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IEET > Security > Biosecurity > Resilience > Rights > FreeThought > Personhood > Economic > Life > Access > Enablement > Innovation > Health > Vision > Contributors > Maria Konovalenko

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A Letter to Sergey Brin


Maria Konovalenko
By Maria Konovalenko
mariakonovalenko.wordpress.com

Posted: Aug 15, 2013

I’ve heard you are interested in the topics of aging and longevity. This is very cool, because fighting for radical life extension is the wisest and most humanitarian strategy. I would like to tell you what needs to be done, but, unfortunately, I haven’t got your email address, or any other way to be heard.

100,000 people die from aging-related causes every day, but what makes the situation even worse is that the scientists know how to tackle this problem, but don’t have clue how to convey their message to those people, who could change the situation and make the creation of human life extension technologies possible.

Therefore, I am simply writing in my blog, hoping, that maybe somehow you will read this letter, or that maybe my friends will give me some advice on how it could be delivered to you, or that maybe someone would send it to you.

So, here it goes.

There is no more important goal than preserving human life. Aging limits our lifespan, and is the main contributing factor for diseases responsible for most human mortality and suffering, including heart disease, stroke, adult cancers, diabetes, Alzheimer’s and Parkinson’s.  Defeating or simply slowing down aging is the most useful thing that can be done for all the people on the planet. It is the most complicated task in the history of mankind. Molecular-genetic studies of laboratory animals, over the last two decades, have demonstrated that the problems of aging are not insoluble.  By modifying regulatory pathways, scientists have repeatedly succeeded in extending lifepan – by up to twofold in insects and rodents, and as much as 10-fold in worms and yeast.  These same studies have greatly expanded our understanding of those pathways, which are remarkably well conserved from yeast to humans.  In view of that conservation, we have every reason to believe that similar strategies will work for humans.

What is most needed now is an adequate commitment of funds to support fundamental research. Long-term and large-scale scientific projects are required. Startups largely focused on rapid commercial effect, will not fill the gap.

A wealth of inspiring breakthroughs, that have transformed the field of longevity research, hints at the progress that could be made with better support.

Firstly, creating transgenic animals that live radically longer than their counterparts.

The record in the area of life extension is shared by Valter Longo and Robert Shmookler Reis.  Longo, from the University of California Davis, was able to extend yeast lifespan 10-fold by turning off the genes ras2 and sch9, while also reducing the calorie intake. Shmookler Reis, from the University of Arkansas Medical School, discovered that either of two mutations inactivating the nematode’s age-1 gene (encoding PI3K, a key intermediate in several signaling pathways) can extend worm lifespan 10-fold.  Rogina Blanca, Professor at the University of Connecticut, found that a mutation in the Indy gene doubles the lifespan of the fruitfly Drosophila.  Andrzej Bartke from the University of Southern Illinois achieved a twofold extension of mouse lifespan by combining calorie restriction (feeding 30% less food than desired) with a mutation that eliminates three pituitary hormones.

The next logical step is to create transgenic mice with other mutations and/or transgenes to mimic the changes that were so effective in invertebrates (yeast, worms and fruitflies). For example, tissue-specific downregulation of IGF1 or PI3K, and targeted or whole body overexpression of genes that control the cellular oxidation state (САТ, TXN, MSRA, SOD1, SOD2), DNA repair genes (GADD45 alpha, beta and gamma), regulators of epigenetic state (DNMT2) and transcription of protective agents (FOXO3), heat shock proteins (HSPA1A, HSPA1B) and other genes (PCMT1, SIRT1, PCK1, PLAU).  At present, over 100 genes have been reported to be associated with alterations in longevity, and several dozen have been confirmed in multiple species (and thus are likely to translate to humans).   Genetic experiments modifying the expression of those genes in mice would be very informative, especially employing combinations of transgenes and suppression of longevity-limiting genes (e.g., mTOR and PI3K).

Creating longevity gene therapy looks very promising.

In 2012, a group led by Maria Blasco at the Spanish National Cancer Research Center used a viral vector to deliver to adult mice an active gene for the telomerase protein that extends telomeres (chromosome ends, which shorten during aging).  Remarkably, gene therapy of one-year-old mice extended their lifespan by 24%, and treatment of two-year-old mice still added 13%.  Treated mice had reduced rates of osteoporosis, reduced loss of subcutaneous fat, but improved neuromuscular coordination and metabolic functions (including less insulin resistance), without any increase in cancers.

Based on this “proof of principle” that longevity can be enhanced via gene therapy, the next step is clearly the delivery of other genes required for longevity, whose activity declines during aging. Candidate “geroprotective” genes are already known from prior studies in yeast, flies and worms; their functional testing in mice only requires a modest investment in this promising research.  There are still, however, legitimate concerns to be overcome before the results can be applied to humans, such as the danger of increasing cancer risk, and efficient targeting to specific tissues or cell types.

An effective approach to slowing down aging may be suppressing mobile genetic element activity, in particular retrotransposones. Retrotransposons are endogenous viral genomes, copied via RNA into DNA elements via reverse transcriptase, which are known to mediate some cancers of mice, and which may destabilize human genomes as well. In recent experiments, inhibition of retrotransposon activity slowed replicative aging of cultured cells differentiating from human stem cells.  While it is not yet known whether this would also slow in vivo aging, development of safe genetic or pharmacological means to inhibit retrotransposition in mammals appears promising.

One clear deficiency of gerontology and medicine at present is simply that aging has not been recognized as a key target for clinical diagnosis and therapeutic interventions, although syndromes of premature aging (progerias) have long been considered diseases.

Aging is a curable disease. Aging is a predisposing condition for many of the most serious diseases faced by our society, and in many ways it makes more sense to target aging than the diseases it promotes. Aging is an “aberration” relative to the youthful state, that can be identified through correlated biomarkers, allowing us to seek both the avoidable factors that aggravate it (e.g., inflammation, thermal and oxidative stresses, ionizing irradiation, etc.), and biological processes or therapeutic measures that postpone it (DNA repair, proteolysis, autophagy, etc.). Aging causes pain, dysfunction, distress, social problems and death of affected person.

It is crucial to make numerous medical organizations recognize aging as a disease. If medical organizations were to recognize aging as a disease, it could significantly accelerate progress in studying its underlying mechanisms and the development of interventions to slow its progress and to reduce age-related pathologies.  The prevailing regard for aging as a “natural process” rather than a disease or disease-predisposing condition is a major obstacle to development and testing of legitimate anti-aging treatments. This is the largest market in the world, since 100% of the population in every country suffers from aging, but currently it is completely dominated by untested supplements promoted through fraudulent claims.

In order to test the effectiveness of geroprotective drugs, it is necessary to develop the diagnostic platform of aging.  The routine annual check-up could easily include testing of diverse parameters that provide the doctor-biologist with critical information about the individual’s aging status and risk profile for age-dependent diseases.  Biomarkers of aging include changes in longevity- and aging-associated genes expression (for example,  p16, p21, ARF, p53, COX-2, SIRT1, NFkB, Lon, IGF-1), changes in microRNA levels (miR-34a, miR-93b, miR-127, miR-18a), altered hormones levels (leptin, melatonin, DHEA), cytokines (TNFa, IL-6, IL-8), advanced glycation end products and many others. The diagnostic platform could contain analyses of genetic, epigenetic, transcriptomic, proteomic and metabolomic data.  The appropriate analysis of those biomarker data, coupled to clinical data, would allow lifestyle modifications and therapeutics to be optimized for each individual, in order to slow aging and to prevent or treat age-related diseases. And it could be done right now. This approach is the basis of personalized medicine, and yet current approaches to personalized medicine largely or entirely ignore the age dimension.

It is possible to extend lifespan pharmacologically. Many compounds have been shown to prolong life of certain model animals and to prevent age-related pathologies.  These include metformin, rapamycin, lipoic acid, 2-deoxy-D-glucose, carnosine, amino-guanidine, fisetin, hydroxycitrate, 4-phenylbyterate, gimnemoside, cycloastragenol, quercetin, nordihydroguaiaretic acid, acarbose, 17-a-estradiol, melatonin, spermidine, thioflavin T, and kempferol.  Others will surely be discovered in large screens that would become more feasible once panels of proven age-biomarkers are developed.

Rapamycin extends lifespan of old mice. In 2009 Richard Miller, Randy Strong and David Harrison showed that mice given rapamycin with their food, even beginning as late as the 600th day of life, lived 9% (male) and 14% (females) longer. Given the fact that lab mice normally live 2 – 3.5 years, 600 days is a fairly advanced age for a mouse.  Rapamycin is an FDA-approved drug, prescribed chiefly as an immunosuppressant for kidney-transplant  recipients. Future studies can design and test advanced geroprotectors, based on drugs like rapamycin, to modify their chemical structure so as to optimally prolong life in humans while preventing or slowing age-related pathologies.

Another global research direction is studying close species that differ significantly in lifespan.

For example, aging mechanisms have been compared between the naked mole rat and its close relatives. The naked mole rat is an African rodent that ages very slowly, perhaps not at all – since its mortality doesn’t increase as it ages. These extraordinary animals have protective mechanisms that allow them to live up to 30 years of age, which is 10 times longer than other rodents of similar size, yet never get cancer.

We have begun to identify genetic and epigenetic determinants of naked mole rat longevity.  For example, they have hyperactive proteolysis and autophagy pathways, which clear damaged proteins and other cellular components.  However, because  only three labs in the world are now studying naked mole rats, and their budgets are very limited, much still remains to be learned from them.

Another animal with little or no senescence is Brandt’s bat. This bat weighs only 7 grams, but lives to 41 years of age, 12 –15 times the lifespan of mice with the same body mass. Brandt’s bat has received little research attention; comparisons with its close relatives, of more modest lifespan, may reveal which genes are responsible for its great longevity.

Fish of the Scorpaenidae family also show little senescence, several of which have life-spans exceeding 150 years. The champion is the rougheye rockfish (Sebastes aleutianus) at 205 years.  It may be possible to learn the biological basis for this remarkable longevity, by comparing genomes and transcriptomes of this species with the shortest-lived species, Sebastes dallii, that lives only 10 years.  The features that appear to underlie great longevity can then be replicated in rodents to test their relevance to mammals.

Fighting aging has to be built on the principles of openness and collaboration. It is necessary to attract hundreds of labs all over the world to collaboration in the framework of a global project that could be called, for instance, Aginome.

We have identified a number of molecular biology laboratories that have made important contributions to longevity research, whose productivity is constrained only by the limited funding now available.  Additional support is virtually assured to accelerate their pace of discovery, and advance the field.  These include groups led by Nir Barzilai, Andrzej Bartke, Mikhail Blagosklonny, Maria Blasco, Judy Campisi, Claudio Franceschi, David Gems, Brian Kennedy, Cynthia Kenyon, Brian Kraemer, Valter Longo, Gordon Lithgow, Victoria Lunyak, Richard Miller, Richard Morimoto, Alexey Moskalev, Thomas Perls, Robert Shmookler Reis, Steven Spindler, Yousin Suh, Jan Vijg and several other outstanding researchers.

Also, the field of fighting aging has some applied projects that can be implemented in the short-term. I could tell you about those projects, if you are interested. I would also like to know your opinion about my plan of action. What would you be interested in doing yourself in the area of life extension?


Maria Konovalenko is a molecular biophysicist and the program coordinator for the Science for Life Extension Foundation. She earned her M.Sc. degree in Molecular Biological Physics at the Moscow Institute of Physics and Technology.
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COMMENTS


Great article, Maria, and a wonderful strategy. People like Sergey Brin have more than enough money to advance life extension, and it’s wise to ask them for help, directly. Well done. I hope your petition is successful!





Hi Maria,
That open letter was a bold and dedicated move, I commend your affords. Progressive determination for research to expand the longevity of life could be an epiphany to combat old age diseases up until now has always been consider a part of growing old.

Just recently, a research group poled a group of people, I think a 100 people or so and asked, would you want to live to be a 120 years old? 80- 90% said ‘no’ crazy right?
For me the answer would be ‘200’ years old and then some, to combat aging and slow down the progression of related diseases, I believe is a noble cause.

He just funded the first test tube burger, that’s why you’re here ‘smart’ to also combat diseases related to processed meats that could have an affect on the longevity of your life. And to keep the dignity of the animals specifically ‘cows’ he not comfortable with the way some animals are treated plus to eliminate the extra additives that processing meats can bring before it hits selves for our consumption.   

Most importantly the great Sergey Brin with that brilliantly blissful mind of his, it shows he cares. Research is key on a plethora of life changing modification, one comes to mind right now: Sergey also has been tested by his wife and shares a genetic mutation himself later in life that could be catastrophic on the longevity of his life, there making advancements but there not there yet, maybe this could be an eye opening experience and add a another dimension to the data that already exist.

Good luck, I see you have me in your corner already, the brilliance of your words should open hearts and minds on such sensitive research.
                     

Sonya Wiley





I certainly agree that developing life extension techniques is a most noble cause, and applaud research along all the lines that you mentioned.
However, at the same time we need to control chronic inflammation, the main cause of cardiovascular disease, arthritis, dementia, etc. We induce these problems ourselves by smoking, improper diet, and tolerating a toxic environment.
Winston T. Cope, M.D.





Yes, we should by supporting Aubrey de Grey’s SENS project (tax deductible scientific research chatty in the US) and also the Mprize project (also tax deductible).  Aubrey’s group has grown to supporting researchers major word class universities.  And I propose that we establish world treaties to impose limits to the worlds military sizes, their R&D budgets (you would not realize the colossal waste that programs like Regans Star Wars budget wasted, that’s just a small example)...millions of people have been killed and damaged by wars and colossal fortunes wasted in just the last 100 years alone!!  Aubrey proposes to defeat aging given 1 billion over 10 years, the worlds militaries spend that in just a few hours!!!





Everything gets old and dies… *EVERYTHING*.  Stars perish, and even protons themselves have a half life, and eventually decay.

I have no problem with dedicating efforts to combating age-related illnesses, or trying to improve the qualify of life for people as they do age, but to suggest that aging itself is somehow a “curable disease” is to turn a blind eye to some very fundamental physical properties about this universe.

It’s called entropy, by the way… and no… it’s not curable.  Not unless somebody who claims otherwise knows of some other universe that we could just magically pop ourselves into.





@markt

As far as we know the universe has not had intelligent life in it though the probability of such is extremely high.

Why cant intelligent life figure out a way to refuel the sun, upload brains/minds to computers, even reverse a big crunch, etc…?





Maria,
  The cycle of generations provides a species with adaptability on a genetic level, so enabling human immortality would shutdown humanity’s biological adaptation engine, which would eliminate our species’ natural ability to adapt genetically to change and eliminate our species’ natural ability to recover from a sufficient catastrophe.  With our natural adaptation engine shutdown, the entire burden of adaptation would then fall upon the shoulders of scientists.  The question becomes whether to continue with an adaptive engine evolved over millions of years, or to gamble the future survival of our species entirely on a body of knowledge which is so much younger that its timeline is miniscule by comparison.  The human mind is a wonderfully powerful tool, but the collective of all human minds understands only a fraction of the mysteries which nature employs effortlessly.





@Damion

The point is, is that we will understand most everything about the universe, consciousness, world, and biology.





As someone who lives in the most overpopulated country in Europe, it seems an extraordinary suggestion that the most important thing for us to research is how to live longer. I would prefer a happier, more comfortable, and shorter existance.

Human population has quadrupled in the last 50 years and the rate of growth is still enourmously high. At what point do we stop? When all the forests have been cut down to grow food?





@Kris

The notion that humanity has been close to understanding everything about the universe has been proclaimed by optimists several times throughout history, and each such proclamation has been followed by discoveries which demonstrated how little we actually know.  The pool of such humbling discoveries is inexhaustible.  Even if our body of knowledge [somehow] becomes infinite, there will still be an infinite remainder of things that we do not know.





@Damion,

I do not understand your reasoning to think that there is “infinite” body of knowledge out there. Even Kuhn said that with each scientific paradigm we get closer and better to understanding the universe.





@Kris

Mathematics, the foundational layer of all science, contains not just one infinite-axiom theory, but an infinite number of infinite-axiom theories.  Throughout history mathematicians have devised purely abstract branches of mathematics with no practical application in sight, then decades later scientists discover that said previously impractial mathematical branch serves to accurately model an observed phenomenon.  History so far has demonstrated that even the most obscure and esoteric mathematics describe real-world phenomenon, and mathematics is an infinite body of knowledge.





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