases of aging at normal (early) age.
Scenario 2. In 20th century London, sanitation, vaccination and other measures have greatly reduced epidemics. The discovery of antibiotics has further prevented death from infections. Famine and violent death are not common either. Those who were treated with rapamycin for life will survive into adulthood and then will age slowly. In the rapamycin-treated group, diseases will be delayed. Furthermore, even its ability to cause immunologic tolerance (‘rejuvenate' immunity) will be beneficial in the elderly by decreasing hyper-immunity and autoimmunity. (Note: rapamycin improves immunity in old animals [28]). So, now, the rapamycin treated group becomes centenarians in good heath. But because deterioration is mTOR-independent, this group will deteriorate at the same rate (but later in life) as the control group, assuming that the medical treatment is equal in both groups (in reality, younger patients are treated more intensively.)
Mikhail (Misha) V. Blagosklonny graduated with an MD and PhD from First Pavlov State Medical University of St. Petersburg, Russia. Dr. Mikhail V. Blagosklonny has then immigrated to the United States, where he received the prestigious Fogarty Fellowship from the National Institutes of Health. During his fellowship in Leonard Neckers’ lab at the National Cancer Institute (NCI), he was a co-author of 18 publications on various biomedical themes, including targeting HSP90, p53, Bcl2, Erb2, and Raf-1. He also was the last author for a clinical phase I/II trial article.
After authoring seven papers during a brief yet productive senior research fellowship in the El-Deiry Cancer Research Lab at the University of Pennsylvania, Dr. Blagosklonny returned to NCI to work with Tito Fojo. Together, they published 26 papers. Moreover, Dr. Blagosklonny published many of experimental research papers and theoretical papers as sole author. The abovementioned sole-author articles discussed two crucial topics. The first of these discussed selectively killing cancer cells with deregulated cell cycle or drug resistance via verifying their resistance. The outcomes and underlying notion were so revolutionary that they were incorrectly cited by other scientists as “reversal of resistance,” even though the publication was titled, “Exploiting of drug resistance instead of its reversal.” One big supporter of this concept was the world-famous scientist Arthur Pardee, with whom Dr. Blagosklonny co-authored a joint publication in 2001.
The second theme throughout Dr. Blagosklonny’s sole-author articles is a research method to develop knowledge by bringing several facts together from seemingly irrelevant areas. This results in new notions with testable forecasts, which in turn can be “tested” via analyzing the literature further. Likewise, the concept was co-authored by Arthur Pardee in a 2002 article in Nature. The first success of the new research methodology was the description of the feedback regulation of p53, as confirmed by the discovery of mdm2/p53 loop; and the explanation why mutant p53 is always overexpressed, published in 1997. The most important result revealed by Dr. Blagosklonny’s research methodology is the hyperfunction (or quasi-programmed) theory of aging and the revelation of rapamycin as an exclusively well-tolerated anti-aging drug, published in 2006. As mentioned in Scientific American, Michael Hall, who discovered mTOR in 1991, gives Dr. Blagosklonny credit for “connecting dots that others can’t even see.”
In 2002, Dr. Blagosklonny became associate professor of medicine at New York Medical College. He agreed to accept responsibilities as a senior scientist at Ordway Research Institute in Albany, New York, in 2005, before receiving another position at Roswell Park Cancer Institute as professor of oncology in 2009.
Since coming to Roswell Park Comprehensive Cancer Center in 2009, Dr. Blagosklonny has studied the prevention of cancer (an age-related disease) via stopping organism aging - in other words, “preventing cancer via staying young.” His laboratory closely worked together with Andrei Gudkov’s and conducted research on the suppression of cellular senescence, namely suppression of cellular conversion from healthy quiescence to permanent senescence. This led to the discovery of additional anti-aging medicines beyond rapamycin. The cell culture studies were complemented by studies in mice, including several models like normal and aging mice, p53-deficient mice, and mice on a high-fat diet.
Dr. Blagosklonny has also published extensively on the stoppage of cellular senescence via rapamycin and other mTOR inhibitors, life extension and cancer stoppage in mice, and combinations of anti-aging medicines to be taken by humans. A rapamycin-based combination of seven clinically available medications has been named the “Koschei Formula” and is now used for the treatment of aging in patients at the Alan Green Clinic in Little Neck, New York.
oncotarget acceptance rate Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executive Manager of the Oncotarget journal . Oncotarget publishes high-impact research papers of general interest and outstanding significance and novelty in all areas of biology and medicine: in translational, basic and clinical research including but not limited to cancer research, oncogenes, oncoproteins and tumor suppressors, signaling pathways as potential targets for therapeutic intervention, shared targets in different diseases (cancer, benign tumors, atherosclerosis, eukaryotic infections, metabolic syndrome and other age-related diseases), chemotherapy, and new therapeutic strategies. After earning her Ph.D. in molecular biology, Zoya was awarded a Fogarty post-doctoral Fellowship from the National Institutes of Health in Bethesda, MD. After successful completion of post-doctoral training, she continued her professional career at George Washington University and Albert Einstein School of Medicine . In 2005 she cofounded the startup company Oncotarget Inc. which is focused on the development of anti-aging and anti-cancer drugs. Her research interests include signal transduction, cell cycle and cellular senescence, and their pharmacological targeting. In 2009 she cofounded the publishing house Impact Journals which specializes in publishing scientific journals. In 2011 she was selected to be a Member of the National Association of Professional Women .
When people refer to today’s medicine, precision plays one of the most important roles and human lives are literally dependent on it. Likewise, any researches pertaining to medicine are required to comply with the top standards. The issue nowadays is that any results of researches can be shared online and used as a reference without being precisely checked and validated. Mikhail (Misha) Blagosklonny of Oncotarget perfectly understood this issue and tried to generate an alternative solution. That’s how a weekly oncology-focused research journal named “Oncotarget” has been founded back in 2010. The key principle of this journal is based on Altmetric scores that are used as a quality indicator. That assists 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 full publications list with corresponding scores higher than 100 as well as reports mentioned above. Mikhail (Misha) Blagosklonny glad to share his new approach and hopes it creates the required help to anybody, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This paper was released back in 2018 by Oncotarget and written by several 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 mentions that “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 aiming to understand the very meaning of it. Based on the Altmetric website, the score indicates “how many people have been exposed to and engaged with a scholarly output.” Hereby, the paper about melanoma, was utilized 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 helpful scientific facts. Oncotarget is happy to have the chance to share with online readers this highly appreciated and top-quality information, that is trustworthy and reliable.
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