Tag Archives: aging is a curable disease

Hacking Aging

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What would you say if I told you that aging happens not because of accumulation of stresses, but rather because of the intrinsic properties of the gene network of the organism? I’m guessing you’d be like: o_0.

So, here’s the deal. My biohacker friends led by Peter Fedichev and Sergey Filonov in collaboration with my old friend and the longevity record holder Robert Shmookler Reis published a very cool paper. They proposed a way to quantitatively describe the two types of aging – negligible senescence and normal aging. We all know that some animals just don’t care about time passing by. Their mortality doesn’t increase with age. Such negligibly senescent species include the notorious naked mole rat and a bunch of other critters like certain turtles and clams to name a few. So the paper explains what it is exactly that makes these animals age so slowly – it’s the stability of their gene networks.

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Fours Stages of Curing Aging

Masha pink hair

Curing aging has 4 stages: mild aging deceleration, dramatic aging deceleration, achieving negligible senescence and rejuvenation. Today we can definitively claim that the task of mild aging deceleration is theoretically solved.

We know the drugs and interventions that slow down aging in mammals. The only thing that we don’t know is dosages, regimes and drug combinations. Defining all of that is the goal of pre-clinical and clinical studies. They can be started immediately. It is also a good idea to do clinical studies of various diets aimed at improving human longevity.

Dramatic aging deceleration will be achieved using gene therapy. Breakthrough studies of lifespan extension in old model animals happened in this area quite recently. We know the genes and delivery methods, now we need a set of powerful experiments aimed at radical life extension. The subject of the intervention will not only be the human genome, but the genomes of the human microbiota.

Rearrangement of how the genome works, as well as genetically modified stem cell therapy and therapeutic cloning can provide negligible senescence.

However, rejuvenation of the organism is likely to be competing with the idea and the very possibility of changing the body as the personality substrate to something else. It is likely that our goal will be not the youth, but creating a more advanced organism capable of solving the task of its own indestructability.

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Longevity Cookbook Indiegogo Campaign Is the Most Effective Step You Can Take towards Your Longevity

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Something amazing has happened! We have launched our Longevity Cookbook Indiegogo Campaign.

Aging steals away your most valuable resource: time. The Longevity Cookbook is a strategy guide to help you get more time to experience the joy from everything that you like in life. Take yourself on a journey starting with nutrients and exercise regimes that goes on to exploring the usage of genetically modified symbiotic organisms and using gene therapy to boost your own longevity.

Contributing to ‪#LongevityCookbook‬ is the best way you can spend your money, because we are fighting for your life. Please, contribute and share the Longevity Cookbook campaign. Let’s defeat aging together!

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You Are Invited to Longevity Cookbook Indiegogo Launch Party

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Longevity Gene Therapy – Updated Projects

While discussing the longevity gene therapy project we encountered various questions and observations that prompted us to broaden the project and slightly change it. Generally, all the comments can be reduced into 5 main points:

  1. You need to enlarge the list of therapeutic genes by adding to it this and that.
  2. You want to use too many genes; therefore you need to make the project simpler by keeping only the most effective genes
  3. If you apply all the genes at the same time, some of them may cancel out the effects of other genes.
  4. Will it be safe to use viral vectors to deliver genetic constructs?
  5. How safe are therapeutic genes for the body?

Some of the observations were of completely opposite nature, so we decided to do 2 versions of the project. One of them is for aging geneticists. In it we almost double the list of the genes extending lifespan. This project will allow testing many poorly studied genes, but promising in terms of aging. Besides, some unexpected results can be obtained, which is always valuable.

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A Letter to Sergey Brin

Dear Mr. Brin,

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?

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Why It Is Ethical to Cure the Disease of Aging

Arthur Caplan, renowned bioethicist, presents simply brilliant argumentation that aging is an unnatural process in this paper. It’s a must-read. I’d love to highlight the main thoughts that I find are profoundly important for the whole fighting aging field.

Why do the doctors treat atherosclerosis and cancer, but not the physiological changes and deteriorations, associated with aging?

Progeria—rapid ageing in a child—is considered a horrible disease, whereas the same changes occurring 80 years later are considered normal and unworthy of medical interest.

The reason is because aging is not being thought of as a disease by doctors and the rest of the world. But it should be!

… in medical dictionaries, disease is almost always defined as any pathological change in the body. Pathological change is inevitably defined as constituting any morbid process in the body… ageing would there- fore seem to have a prima facie claim to being counted as a disease.

One thing that does differentiate ageing from other processes or states traditionally classified as disease is the fact that ageing is perceived as a natural or normal process.

So, the main thesis of the article is that aging is an unnatural process. Dr. Caplan says that if that were not true, then there must have been compelling evidence that aging is natural “and, as such, intrinsically good thing.” This brings us to figuring out what is believed to be natural in medicine. Well, it turns out, one view is that it’s common and normal process that affects 100% of the population.

Coronary atherosclerosis, neoplasms, high blood pressure, sore throats, colds, tooth decay and depression are all nearly universal in their distribution and seem to be inevitable phenomena, yet we would hardly call any of these things natural. The inevitability of infectious disease does not cause the physician to dismiss infections as natural occurrences of no particular medical interest.

The other point of view on what is natural and what’s not comes from considering purpose and function. In order to decide whether aging is natural or not, we should define its function. There are two explanations. The first one is religious, where the vindictive god wants the people to remember they are morally weak. As Dr. Caplan notes, this can’t be used as a scientific explanation, which leaves us with the second point of view “that the purpose or function of ageing is to clear away the old to make way for the new.” Evolutionary biologists tried to explain what aging is and why it is needed based on the concept of natural selection.

More surprisingly, the scientific explanation of ageing as serving an evolutionary role is also not true, because it rests on a faulty evolutionary analysis.

Given that selective forces act on individuals and their genotypes and not species, it makes no sense to speak of ageing as serving an evolutionary function or purpose to benefit the species.

I find this thought genius. It seems to me so obvious now when I’ve read it. Indeed, this has always been overlooked by aging biologists. Evolutionary theories have always seemed so dangerously appealing that it might have drawn aging biologists (like Tom Kirkwood, for example) away from fighting aging. A lot of scientists still think aging is natural and I believe the evolutionary theories have played a major role in forming this belief. This may be the underlying reason why researchers can’t accept the thought that aging can and should be cured. Dr. Caplan defines aging in the following way:

Ageing exists, then, as a consequence of a lack of evolutionary foresight; it is simply a by-product of selective forces that work to increase the chances of reproductive suc- cess. Senescence has no function; it is simply the inadvertent subversion of organic func- tion, later in life, in favour of maximizing reproductive advantage early in life.

The common belief that ageing serves a function or purpose, if this belief is based on a misapprehension of evolutionary theory, is mistaken. And, if this is so, it would seem that the common belief that ageing is a natural process is also mistaken. And if that is true, and if it is actually the case that what occurs during the ageing process parallels the changes that occur during paradigmatic examples of disease (Boorse, 1975), then it would be reasonable to consider ageing as a disease.

The explanation of why ageing occurs has many of the attributes of a stochastic or chance phenomenon. And this makes ageing unnatural and in no way an intrinsic part of human nature. As such, there is no reason why it is intrinsically wrong to try to reverse or cure ageing.

There is no reason why we can’t call aging a disease. There is no ethical reason why we shouldn’t try to slow down or reverse aging. There is no ethical reason why we shouldn’t fight aging – the worst disease of all times.

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