Category Archives: genomics

We Can Learn a Lot from Yeast How to Slow Down Aging

Valter Longo's lecture

Dr. Valter Longo hold the record of yeast lifespan extension. He was able to increase longevity of this species 10 fold. This a one of the most remarkable results in longevity science. Here Dr. Longo is giving us a lecture on yeast genetics. Let me summarize what he told us.

Yeast are unicellular organisms. They have 6,000 genes packed in 16 chromosomes. They divide every 90 minutes. They are one of the widely used model animals for research, and not only aging research, because they are safe, quite easy to handle and inexpensive. One of the best feature for aging research is that their lifespan is really short. I will use a vague term – about a week, because it depends on the way how you measure their longevity.

There are two major methods to see how long yeast live – replicative and chronological lifespan analyses. The first one looks at the dividing mother cell and determines how many times the  division happened. People can distinctly distinguish the newly formed daughter cell and the mother cell, because daughter cells are smaller in size. This work is really tedious, because it relies on manual sorting of the cells. None the less, this is how we can measure the yeast health span – the period of time when the cell is able to give progeny. After it has no more “babies” it doesn’t die though immediately (humans don’t too), however this assay doesn’t include the time when the cell remains alive.

The chronological lifespan analysis looks at how long the non-diving colony of cells live. The number of cells alive at each particular moment is estimated by the number of colonies that they form on a plate with nutrients that allows growth so the colonies can be visible. In order to bring the yeast to a non-diving state, they are stripped of nutrients in the medium, so they switch to a growth arrest state to ensure survival rather than reproduction. This is called a post-diauxic phase. Their survival is approximately 6 days in this state. And the metabolic rates are very high.

One of the ways to extend yeast lifespan is to remove all nutrients from the medium and simply substitute it with water. They will then enter a stationary phase when their metabolic rate is reduced, which allows better stress resistance and longer survival, about 17 days.

There is an even great lifespan extension mode that allow yeast cells live years – spore state. If you put the cells in 1% potassium acetate, the cells will convert into spores and will be able to live several year. They will be dormant and highly stress resistant. I can’t say anything about their metabolic rate though, and do you know why? Because nobody in the world in studying that. Can you believe it? I was so surprised. The reason why is I guess because of lack of funding. So, there is no person or agency in the world that is interesting in learning how an organism that normally lives just 6 days can manage to stay alive for several years. This is just so hard to grasp for me.

In yeast the best gene found so far for longevity interventions is Sch9. It is an analog of the S6 kinase that mammalian cells have to sense nutrients and respond in growth and division. Sch9 is more central in nutrient signaling than tor1. This is probably true for all eukaryotes. We know interventions for mTOR, which is a drug that suppresses mTOR activity, called rapamycin. Apparently, there maybe even more potent drugs that slow down aging that work on the S6 kinase. They haven’t been identified yet.

Another very interesting genes in yeast is rash. It senses glucose. Mutant yeast that don’t have this gene also live longer, but not as long as the “top record holder” Sch9 mutants. Sch9 can be seen as a conductor that orchestrates what is happening in the cell. I loved this beautiful analogy that Dr. Longo used, because it really makes you understand why sometimes if a trumpet plays really loud (and a trumpet is a very nice instrument), the whole orchestra doesn’t sound better. It’s the same when you activate one thing, one very good thing on its own, but all together you don;t see an improvement in life extension. The reason is because you need to influence the “conductor”, a gene like Sch9 in yeast.

Sch9 operates through msn2 and msn4 genes that pass on the orders of the “conductor” and activate various genes like cytoplasmic catalase T (anti-oxidative stress gene), DNA damage response genes, heat shock protein 12, trehalose phosphate phosphatase (stress protectant) and others. Also MnSOD (superoxide dismutase, anti-oxidant enzyme) is required for the longevity effect of switching off Sch9 to take place. This effect is 3 times lifespan extension, by the way. Over expressing SOD can only give 10-30% lifespan extension, so it’s crucial when it works together with the “conductor”.

Mutations in tor1 and school that delay aging cause a metabolic shift from the catabolism of glucose and ethanol to respiration and production of glycerol. Glycerol for yeast appears to be a neutral carbon course that does not promote pro-aging phenotype. It’s kind of like “good fat”, like olive oil. Mitochondrial superoxide is a major mediator of DNA mutations, aging, death, and the release of nutrients. Mutations in the Sch9 or Ras pathways extend life span in part by increasing protection against mitochondrial superoxide.

1 Comment

Filed under genomics

Turning Off Pain Receptor In Mice Lengthens Their Lifespan by 10% by Neomatica

Here’s an interesting article posted by a great site about science, technology and humanity – Neomatica.  You should totally check it out.

Biologists from the Salk Institute, who were led by Professor Andrew Dillin (a Howard Hughes faculty member who also has joint appointments at UC Berkeley and Glen Center for Aging Research) found that removing a pain receptor in mice has the trifecta effect of lengthening life spanimproving cognition, and protecting them against obesity.

This effect had been seen before in roundworms and flies but as mice are mammals like us these new results showed that the pain receptor in humans might be a control knob biologically relevant in humans.  A summary of the effects is given by the researchers:

  • Mutation of pain receptor extends lifespan in mice and worms
  • The pain receptor has an impact on insulin secretion, thereby alters metabolism to make mice healthier
  • The mice with mutations in the pain receptor grow normally but have youthful metabolism even when old
  • Using a chemical to block the downstream effect of the pain receptor also increases metabolic health at old age

Judging from the “survival curves” which show the survival of a population of mice over time, normal mice lived about 30 months in the study whereas the specially engineered mice lacking the pain receptor lived about 33 months, a 10% effect.

Previously, in 2007 UCSF scientists headed by Professor Cynthia Kenyon, and Baylor scientists led by Professor Scott Baylor, found that mutations in the analogous pain receptor lengthened the life spans of two very distantly related organisms: roundworms (C elegans) and flies (D melanogaster).

The fact that the effect was duplicated and verified in two organisms presaged the new study that showed the same relationship between longevity and the receptor.

Specifically, Dillin found that the pain receptor TRPV1, when active, sends molecular messages to the nucleus of cells which tells them to churn out proteins many of involving metabolism.  Key proteins affected are calcineurin, CRTC1 and the transcription factor CREB.  In particular, CREB itself was identified as a longevity controller in another earlier study therefore the significance of Dillin’s work is a more “upstream” or “master” regulator was discovered.

The mice are not without side effects.  Without the receptor they areless responsive to pain and stimuli that precede pain (such as strong pressure or near painful levels of heat).

The same receptor is also the one that binds capsaicin, the chemical responsible for sensations of spiciness.  Therefore these mice, were they to be tested, would likely to be found less sensitive to spicy food.

On a more practical level, the work is notable for uncovering yet another mechanism that controls lifespan.  It is probably unwise to genetically engineer out any of the pain receptor genes as sensation to pain is a powerful survival sensory mechanism.

Instead scientists may want to design drugs that block the signals being sent to the metabolic pathways that are linked to aging, thereby finding a “drug-like” strategy to mimick the same effect as removing the gene.

The research was published in Cell.

Leave a comment

Filed under genomics

Vote Kennedy in the Presidential Election

kennedy-brian-1

If your life depends on someone other than yourself, that would be Brian Kennedy. Dr. Kennedy is the President of the Buck Institute for Research on Aging, a world’s leading research institute that brings together outstanding scientists who work together on solving the mystery of aging and revealing the ways of increasing our health span. Basically, it’s up to the successes of the large team led by Brian Kennedy whether you will live a long and enjoyable life, or not.

An excellent example of my  words is the most recent amazing work done by Dr. Pankaj Kapahi and his research group, who was able to extend nematode’s lifespan 5-fold. The trick was to switch off two genes in one worm simultaneously – the TOR  and the insulin-like growth factor-1 receptor (named daf-2) genes. It has been known that turning off TOR in a worm gives it a 30% longer lifespan, and turning off daf-2 doubles the lifespan. One could think that 100% + 30% = 130%, but Dr. Kapahi’s worms decided they know Math better and lived 5 times longer, proving that sometimes  100% + 30% = 500%. What happened is the synergy between blocking the two aging mechanisms – the TOR and insulin/IGF-1 signaling. I have always said that there are so many things  we know that extend lifespan – let’s try the combinations of those things. Indeed, this proved to be a fruitful strategy. I am looking forward to seeing more and more papers combining different interventions in aging mechanisms and getting synergistic results.

pankaj kapahiPankaj Kapahi's paper

Regardless of the country where you live, it always makes sense to vote for someone who may increase the chances for extending your lifespan. Of course, Dr. Brian Kennedy is not participating in the presidential elections, however it would be excellent if the politicians fought for our lives. I think it’s up to us to demand that the politicians include increasing funding for aging research as part of their programs. We have to show it matters. A lot.

2 Comments

Filed under genomics, Mechanisms of aging

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.

1 Comment

Filed under genomics

What Happened after Human Genome Project – Numbers

hgp_measuresWe now know the molecular basis of more than 4.5 thousand diseases. All of the above is thanks to some brave and very talented organizers who managed to persuade the governments of several countries that spending $3 billion on sequencing human genome is a good thing. Now we need the Human Aginome Project to find out the mechanisms of aging and creating therapies to cure this deadly disease.

Our task is to study the experience of how the Human Genome Project was started and learn from this experience. If you have any information on the beginning of this large-scale project, the people and stories behind it, please,  share.

 

3 Comments

Filed under genomics

Understanding Cancer Mutations Makes Testing and Prevention Necessary – Same for Aging

Did you know that there are only 138 mutations that play the major role in making a cell cancerous? Well, 138 found so far, however, the number of these driver mutations inside the genes won’t grow significantly, at least that’s not anticipated. Obviously there are thousands of mutations in cancer cells, but not all of them give the selective grow advantage. This beautifully written review of cancer genetics tells us what the researchers all over the world have learned about differences in normal and cancer genomes. Sequencing technologies are becoming less and less expensive and hopefully very soon we will see sequencing as part of routine clinical testing. Although we are not there yet. The authors of the article provide this outline:

1. Most human cancers are caused by two to eight sequential alterations that develop over the course of 20 to 30 years.

2. Each of these alterations directly or indirectly increases the ratio of cell birth to cell death; that is, each alteration causes a selective growth advantage to the cell in which it resides.

3. The evidence to date suggests that there are ~140 genes whose intragenic mutations contribute to cancer (so-called Mut-driver genes). There are probably other genes (Epi-driver genes) that are altered by epigenetic mechanisms and cause a selective growth advantage, but the definitive identification of these genes has been challenging.

4. The known driver genes function through a dozen signaling pathways that regulate three core cellular processes: cell fate determination, cell survival, and genome maintenance.

5. Every individual tumor, even of the same histopathologic subtype as another tumor, is distinct with respect to its genetic alterations, but the pathways affected in different tumors are similar.

6. Genetic heterogeneity among the cells of an individual tumor always exists and can impact the response to therapeutics.

7. In the future, the most appropriate management plan for a patient with cancer will be informed by an assessment of the components of the patient’s germline genome and the genome of his or her tumor.

8. The information from cancer genome studies can also be exploited to improve methods for prevention and early detection of cancer, which will be essential to reduce cancer morbidity and mortality.

Those 138 mut-driver genes (oncogenes and tumor suppressor genes) can be classified into one or more of 12 pathways. And these pathways can be grouped into three large groups: cell survival, cell fate and genome maintenance. All these things go wrong during aging. The majority of the listed pathways play a role in aging. Naturally, cell senescence is seen as an anti-cancer strategy of the cell. And it works well until it doesn’t. The relationship between these  two processes is not understood completely and more research is definitely needed to answer the question what happens over time. What distorts the balance?

cancer pathways

Cancer is truly an age-related disease. Aging brings decline in DNA repair efficiency and other mechanisms of genome stability maintenance. I think that if we figure out a way how to keep those mechanisms intact, working as good as they do at the age of 16, for example, there’s a good chance we will eradicate cancer, at least the solid tumors. This will be a huge step in increasing human longevity.

I wholeheartedly agree with the authors of the article on the following matter:

“plan A” should be prevention and early detection, and “plan B” (therapy for advanced cancers) should be necessary only when plan A fails. To make plan A viable, government and philanthropic organizations must dedicate a much greater fraction of their resources to this cause, with long-term considerations in mind. We believe that cancer deaths can be reduced by more than 75% in the coming decades (152), but that this reduction will only come about if greater efforts are made toward early detection and prevention.

This idea of prevention is valid not only for cancer, but for aging in general. In my opinion, if we develop the tests, that will definitely include cancer testing, we will be able to see what is happening, what is going wrong on molecular level, and we won’t wait until 90% of the organ is non-functional, until Alzheimer’s have consumed the personality of our loved one, until we feel we can no longer walk up three staircases. We will fight the disease in its infancy, and we will fight aging to remain youthful for as long as we choose to be.

5 Comments

Filed under genomics

Another Possible Longevity-Securing Gene

Interesting research was performed by Dr. Natalie Berube’s group from Western University and Lawson Health Research Institute about the role of ATRX gene and its role in brain function and aging. The paper, published in the Journal of Clinical Investigation, tells us the story of premature aging in mice that lack ATRX gene.

Apparently, if we completely switch off this gene, mice will have reduced growth, shortened life span, lordokyphosis, cataracts, heart enlargement, and hypoglycemia, as well as reduction of mineral bone density, trabecular bone content, and subcutaneous fat. These all are signs of premature aging. Researchers found that on molecular level animals with no ATRX gene develop severe damage of telomeres in their brains, specifically in the forebrain and anterior pituitary and reduced levels of thyroxine and IGF-1.

Basically this means that ATRX gene is responsible for maintaining DNA integrity. Less DNA damage – better survival. The animals didn’t have ATRX gene in their brains only, therefore all of the detrimental effects were apparently due to effects of embryonic development. Hence, ATRX must be a crucial protector from DNA damage in proliferating cells.

Here comes the important question – what happens to ATRX activity in humans during aging? Does it remain the same as it is in a young body? It would be interesting to investigate this, because if ATRX activity is lover in older people than in younger ones, then it means that this gene is securing our longevity, apparently by protecting us from DNA damage. In this case, it could be another target for longevity therapy.

2 Comments

Filed under genomics