Monthly Archives: August 2013

Genome of Long-Lived Brandt’s Bat Sheds Some Light to Its Exceptional Longevity

Brandt's bat

 

Congratulations to my colleague, Dr. Alexey Moskalev, who, with collaboration with Dr. Vadim Gladyshev, published this awesome paper on genetic basis of exceptional longevity of the Brandt’s bat. This is an amazing animal – it lives up to more than 40 years of age, but weighs only 4-8 grams. A tiny “centenarian” creature. It lives in caves, sleeps during the day, echolocates and hibernates during winter. Every trait has its genetic background. The authors tried to decipher the background of the bat’s longevity.

The most important thing that they found was that Brandt’s bat has altered growth hormone and insulin growth factor 1 signaling (GH/IGF1). This signaling is reduced, there is a kind of dysfunction, that contributes to the animal’s longevity along with the adaptations like hibernation and low reproduction rate. There are other interesting findings. For example, olfactory function is also reduced in these amazing animals. It’s interesting, because olfactory system plays a role in regulating longevity. For example, if you put drosophilas on a restricted diet, they start to live longer, but if you let them smell food, then life extension effect goes away.

I think that this work is crucial, because if we are able to identify the genes that are responsible to exceptional longevity in species like naked mole rats, whales and rougheye rockfish, we’d be able to find the way to alter the activity of those longevity genes in our bodies, for example, pharmacologically. Eventually this will lead to creating life extension therapies that would make us live longer, healthier and happier lives.

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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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