Martin Wapenaar (Mentor)
I am a biologist and researcher, specialized in human molecular genetics and genomics, and co-producer of the free online course 'Why Do We Age? The Molecular Mechanisms of Ageing.
Location European Research Institute for the Biology of Ageing (ERIBA), University Medical Centre Groningen and University of Groningen, Netherlands.
Activity
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This is an old question concerning the enigma of morphogenesis and cell differentiation. Essentially, the position of an undifferentiated cell within a morphogenetic field determines what next cell fate decision steps will follow as part of a developmental program. It all depends thus on position and cell signalling via agents called morphogens. These are...
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Elton, daughter cells budded off from older mothers inherit more ageing factors as their mothers (1) accumulated more of them during replicative ageing, and (2) are less efficient in retaining these ageing factors by asymmetrical division. This is indicated in fig 2 of the PDF Replicative_Ageing_Part1 in step 2.6
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Thanks Chris for pointing out this breakthrough technology that may turn out to be a real game changer. For those who would like to read more about its history of discovery and potential applications in the biomedical field, this review (free access) might be useful as an extension to this introductory YouTube...
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Sorry for the confusion caused. The Geometric framework concerns the macronutrients, meaning the major dietary components: carbohydrates, proteins, and lipids. I have corrected the two errors in the transcript file.
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Donald, your comment that "men seems to be just to fertilise the egg" and "the male dies having fulfilled its main functions" only applies to some species of fish,turtles, and lower organisms that do not care for their progeny (characterised by their huge numbers of offspring) and only fertilize once in a lifetime (semelparous). Since the difference between...
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See the similar question from Sherry Vermette (01 July) and my reply to her (02 July).
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Actually, scientist specialized in protein structure indeed use these type of spectacles together with powerful 3D software to study the interactions between enzyme and substrate.
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A beautiful bedtime story that belongs in the category of Science Fiction, rather than that of empirical Science.
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Hi Steve. I recommend you to read this chapter from the Scitable eBook 'Essentials of Genetics' to get a correct notion of meiosis and sexual reproduction: http://www.nature.com/scitable/ebooks/cntNm-8/135497480#bookContentViewAreaDivID
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As mentioned by Hasan below, peptides needs to adopt the proper 3D structure (tertiary structure) to become fully functional. Enzymes (catalytic proteins) e.g. use these structures so that they create a pocket in which the substrate exactly fits. If the structure is disturbed by accidental misfolding or a mutation then the substrate doesn't fit and the...
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According to Darwin natural variation (mutations), natural selection, and survival of the fittest individuals go hand in hand in the evolution of species.
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Martin Wapenaar (Mentor) replied to Ian Hunt
Glynis, every participant of the course can take as much time as needed to digest all the information offered. I hope you may find time to finish the course. How about sitting in your garden and reading the transcript and figures? You might get inspired to write an essay as well ;)
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Keep in mind the difference between longevity and average lifespan (life expectancy). In those early historic days until recent times death in infancy was very high. Those who survived infancy had life expectancies that for the very strong (and lucky) ones could reach 70 to 80 years. King David (if he ever existed as a historical person) would probably have...
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A good point you raise here, Deana. I'm inclined to say that progeria syndromes mimic ageing symptoms. These syndromes of premature ageing are caused by mutations in a single gene. We know that in general this is not the case for conventional ageing. However, the process of premature ageing in these patients recapitulate in a shorter timespan many of the...
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Microorganism have a much short generation time and therefor accumulate more mutations than humans. This allows the population (but not the individual organism) to survive and adapt to changing environmental conditions due to raped genetic change over a short time interval. Humans, however, are as individuals and populations extremely adaptable as we can live...
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Martin Wapenaar (Mentor) replied to Anne Mackay
UV-light damages DNA in a specific manner, regardless of who is the host of this DNA - bacteria, yeast, or humans. In the lecture of Victor Guryev in Week 3 you will learn more about DNA damage and repair, including UV-induced mechanisms.
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Individual cells don't benefit from telomere attrition as the consequence is senescence and apoptosis. However, the individual may benefit as it prevents cells becoming cancerous due to the age-related accumulation of precancerous mutations. Remember also that natural selection acts on the level of individuals.
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The essence is that somatic (body) cells acquire and accumulate mutations over time but germline cells don't, or to a much lesser extent. Also natural selection mechanisms are in place that prevent most of the new mutations to be transmitted to the next generation. In this way there is not an accumulation of mutations over subsequent generations that may...
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This is very unlikely. Aneuploidy randomly affects individual cells and may only clonally expand in case of tumour growth. Diabetes type I affects all beta cells in the islets of Langerhans simultaneously due to a Th1 autoimmune response directed against these cells. As a result these beta cells either die or go into (permanent) dormancy to avoid the...
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Thanks for attempting to write the essay of your choice. Indeed, one of the purposes of this assignment is to challenge you to think actively and critically about what you have learned in the course from tutors, fellow students, and shared references. Writing an essay or explaining to somebody else what you have learned forces you to organise your thoughts and...
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Control over fire and the ability to cook food (particularly plant-based) released valuable nutrients in quantities not available before. This allowed the brain to grow and become more complex. It also made time free to develop cultural activities. In this manner the initial brain development created conditions that would advance its further development. Some...
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A cow needs this long gestation time because it is a much larger animal. This also explains why its brain size is larger (but not so complex). A cow is as smart as it needs to be for what it does, eating grass. As a herbivore it also takes up much less energy from its nourishment than the generally more cunning carnivores. A larger and more complex brain...
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Yes you're correct. It must have been a slip of the tongue by Ellen. I'm sorry because this makes it confusing. See also my earlier comment on 2 July.
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Barbara, I think we have to accept these reports as they are. As the vet in this article stated is was something of a recent development he observed with dogs getting older because of new possibilities of treatment not available before. Maybe it takes special circumstances as with these pets to age to the point that some of them may experience symptoms...
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Martin Wapenaar (Mentor) replied to Ian Hunt
Thanks for all your kind words, Ian. I'm happy we were able to open an entire new world for you. You persevered and learned, as you put it, to understand a 'new language'. To comprehend the essence of this course you had to learn in a short time the basics of molecular biology and genetics. By doing so you will from now on be able to readily comprehend similar...
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These mechanisms for protein refolding and degradation are conserved throughout eukaryotic evolution, from yeast to human.
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Martin, the opposite of DNA sequencing is DNA synthesis. Trying to do this for entire chromosomes from complex organisms like plants and insects is still too difficult. This field of synthetic genomics and synthetic biology is rapidly evolving and particularly focussed on engineering new useful bacteria. This review paper gives an overview of the history and...
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This is not likely since death by heart attacks usually occur after the reproductive years. It is neutral with respect to the progeny and not influenced by natural selection. Lifestyle has an enormous impact on heart diseases and gradually the gap in the survival curves of men and women are diminishing. Women will always have the benefit of the protective...
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The answer is no. Overall, the mutation load is in absolute numbers still low despite the age-dependent increase. Severe mutations won't make it to the next generation due to natural selection of sperm and embryogenesis. The old fathers' effect has been measured in an increased number of children with mental disorders like autism and schizophrenia.
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Robert, theoretically it is possible that when a chromosome replicates it ends up with a metaphase chromosome that contains two different chromatids - one with, and one without an active gene. After cell division only ONE of these chromatids (now chromosome) segregates to a daughter cell - either with the active or inactive gene. Be careful with the...
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Indeed, a replicating chromatid contains multiple replication bubbles (origins of replication) that replicate new DNA strands form the template strands in two directions. Each bubble contains two leading and two legging strands. Important is that the original template strands (Watson and Crick) are used for DNA sequencing while the newly synthesized strands...
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The laws of Mendel apply during meiosis since daughter cells receive (if correct) a complete haploid set of chromosomes. The distribution of the chromosomes is random, meaning no preferential set of parental or maternal chromosomes to a gamete. Free assortment to maximize genetic variation.
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Indeed Spike, the drop in estrogen level has a negative impact on women health, even beyond that of CVD, like e.g bone mineralization. It appears that estrogen protects women during their fertile years and may be explained in evolutionary terms.
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The deterministic aspect of epigenetics means that the epigenetic state is correctly transferred to daughter cells. However, small (stochastic) mistakes can occur in this process and accumulate with age. Gradually the original epigenetic state becomes corrupted. In this way the stochastic process proceed at the expense of the original deterministic state,...
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I see your point. Purely a numerical chromosome change is neither beneficial for a normal cell nor for a pre-cancerous cell. As Floris explained in his lecture, aneuploidy brings the cellular homeostasis out of balance, which is unfavorable for the cell. Only additional growth-promoting mutations may overcome this initial disadvantage. However, aneuploidy...
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Interesting supporting information. Phil, could you please summarize the essence of this paper and fill it in with what you have learned during this course, both during lectures and discussions)? Keep in mind how the wild type 'dog' evolved.
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You have learned that two out of three cancers are characterized by aneuploidy, suggesting a strong causal relation between the two. Now you have also learned that aneuploidy is not a primary initiator of cancer but accelerates cancer once it has been established by other mutations. This aneuploidy-induced growth acceleration may happen through new genetic...
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The clue may indeed hide in what distinguished us and our ancestor hominids from other primates: brain development, extended and complex social networks, language, culture, long period of childhood dependency. These intertwined ingredients basically all boil down to the extraordinary complex brain development in hominids. Interesting in this respect is that it...
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The best way to find out is always to check first the references in the original publication and complement this with your own publication research using PubMed (http://www.ncbi.nlm.nih.gov/pubmed).
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Despite biological systems (organisms) evolve over time, their constituting elements do less due to functional constraints. Genes and proteins, particularly their essential structures, remain highly conserved through evolution. So are the molecular pathways in which they act, albeit less stringent. Most essential life processes (e.g metabolism) proceed in a...
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This preprint manuscript from the group of Kun Tang (Shanghai) tries to explain this from the unique brain evolution of humanoids over a longer timespan of 500,000 years. It is extremely hard to understand the details of this population genetics paper but the abstract and the general conclusions are easy to understand and are truly...
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Bernadette, you and others have sufficient time to turn in your essays as this course for registrants remains open for a long time.
I'm not aware of a role for viruses in general ageing, accept for viruses that have integrated in the genome and contribute to genetic instability as pointed out by Victor Guryev. It could be that virus-induced diseases have a...
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Interesting comment. Thanks Elaine.
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CVD kills men earlier because they lack the protective effect of estrogens but in the end more women die of these diseases than men.
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Martin Wapenaar (Mentor) replied to Andrew Kahr
All GWAS studies share the same 'problem' that they insufficiently account for the heritability of traits as observed in twin studies. This is the problem of the 'missing heritability'. This could be intrinsic to the statistical methods used as the impact of each DNA/gene variant is tested independently for its effect on the phenotype. The added effect of all...
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There is not a single answer that satisfies all questions on all species. We have covered several important, but not all mechanisms and aspects of longevity and ageing. Each species observed today is most fit to its current living conditions and has been selected for its unique requirements. Even closely related species may have widely varying lifespans....
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In your 'conclusion' you now ignore the heritability of longevity altogether. Also the results of GWAS and genetic linkage studies support the genetic aspects and give insight in the molecular pathways involved. You seem to waver between 'determinism' and 'nihilism' when it comes to the genetic aspects of ageing. Genetics can never be seen in isolation form...
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An added note to your remark on the BRCA gene. In general, the further we go down the evolutionary tree orthologous genes may have evolved different biological functions. Even paralogs may have acquired different functions. The prime function of a gene is not to be a disease gene, despite the media frequently state that a 'new disease gene' has been...
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This discussion started with comparing different wild type mammalian species regarding lifespan, metabolic rate, and reproductive cycle. Dogs breeds are highly inbred and recent varieties within a single, relatively recent, species and intensely selected for extreme phenotypes. In this man-made procedure, avoiding natural selection, normally rare recessive...
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Your comment, although I don't concur your protein-depletion hypothesis, made me think of a way of proving whether the male testicles negatively affect lifespan - castrati and eunuchs may give a clue. This news item discusses some of these studies and may be of interest to...
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Martin Wapenaar (Mentor) replied to Janet P
In this respect the recent publication of a Cambridge UK study on the age-related accumulation of pro-cancerous mutations in the skin is of note: "Thus, aged sun-exposed skin is a patchwork of thousands of evolving clones with over a quarter of cells carrying cancer-causing mutations while maintaining the physiological functions of epidermis". The BBC devoted...
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Eugene has addressed your question in this forum. "Follow" this educator to quickly retrieve his comment by selecting "Following".
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The original parental template strands are called the Watson and Crick strands (distinguished by two colors in the animation). The naming of the template strands as to which one is the Watson or the Crick strand is arbitrary. The newly synthesized complimentary DNA strands with incorporated BrdU will be degraded.
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Indeed Susan, that's the essential difference between the two studies and that may explain why one study yielded a positive outcome while the other had negative result.
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Yes, in general, multifactorial traits and diseases show an interaction between complex genetic factors and an variety of environmental and lifestyle factors.
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This comparison between large cohorts of affected and non-affected are the basis for Genome-Wide Association studies (GWAS), a method from genetic epidemiology. By including larger cohorts, or combining studies in meta-studies, the statistical power of GWAS studies are increased and allow for the identification of significant genetics risk factors (DNA...
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You have an interesting point here, Denis. We question why on average do women outlive men. This difference is compressed to the last non-reproductive years of their lives. We could also approach this question from another angle: Is it not remarkable that throughout most of their lives - birth, development, reproductive years, and beyond - the ratio of males...
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I seems so obvious, on average men life shorter than women, and only men carry Y chromosomes. Hence, the shorter Y chromosome must be the culprit. It may be, but it could also be association without direct causality. Remember the lecture of Peter Lansdorp on telomeres where he showed that even from birth men have shorter telomeres than women? It has been...
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Twin studies have shown that the heritability of longevity is ~30%, meaning that gene variants may explain 30% of the difference in lifespan. The difficulty is in finding which gene variants are responsible. Three means have been at our disposal: 1) testing of (functional) candidate genes in population studies; 2) pedigree studies in families enriched for...
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These acronyms are highlighted as hyperlinks in the text. The lead you to the NCBI database of genes and explain their name, function, genomic location, and references to research publications. It is just a click of the mouse away...
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I would not bother too much about an exact word count. It was roughly an indication of the length of what is expected of an essay (~1,000-1,500 words). Most important is that you can make your argument. You may indicate the reference in the body of the text with a number or name & year, and a reference list (numbered or alphabetical) with the publication...
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Martin Wapenaar (Mentor) made a comment
An interesting article from the BBC about the various ageing strategies in plants and animals. It covers all the elements you have encountered in the course with some fascinating examples:
http://www.bbc.com/earth/story/20150622-can-anything-live-forever -
These rules of thumb are confined to comparing mammals. Rate of heartbeat and metabolism, and development towards independence and reproductive age appear related and can be summarized as 'live fast, die young'. Why, you ask. Probably the enhanced metabolism and growth rate also produces faster waste and side products, e.g. free radicals, that accelerate ...
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See below.
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Elaine, much of this experienced extra energy may be attributed to the considerable weight loss. It makes a huge difference not carrying around 20-30 kg of useless weight - compare it to walking around the entire day with a heavy rucksack. However, this can be achieved with a sensible diet/exercise regime without the hardships and risks of a genuine CR.
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I would like to draw your attention to the Alzheimer's Disease Genetics Fact Sheet (PDF) from the NIH National Institute on Aging:
https://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-genetics-fact-sheet -
A lifetime risk up to the age of 85 includes also all the individuals who had Alzheimer's disease (AD) but died before the age of 85. It is a cumulative risk regardless at which age you die. The latter graphs are based on the prevalence of AD in a cohort of individuals all with the age of 85. The later age groups, though more vulnerable to AD, will also be...
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I placed a comment (with a link to a review) in part 3 of Ellen's lecture in reply to Sally's comment on 1 July, and as a follow-up to the Guardian article referred to by Anthony and Sally.
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Thanks for mentioning this news article, Sally. A potentially interesting development.
PERK is one of the three pathways in the unfolded protein response to escape cell stress upon dysfunction of the endoplasmic reticulum. Activation of these pathways attenuate protein synthesis and activates genes that help cells to de-stress. If this fails it prepares...
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Vitiligo is probably an autoimmune disease with a complex genetic component. I'm not aware of an ageing component or drift towards a younger age of onset. "The average age of onset of vitiligo is in the mid-twenties, but it can appear at any age."
http://ghr.nlm.nih.gov/condition/vitiligo -
Thanks Michael,. I think you're right. I will check.
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There is much research going on in this field because there are suggestive results that the microbiome (a highly complex community of symbiotic microorganisms) play an important role in health (e.g. metabolism, obesity, immunity, development, etc.) and may be even considered as an extra organ with its enormous complex genome. It is a varied branch of science....
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Joan, some helpful...
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There are an estimated 20,000 genes in the entire human genome. These may code for about 100,000 proteins. All these genes have unique names and acronyms designated by a nomenclature committee. Some genes have multiple names because of historic reasons. Below a link to a searchable database from the NCBI with these gene names. The protein-coding parts of the...
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You could speculate that that may be the reason. You see also that throughout life this difference between males and females is maintained. It could be that the prenatal growth spurt in males is driven by testosteron and that this consumes more of their initial telomere lengths.
Man may provide more of the genetic variation in this way than females. Older...
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1) Yes, they are also C-rich. However, because of the single-stranded 3'-overhang there is more G in the sequence and that may be the reason to call it G-rich. A convention, also because of the 5'-3' directionality.
2) I'm not aware of sperm cancer but testicular cancer is not uncommon. I'm not sure if that involves mainly epithelial tissue or also gonadal... -
I see, the glossaries of week 4 and 5 still need to be uploaded as PDFs. We will take care of that.
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In essence it does not make a difference for the total amount of calories whether they are derived from sugar or complex carbohydrates. Having said that, fast sugars lead to a sharp rise of the blood sugar (glucose) levels while complex carbohydrates lead to a more gradual increase of blood sugar. This has consequences for the insuline response required and...
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You're right that the calorie requirement is related to the energy consumption by activities. In these experiments it is about the composition of the macronutrients at a certain calorie level. Thus the ratio of proteins/carbohydrates at a given calorie supply. I guess that exercise has many more positive health and lifespan effects (e.g. muscle and bone...
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Thanks for noting. It will be corrected.
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Concerning those people that we all envy that stay slim while eating without any limitations. To make matters even more complicated, recent researches in mice suggested that also the type of microbiome (intestinal flora) may play a significant role in the vulnerability to obesity. Athletes drink energy drinks because they need quick carbs (glucose/fructose)...
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See my answer above to Maureen Twiddy on 20 June.
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Anthony, the question mentioned the identification in the genetic screens. In these genetic screens these modifiers of aggregation were identified because they were inactivated and thus protect against toxicity. The essence of the question, however, was which genes were tested in human cells. We will consider rephrasing the question though.
Sherry, I...
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Read Jeanne's comment below for a clear summary. Depletion of MOAG4/SERF or TDO-2 reduces the effects of toxicity and aggregation and increases lifespan.
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Jeanne, an excellent summary. As usual, I may add.
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Thanks for notifying us. I will make changes.
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Anthony, TDO-2 drives protein toxicity, likely by DECREASING the levels of tryptophan. Sorry for the confusion caused. TDO-2 depletion reduces toxicity and extends lifespan. TDO-2 is an enzyme that converts tryptophan, and tryptophan protects against toxicity. The model is that with age the level of TDO-2 increases and thus the level of tryptophan decreases...
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Interesting point. So, an example of antagonistic pleiotropy?
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Briefly, an orthologue is a homologous gene in another species, e.g. YAP1802 is the yeast orthologue of the human PICALM gene.
You may encounter the terms HOMOLOGUE, ORTHOLOGUE, and PARALOGUE. Genes (or DNA sequences) may show similarity without being identical. We say these genes are homologous and we can express the extent of homology in a percentage of...
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The role of the human orthologue PICALM in Alzheimer disease was established by the genetic association of variants of this gene in a large population study (GWAS, Genome-Wide Association Study). This means that genetic variants of PICALM are statistically associated with an elevated risk of contracting Alzheimer's disease. Additional data suggest that...
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Jeanne Mitchell (29 June) wrote a clear explanation to solve this paradox of the amyloid-beta plaques.
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Essentially, this is the hypothesis. The final amyloid aggregates may be protective while the intermediates might be the toxic ones. If the steady supply of intermediates become too much to process by aggregate-sequestration then their amount may rise to the point that they become toxic to the cell, up to the point of neurodegeneration.
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Well Donald, the next lecture series by Ellen Nollen might convince you that this is possible. Maybe you can repost your question, or even come-up with a possible explanation, why this slow process in humans can be recapitulated in roundworms within just 3 weeks.
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Thanks Phil for your extensive commentary and provided links to useful reading. Indeed, you may defend the view that Huntington's disease is a bit of an oddball in this group of typical age-related neurodegenerative diseases. Particularly because of its autosomal dominant transmission with anticipation effect. However, you pointed out the similarities as well...
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In case of personal genetic questions you may consult a clinical geneticist who can inform you on genetic diseases, family recurrence risks, and the possibilities of genetic testing.
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These large structural variants may affect multiple genes and in that case could either be incompatible with life or diminish the procreation of the affected patient. Most serious defects will lead to an interruption of early embryogenesis and (unnoticed) natural abortion.
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Indeed, that's the theory. The way the retrotransposon copies its DNA via a mRNA intermediate into another genomic location is reminiscent of a retrovirus like HIV. The difference is that retrotransposons lost the ability to produce virus particles. It has become fixed to its host like an endoparasite. You may hypothesize that this primordial retrovirus...
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Thanks for noting, Steve. I adjusted the text to prevent further confusion. This discussion step does not require knowledge of the barcoding method per se. Barcoding to trace the fate of individual stem cells will appear in part 2 of Gerald's lecture (4.14). This technique will also be described in a separate article (4.15).
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You will learn much more about this topic in the lecture series of Michael Chang, Peter Lansdorp, and Gerald de Haan, in respectively weeks 2, 3, and 4.
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Michael, this is utterly nonsense. Could you please stop your continued attack on X chromosome inactivation as a cause of ageing. It is baseless and confusing to others in the forum. I replied you several times on this point but you continue spreading this false information.
