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.
We 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.
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 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.
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.
This is Dr. Johnathan Rothberg of Life Technologies who is the first researcher to oficciall register for participation in the Archon Genomics X Prize. The Archon Genomics Prize is an award given by the X Prize Foundation for the first man to sequence 100 whole genomes of centenarians in less than 30 day for $1,000 or less. BBS reports that Dr. Rothberg believes this may be a good start towards finding the “fountains of youth”.
I found it very interesting that Dr. Craig Venter is the originator of the prize. This may be an indication that he is pro-longevity in mind. We’ve already known that he is one of the greatest biologists, but this may serve as an indication that he is in favor of life extention technologies. It would be really great if he worked in this area himself, because ssynthetic biology holds a lot of promise for advancing the longevity technologies. Just imagine a bacteria that lives together with the cells and adds the “good” longevity proteins and suppresses the production of the “bad” aging ones. There’s a chance we can make the cells live longer. Of course, gene regulation is extremely complicated, but one can always start with a simple model and see if it works.
I really enjoyed the talk by Cynthia Kenyon on possible “weak points” in aging processes that can be “attacked” with drugs. Her idea is to identify substances that would make FOXO proteins more active. These proteins are associated with longevity not only in model animals, but also in humans.
The more TED Talks about ways to intervene in aging processes we have, the faster people all around the world would understand the feasibility of life extension therapies. By the way, I was glad to see that there are quite a lot of folks, advocating for longevity in the comments discussion about the video. I think this is another sign of TED audience becoming more and more educated and open-minded in regard to the idea of radical life extension. I would like to address the TED events organizers and ask them to do more talks on the topic of aging.
I found it quite interesting that mutations in multiple myeloma are located in the genes involved in NFkB pathway. This chain of events in the cell activates as a response to various kinds of stress, such as cytokines, free radicals, ultraviolet irradiation and other stressors. NFkB is a transcription factor which is responsible for activating genes linked to increased inflammation. Multiple myeloma genome sequencing revealed that this molecular pathway is altered. So apparently there’s a link between the aberrant activity of NFkB and cancer, and I would like to point out that there’s probably a link to aging as well. It is most likely that inhibition of this pathway may lead to cancer incidence reduction and also anti-aging effects. It has already been shown that pharmacological blocking of NFkB pathway prolongs lifespan in drosophila. Read the paper by Dr.Alexey Moskalev who’s done this experiment.
Open genetic data combined with medical and phisiological information will change the way medicine works – treatments will be personalized and more effective, plus there will be new therapies created specifically for particular patiens. This will significantly improve and prolong our lives. George Church started the Personal Genome Project wich has this exact goal.
I enjoyed the Technology Review interview with Dr. Church about the future of induced pluripotent stem cells. Loved the quote:
“I’m thinking a lot about using regeneration as the key to treatments and keeping people healthy.”
Massive genome sequencing holds promise for entirely changing our society. Cancer genome sequencing already proved to be effective, we’ll find out a lot about our disease risks and causes and we’ll be able to cure and prevent deleterious diseases. That all will prolong our lives. Plus we’ll be able to find all sorts of new links between our genomes and behaviour like the “cheating” gene.