Do Model Animals Tell Us Anything about Human Aging?

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I wrote a tiny report on the pluses and minuses of using model  animals in aging research.

Using model animals in gerontological studies has yielded an enormous wealth of useful information about the mechanisms of human aging and longevity. Animal models were crucial in identifying the conserved pathways that regulate human aging. Model organisms are fundamental for aging research, because there are serious limitations of using human subjects, such as the length of lifespan, genetic heterogeneity and vast differences in environmental influences. The shape of survival curves represents the health of the organism over time. Model organisms display significantly different lifespans, however the survival curves resemble those of humans quite remarkably. Despite this general similarity in the way we describe aging between humans and model animals, there are some distinct differences (Mitchell, Scheibye-Knudsen, Longo, & de Cabo, 2015). For instance, increasing Sir2 gene expression in yeast (Kaeberlein, McVey, & Guarente, 1999), nematodes (Tissenbaum & Guarente, 2001), and flies (Rogina & Helfand, 2004) boosts animal longevity. A small molecule called resveratrol was found to activate Sir2 and its mammalian ortholog SIRT1 (Howitz et al., 2003). Resveratrol extends lifespan of mice fed a high-fat diet (Baur et al., 2006), however it failed to have a beneficial longevity effect in mice on a standard diet (Pearson et al., 2008). This example highlights the fact that we cannot simply transfer the results of longevity interventions to humans and expect the same efficacy as in invertebrate models.

Everyday the researchers are broadening the understanding of human biology of aging with the help of various model systems. Each of them has its advantages and drawbacks. Let’s take a look at what those are for the most widely used animal models.

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Transhumanism Strategy Boils Down to Choosing a Crowdfunding Project

Maria in the library First of all, let’s draw a line between a strategy and wishful thinking. There are plenty of wonderful transhumanist projects. A viral video, a global portal, attracting celebrities, proof that aging is a disease, convincing billionaires, educational programs, letters to politicians, civil actions, participating in elections, creating a strong community, clinical trials of combinations of existing age delaying drugs on animals, TV shows, Hollywood blockbusters, creating a political committee, conferences on transhumanist topics, scientific megaproject on life extension, cryonics company, crowdfunding, a lot of startups relevant to transhumanist topics, active use of AI elements in all areas and so on . The only question is how can we do all of this? Often, when a person gives advice that we need to do this and that, they have a feeling that they solved the problem. However, “this and that” won’t just appear by itself. There is merely a feeling that the problem is solved. This is how a person solves the problem of being involved in transhumanism by giving a piece of advice. It should be noted that all pure transhumanists projects either failed, or lead a miserable existence, or degenerated into something unreliable. Continue reading

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Transhumanism Strategy

We’ve put together the survey on transhumanism strategy to reveal the inner discussion inside the transhumanist movement. Our goal is to inspire the people to act.

We believe the greatest sin in our field is wishful thinking. It’s when a person is saying that it would be good to do something, like for instance, to shoot a viral video, but at the same time this person is not doing anything. His or hers advice has to be implemented in real life somehow on its own.

We also tried to get away from discussing whether it’s going to be boring to live, what about overpopulation, and whether we should argue with nature or not. We can’t be talking about this nonsense forever.

We will take the liberty of commenting on the obtained results from 223 respondents and share our own opinion on the proposed questions.

58% think a global movement is needed. I suppose we agree with it, but it’s not necessary that right now there have to be a lot of people. It is more important that the people understand the situation and the goals of transhumanism and are ready to act.

20% believe that the cure for aging can only be created as a non-profit project, and 80% think not necessarily. Our position is that only a non-profit initiative can achieve significant deceleration of aging. We’ve witnessed tens of commercial projects in life extension and every time the idea to earn money wins over the idea of living longer. Radical life extension idea is extremely complicated and burdening it with making money overcomplicates everything.

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Cure for Aging Can Be Created Using Directed Evolution

Project description:

Accumulating evidence suggests that microbiota plays an important role in modulating lifespan. This makes possible to use symbiotic bacteria as “living drugs”, which live in the host organism and promote its longevity. We propose to create bacteria, which dramatically extend lifespan of its host. Such bacteria have to produce not one, but a set of longevity-promoting substances with optimal concentrations and dynamics of secretion. To obtain such bacteria we propose to use directed evolution, a process that mimics Darwinian selection on a laboratory scale. This approach has never been applied to drug development before. Directed evolution enables simultaneous modulation of a number of bacterial metabolic pathways andsubsequent selection of the most effective longevity-promoting variants. Experiments will be conducted on a model system consisting of C.elegans and its intestinal symbiont E.coli. Due to highly conserved aging pathways, obtained bacteria may be further used to develop longevity-promoting human drug.

Bacteria E.coli serve as the food source for C.elegans, but at particular stages of the nematode life course they can also exist as intestinal symbionts. Moreover, it was shown that E.coli influence physiology and lifespan of C.elegans. It was revealed that several mutations in E.coli genome increase or vice versa reduce the nematode lifespan.

Symbiont 1

The relationship between C.elegans and E.coli at different stages of the life course of the nematode

Left picture – During development, bacteria mainly serve as a source of food for C.elegans

Center picture – In adult worms some bacteria are not digested and become symbionts

Right picture – As the worm ages, bacteria proliferating within the lumen of the gut become detrimental to the host (Cabriero and Gems, 2013)

The project aims to create E.coli strains that are able to extend the lifespan of C.elegans. For this purpose we propose to employ directed evolution – a process that mimics Darwinian selection on a laboratory scale. At first, phenotypic diversity of E.coli is generated using global transcription machinery engineering (gTME) approach. The gTME randomly alters key proteins regulating the global transcriptome and generates a new type of diversity at the transcriptional level. Then a set of bacterial strains with reprogrammed transcriptome (a bacterial library) is created and E.coli strains which demonstrate the highest ability to extend C.elegans lifespan are selected. We propose to perform not less than 2 cycles of gTME.

For gTME we propose to alter genes of transcription initiation factors σ, which regulate expression of hundreds of genes. At the first cycle of gTME the gene which encodes the main sigma factor σ70 (RpoD) is subjected to random mutagenesis. At the second cycle of gTME the gene of sigma factor σ38 (RpoS), which regulates expression of stationary phase genes, is targeted for mutation.

The selected bacteria are studied to identify transcriptome, proteome and metabolome modifications which result in longevity-promoting phenotype.

Research goal:

Creation of symbiotic bacteria, which are able to increase the lifespan of the host, and study of biological mechanisms underlying these longevity-promoting interactions.

Symbiont 2Research plan

I stage – Creation of bacterial strains which extend the lifespan of C.elegans

(duration – 1,5 years)

1) Construction of library of E.coli strains with reprogrammed transcriptome

– Random mutagenesis of σ-factor gene using error-prone PCR.

– Cloning of obtained sequences into plasmids and transformation into E.coli.

2) Selection of E.coli strains which demonstrate the highest ability to extend C.elegans lifespan

C.elegans are raised on one of the bacterial mutant strains and analyzed for their lifetime. 1500-2000 strains from mutant library are screened.

– Selection of E.coli strains which demonstrate the highest ability to extend C.elegans lifespan.

2nd cycle of gTME using the gene of another σ-factor – iteration of experiments 1)-2)

II Stage – Study of E.coli strains which extend the lifespan of C.elegans

(duration – 1 year)

– Analysis of transcriptome, proteome and metabolome of E.coli strains which promote longevity of C.elegans.

– Identification of E.coli genes and biological pathways which affect the lifespan of C.elegans.

Expected results:

  • Development of longevity-promoting “living drug” based on symbiotic bacteria.
  • Demonstration of the possibility of directed evolution to create symbiotic bacteria with such a complex phenotype as ability to extend the host lifespan.
  • Identification of new genes and biological pathways of coli which affect C.elegans longevity.

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Main Mistake of Steve Jobs

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I’m quite fed up with the argument against life extension and physical immortality mentioning Steve Jobs who said that “death is very likely the single best invention of life». It’s actually a form of the Buyer’s Stockholm Syndrome, when a person makes a not necessary and expensive purchase and starts to look for arguments that it’s not too bad after all. Only despair and hopelessness make a person justify death. Death is not the single best invention of life, but the worst thing that can happen in it. The whole essence of life is to struggle against death and fight for survival.

Yes, death emphasizes the beauty of life, but it can well do that in a theoretical sense. Like the worst-case scenario that should be avoided. While people are mortal, a human life is a tragedy. Regardless of what a person was doing in life, everything that they lived for will disappear including them. Only striving to immortality and the infinity of goals make sense. Otherwise one can always put the person at a stand by asking the repeating question “why are you doing this?” and regardless of the answer, ask again “and why is this?” If there is no infinity then the person comes to an unavoidable loss of sense.

My answer is that the meaning of my life is in having a tomorrow. I want every tomorrow to have its own tomorrow. Death is when your tomorrow never comes.

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Longevity Cookbook

Longevity cook book menu draft 1

My colleagues and I would like to launch the Longevity Cook Book crowdfunding campaign in upcoming three months.

We would like to raise funding to create a book that will tell the story about what longevity depends on, what processes are going on in our bodies during aging and how they can be slowed down, dieting in the right way, based on the current scientific knowledge. The book will contain the most up-to-date research data on the beneficial properties of various foods, their longevity effects and abilities to prevent different age-related diseases.

Longevity Cook Book will give you the special recipes, developed with the help of professional chefs, on how to cook longevity-boosting dishes from the healthiest ingredients possible.

Besides the recipes, the book will tell you how to “cook” longevity in terms of science. I will explain the existing directions in aging research and the most promising experiments that need to be carried out to make a truly long and healthy life a reality.

Here’s the Longevity Cook Book plan:

Part 1

  • The role of diet in health and longevity. I will describe the diets that increase longevity and prevent age-related pathologies (with proof in humans and model animals)
  • Physiology of nutrition. I will explain how food is digested, how the nutrients are absorbed in the intestines, how they enter blood stream, what they do inside the cells. There will be some pretty pictures to illustrate all of that.
  • Brief and easy-to-understand description of aging mechanisms and the mechanisms of age-related pathologies (like cardiovascular diseases, diabetes, etc.) and how diet can influence those mechanisms

Part 2

Description of the healthy foods including scientific papers, illustrating why they are healthy, and biological mechanisms that those foods influence

Part 3

Longevity Menu. Dishes made with longevity foods cooked the healthiest ways accompanied by pretty pictures of the dishes.

Part 4

“Cooking” longevity. I will describe the main approaches to solving the problem of aging and the most promising experiments.

How do you like the idea? Would you be interested in reading such a book?

For the crowdfunding project to be successful it has to have a powerful start, therefore I’d like to agree on reposting the campaign when it launches in advance.

I call upon everybody to, please, let me know, who would be up to spreading the word about this project when the time comes.

If you have some nice amount of people following you on twitter or other social networks, I’ll be happy to collaborate.

I also welcome advice on how to engage a larger audience. Maybe you have some journalists or bloggers that you know?

I present a draft of a possible layout of one of the pages.

There will be many different icons that tell you various bits of information about the dish. In particular on this page a face means the research on the given type of food was done in humans, a mouse – on mice, a test tube – on cell cultures.

We haven’t yet put together the pictures of aging mechanisms, but we will definitely do it.

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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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