Tag Archives: longevity research

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?


Filed under Life Extension

Robert Shmookler Reis on Fighting Aging Approaches and Role of Basic Science

Dr. Reis talks about the main trends in longevity research, potential for creation life extension therapies in the nearest future, his favorite genes, preferable ratio of basic to applied research funding and the overall hurdles of aging research field.


Filed under Funding, Genetics

New DNA Repair Process Discovery May Lead to Human Life Extension

A key component of aging is the accumulation of errors in cells genetic’ genetic code or DNA. Once enough errors accumulate, the cell makes faulty proteins leading to irreparable cell damage and death, or in some cases cancer.

In a new study published in the Journal of Biological Chemistry researchers discovered that DNA acetylation governs DNA replication and repair. This process adds acetyl groups to DNA segments which then determines what path of DNA doubling that segment will take.

Cells are known to use a high fidelity yet high energy consuming path for DNA that encodes for proteins.  A low cost yet lower fidelity pathway is used for non protein encoding segments of DNA. The acetylation process just identified tells the cell which repair process the section of DNA should undergo.

Once the process of DNA acetylation can be exploited and applied at will it is possible to ensure cells have very low DNA error rates and thus live longer.

“Our research is in the very early stages, but there is great potential here, with the capacity to change the human experience,” said Robert Bambara, Ph.D., chair of the Department of Biochemistry and Biophysics at the University of Rochester Medical Center and leader of the research. “Just the very notion is inspiring.”

Though exciting it could take a while before this research leads to human lifespan extension.

“The translational rate is becoming better and better. Today, the course between initial discovery and drug development is intrinsically faster. I could see having some sort of therapeutic that helps us live longer and healthier lives in 25 years,” said Bambara.

Source (Eureka Alert)


Filed under Article, Life Extension, Stem Cell Research

Don’t most businessmen want to live?

Funding of life extension research is extremely close to zero. It lookes like there’s just a couple of men interested in their own lives. The rest seems to want to die. One of those few smart businessmen, Jason Hope announced a half a million dollar donation to the SENS Foundation, a California-based non-profit organization that works to develop, promote and ensure widespread access to rejuvenation biotechnologies which comprehensively address age-related diseases.

“I have had great interest in the SENS Foundation and Dr. Aubrey de Grey’s work for some time now.  I believe their work is essential to the advancement of human medicine and their approach to the overall problem of human aging and its associated diseases (Alzheimer’s, Atherosclerosis, Diabetes, etc.) is the only way to go.  Their work and the work of others that they support will drive the complete redefinition and reshaping of the healthcare, pharmaceutical, and biotech industries as we know them today.  The advancement of rejuvenation biotechnologies is not only extremely important, but it is the future. I am honored to support the SENS Foundation in its efforts, and hope my support helps drive faster results for all of humanity,” said Jason Hope.

The donation was announced by SENS Foundation CEO, Mike Kope, at Tuesday’s ‘Breakthrough Philanthropy’ event hosted by the Thiel Foundation, in the Palace of Fine Arts in San Francisco – an event that was covered here on my blog this past week.

“We need to create an entirely new biotech industry. That’s why we created SENS Foundation: to be a credible catalyst for change; to be a public research and outreach organization devoted to the creation of a new field- rejuvenation biotechnology.  To that end, we are proud that our projects are capturing the imaginations of top tier collaborators in biotech and regenerative medicine.  Jason Hope’s donation is a major contribution, enabling us to build on our existing collaborations in 2011, and accelerating our progress in the fight against age-related disease,” said Mike Kope

“I enjoyed hearing a lot of great presentations at the Breakthrough Philanthropy event,” said Thiel Foundation chairman Peter Thiel. “But for me, the highlight of the whole evening was hearing about Jason’s bold commitment to defeating aging.”

SENS Foundation CSO, Aubrey de Grey, described the use to which Hope’s donation will be put:

“Arteriosclerosis – hardening of the arteries – is the main cause of increased blood pressure (hypertension) in the elderly, which in turn exacerbates major aspects of aging such as diabetes. It is caused largely by the unwanted accumulation of molecular bonds between the proteins that hold the cells of the artery in place – the extracellular matrix. The same process causes long-sightedness (presbyopia) and contributes to skin aging. I am delighted that Jason’s donation will fund our work on the pharmacological breaking of these unwanted molecular bonds, and the restoration of elasticity to the body’s extracellular matrix.”

Read Mike Kope’s announcement at Tuesday’s ‘Breakthrough Philanthropy’ event and to learn more about SENS Foundation


Filed under Funding, Life Extension, Regenerative medicine

Gene Sequencing interview with expert: William Andregg

William Andregg is the CEO and founder of Halcyon Molecular. He invented a technology called “core polymer placement” which offers quicker and cheaper DNA sequencing. Mr. Andregg feels that the cost of complete human genome sequencing will be as low as $1000 as soon as the year 2013!

Here is the interview done by Sander Olson, Internet journalist and creator of nanomagazine.com, a website dedicated to interviews of nanotechnology researchers:

Question: How much does it currently cost to sequence ones genome?

Answer: Depends on what you mean by “sequence ones genome”. If you want a truly complete sequence, you can’t get that now. You could spend millions of dollars and you still wouldn’t have even a single truly complete human genome. There are much cheaper options to get something far less accurate and useful- getting down to about $10,000 currently. But we’re hoping that in five years when people talk about “sequencing ones genome”, they really mean it- really sequencing the whole thing, not just seeing part of it.

Question: How much of the entire human genome have we currently sequenced?

Answer: The most comprehensive reference assembly for the human genome still contains hundreds of gaps as of 2010, with millions and millions of missing bases.

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Filed under genomics, Uncategorized

The FDA Needs to Rethink Aging

I wanted to share an interesting perspective by statistician Gary Liberson, PhD. He recently published some valid points on the present system of FDA licensing and the difficulty that companies face in finding an economic justification for longevity research without seeking a specific disease.

According to Liberson, the problem lies with the FDA approval system that requires a pharmaceutical company show three things: (1) a mechanism of action (i.e., identify why a drug works), (2) safety and (3) efficacy in managing a measurable biologic end point associated with a disease. This last condition, according to Liberson is a  problem.

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Filed under Biomarkers, Mechanisms of aging