Sunday, 9 May 2010

New insights into sensory representations-Lessons from the auditory cortex

ResearchBlogging.orgIn the brain, there are highly ordered representations of sensory input. The existence of orientation columns in the visual cortex where columns of neurons situated next to each other respond to slightly different stimulus orientations and the barrel cortex in S1 where each barrel faithfully receives inputs from one whisker are testimony to this. Recently two papers in the same issue of Nature Neuroscience dealt with the fidelity of sensory representations in the auditory cortex. Rothschild et al. and Bandyopadhyay et al. used in-vivo two photon microscopy to map tone evoked activity in the primary auditory cortex (A1). This is done by bulk loading a large area of the cortex with a membrane permeable calcium dye. When a neuron that has taken up the dye fires an action potential, there is also a transient influx of calcium (related to synaptic transmission). The interaction of the calcium ions with the calcium indicator can be visualized under a two-photon microscope. 

Both studies showed, that unlike the visual and barrel cortices, the auditory cortex appears to have a tonotopic map that is fractured. Firstly, less than half the neurons were responsive, and even if they did respond, neurons with similar tuning curves were as likely to be located next to each other as neurons with very different tuning curves. Fig 1 (taken from a review by Castro and Kandler, Nature Neuroscience 2010) elaborates on this.

Fig1a would be the classic tonotopic map where there is a smooth change in frequencies along the rostrocaudal axis with more rostral neurons coding for higher frequencies while more caudal neurons code for lower ones. Here, tonotopy is maintained on the local as well as the global scale. Fig 1b summarizes the results of Rothschild et al. and Bandyopadhyay et al. Although the tonotopic organisation is maintained on a more global scale, locally the map appears to be fractured (From Castro and Kandler, 2010)

So why is the tonotopic map fractured? One possibility is that the thalamocortical projections from the auditory thalamus to A1 become scattered en route. Alternately, thalamocortical axons may be arranged tonotopically but resulting intra-cortical processing may result in the fractured nature of A1. To distinguish between these two possibilities, Bandyopadhyay et al labeled cells with two different calcium indicators, Fluo 4, a low affinity indicator that responds only to spikes in the cells, and OGB-1,  a high affinity indicator that responds to subthreshold synaptic inputs into the cells. They found that subthreshold maps were more ordered in comparison to suprathreshold maps based on spiking (Fig 2).

Fig2; Subthreshold and Suprathreshold maps (From Castro and Kandler, 2010)

So what does all of this mean? Bandyopadhyay et al suggest that although two neighboring neurons may receive similar , correlated inputs, they may be part of different fine-scaled assemblies that could process inputs differently. Two adjacent cells may be selective for different input features or different stimulus attributes. Taken together, both studies indicate that frequency is perhaps not the most important feature coded by A1 neurons. Neither is intensity tuning or bandwidth. A1 neurons probably respond to meaningful stimuli and not just to simple sound parameters. This is supported by studies that have shown that A1 neurons are best driven by spectrally and temporally rich stimuli.


Castro JB, & Kandler K (2010). Changing tune in auditory cortex. Nature neuroscience, 13 (3), 271-3 PMID: 20177415

Rothschild, G., Nelken, I., & Mizrahi, A. (2010). Functional organization and population dynamics in the mouse primary auditory cortex Nature Neuroscience, 13 (3), 353-360 DOI: 10.1038/nn.2484

Bandyopadhyay S, Shamma SA, & Kanold PO (2010). Dichotomy of functional organization in the mouse auditory cortex. Nature neuroscience, 13 (3), 361-8 PMID: 20118924

Saturday, 24 October 2009

Why it pays to be a biologist

I have nothing against theoretical physicists or mathematicians, but it's a lot safer being a biologist. Here's why

For more geeky humor, visit xkcd

Sunday, 18 October 2009

Deep Sea Killers-C. megalodon

Many consider the Great White Shark (Carcharodon carcharias) to be among the most incredible creatures to roam the oceans today. Growing up to a length of 6m (20ft), it is the infamous creature made famous by the success of the movie Jaws.

The Great White Shark as a species can be traced back to the early Pliocene (5 million years ago). It's fossilized teeth (Fig.1) can be found almost anywhere, worldwide, in marine sediments of the correct age. Teeth found in the Miocene (15 to 13.5 million years ago) are slightly rolled and have an eroded edge. Common synonyms for these teeth are Carcharodon rondeletti and Carcharodon sulcidens, but the teeth are identical to those of the living species not regarding intraspecific variation.

Fig. 1. Fossilized tooth of Carcharodon carcharias. Height: 5 cm. Early Pliocene, Sacaco/Peru © L. Andres

About 16 million years ago (during the Miocene), a distinct species appeared in the world's oceans. Carcharodon megalodon (or C. megalodon) was possibly the biggest shark species to have inhabited the oceans. It may have attained an astonishing maximum length of 15 m (50ft) and weighed as much as 50 tonnes (Fig.2)

Fig. 2. Comparing C. megalodon (13 m) and the Great White Shark (6.5 m) © L. Andres

Such estimates are obtained from teeth and certain skeletal components (as sharks have a skeleton made out of cartilage that does not fossilize easily; the teeth however are very durable). Traditional research holds C. megalodon as an ancestor of the white shark. Recent research suggests that it may have been a close relative. It's triangular teeth may have reached a maximum height of 17 cm (Fig.3). It may have hunted in the same stealthy manner as white sharks do, stalking beneath it's prey and rising upwards at great speeds to deliver a forceful, and often fatal, first bite.  It's prey probably included primitive whales and other large marine mammals.

Fig. 3. Fossilized tooth of Carcharodon megalodon. Height: 13 cm. Middle to Late  Miocene, Florida/USA © L. Andres

Around 1.5 million years ago (towards the end of the Pliocene), C. megalodon became extinct. The development of megatooth sharks can be traced back until the Cretaceous period. It is directly linked with the development of other animals. In the Cretaceous not only sharks, but also marine reptiles ruled the waters. This condition changed, however, after the extinction of the dinosaurs (65 million years ago) in favour of the sharks. Sharks now occupied the ecological niches for predators. Additionally, the basis for a more energy-rich nutrition was created by the rise of marine mammals (such as the cetoheriids; ancestors of baleen whales) in the Eocene (55 to 33 million years ago). During the Late Oligocene (30-25 mya) the climatic conditions were much more favourable. Temperatures were significantly higher than they are today, tropical and subtropical waters reached much further into the higher latitudes of the polar regions. During the following epoch, the Miocene (25-5 million years ago), modern baleen whales (Mysticeti) developed and spread more and more. There was an increase in size in whales and simultaneously in megatooth sharks. During the spreading out of the whales they presumably reached cooler polar waters that provided them with a richer food supply to which the whales adapted themselves. The whales were migrating between cool water feeding grounds and warm water breeding grounds. The climate became colder at the end of the Miocene and the beginning of the Pliocene (about 5 million years ago). The ice cover of the Antarctic polar region grew bigger and the mean sea level dropped. Living conditions and habitat for C. megalodon, who probably loved warm waters, obviously were restricted to such a degree that the species became extinct during the Pliocene. 


C. megalodon-Megatooth Shark by Lutz Andres

Roesch, Ben S. 1998. A Critical Evaluation of the Supposed Contemporary Existence 
Carcharodon megalodonThe Cryptozoology Review 3 (2): 14-24.

Tuesday, 29 September 2009

Evolution of scorpion venom

The predominant pharmacologically active components in scorpion venoms are small polypeptide molecules, usually basic in nature. Scorpion venoms and their component elements have been studied for over 35 years; but lately the focus in these studies has shifted from their pharmacological and electrophysiological properties to their molecular structures. This came about due to the realization that many classes of peptides seem to bind to characteristic spots on their targets, which for the most part are ion channels. The peptide toxins also show considerable identity in their arrangement of cysteine residues within the polypeptide chain. These cysteine residues are terribly important because disulphide bonds are one of the major contributors to conformational stability in small peptides.

The first pharmacological studies on scorpion toxins concentrated on their effects on mammalian model systems, so mice were the first ones to draw the short end of the hypodermic syringe, for a while. Peptides were consequently classified into the alpha- and beta-types, where each type bound to its own special site on voltage-gated sodium channels. Eventually, however, it was discovered that some peptides worked against ion channels in insects, and now Sarcophaga argyrostoma blowfly larvae were adopted as the victim model system of choice. All anti-insect toxins induced paralysis, but one class of toxins was found to induce a contraction paralysis, while the other induced a depressant paralysis.

For a while it seemed that all peptides could be neatly docketed in this way, but continuing studies unearthed peptide toxins that were primarily anti-mammal but showed some anti-insect activity too. Subsequently peptides were found that showed comparable anti-insect and anti-mammal activities, one of which – showing anti-insect as well as alpha-type and beta-type anti-mammal activities – was first reported in the paper (Loret et al., 1991) referenced below. This sparked off a line of thought on how the types of peptides found in scorpions in different parts of the world could be used to put forward theories about where scorpions first appeared and how they diverged into the large number of species we see today.

The reason this cross-reactivity of toxins against insect and mammal receptors was such a big deal was this: Before this was discovered, toxins were found to be easily classifiable not only on the basis of their primary peptide sequences and pharmacological activities, but also based on geography. Alpha-type anti-mammal toxins came only from Old World scorpions and beta-type anti-mammal toxins came only from New World scorpions. All anti-insect toxins had been purified from Old World scorpions only. Deviations from this geographical structure brought to light interesting ideas about venom evolution in scorpions.

For example, the toxin mentioned above which had a high effect on mammals but a low effect on insects was a beta-type toxin from Centruroides (a New World species) which was toxic to insects, but 50 times weaker than Old World anti-insect toxins (these studies happened in the 80s). This could indicate that anti-insect activity is just starting to evolve in New World venoms, but has already become established in Old World ones, indicating that the Old World venoms appeared first in their evolutionary history.

The paper referenced below is a report of a toxin from Androctonus australis Hector (pictured below), called AaH IT4. The toxin was purified by successive steps of chromatography, on gel filtration, DEAE-Sephadex and C8 HPLC columns. Toxicities were tested on S. argyrostoma larvae and male C57/BL6 mice, and the ED50 values (for larvae) and LD50 values (for mice) were recorded. Binding assays using 125I-iodinated toxins on synaptosomal preparations from cockroaches and rats; radioimmunoassay assays to check for cross-reactions with rabbit antisera against known anti-insect, alpha-type and beta-type toxins; and circular dichroism analyses for structural data were carried out. In addition, sequence analysis and sequence alignment against various other scorpion venoms were carried out.

The experimental data showed that AaH IT4 competed with all three types of toxins for target-binding, and that it cross-reacted with the antibody against a beta-type toxin, indicating some structural similarity with the beta-toxin class. The dendrogram generated from the sequence alignment showed that AaH IT4 is more closely related to beta-type toxins than to either alpha-type or anti-insect toxins (which supports the result of the RIA experiment), although the divergence between AaH IT4 and the beta-type toxin lineage took place a long time ago. This an important point because beta-type toxins come from New World scorpions while AaH IT4 was purified from an Old World toxin, so any sequence similarity suggests that some relationship may exist between the two.

Another point to be made about AaH IT4 is that the sequence analysis shows an absence of the amino acid proline. Proline had previously been found in every purified and studied peptide scorpion toxin, and was suspected to play a role in the stability of their conformations, since proline is more conformationally restricted as compared to the other amino acids. One explanation for the binding of AaH IT4 to three different kinds of binding sites is that the absence of proline allows a certain amount of backbone flexibility which may allow the peptide to switch between conformational states that preferentially bind to each of the target sites.

The authors themselves hypothesize that since the evolution of insect-specific toxins is clearly advantageous to scorpions (for whom insects form a major part of the diet), it is possible that AaH IT4 represents the closest approximation available right now to some kind of ancestral toxin sequence/structure, which later diverged into anti-mammal and anti-insect varieties.

I think it’s worth mentioning, in addition, that the isolated AaH IT4 corresponds to 0.06% of the total protein in the venom, so it’s possible that the production of this particular venom component may have undergone some down-regulation over the years, as a result of the development of other, more specialised toxins.

Post-1991, of course, the issue of toxin classification has become even more complicated, and the venoms being studied now include those with anti-arthropod specificity, and the set of recognised targets have grown to include voltage- and ligand-gated potassium- as well as calcium-channels instead of just the initial emphasis on voltage-gated sodium-channels. Peptides with microbial activity have also been reported.


Loret, E., Martin-Eauclaire, M., Mansuelle, P., Sampieri, F., Granier, C., & Rochat, H. (1991). An anti-insect toxin purified from the scorpion Androctonus australis Hector also acts on the .alpha.- and .beta.-sites of the mammalian sodium channel: sequence and circular dichroism study Biochemistry, 30 (3), 633-640 DOI: 10.1021/bi00217a007

Saturday, 26 September 2009

Innate Immune Cells: Mediators of the Angiogenic Switch?

ResearchBlogging.orgThe role of Matrix metalloprotease type 9 (MMP-9) in the activation of Vascular Endothelial Growth Factor (VEGF), the induction and maintenance of chronic angiogenesis and early stage tumor growth has been well established. But what is the source of MMP-9 ? In a study published in 2006, Nozawa and co-workers, using the RIP1-Tag2 transgenic mouse as a model, identified two inflammatory cell types, neutrophils and macrophages, as the major sources of MMP-9.

The RIP1-Tag2 transgenic mouse is a well characterized model of multistep carcinogenesis involving the pancreatic islets. Nozawa and co-workers first isolated constituent cell types from a tumor and cell-sorted Gr-1+ and Mac-1+ cells and then carried out a semi-quantitative RT-PCR (see Fig.1)

Fig. 1: Semi-quantitative RT-PCR. MMP-9+ is expressed by Gr-1+ and Mac-1+cells innate immune cells (Adapted from Nozawa et. al, 2006)

Clearly, MMP-9 was expressed predominantly by innate immune cells positive for the Gr-1 and Mac-1 markers.

In order to determine the localization of these cells , a double label immunohistochemical staining of various leukocyte markers in normal and neoplastic tissue was performed. CD68 and F4/80 are two macrophage markers. Cells positive for both markers were observed inside as well as on the periphery of angiogenic islets and tumors (see Fig. 2). However, the cells inside were MMP-9- while those along the periphery were MMP-9

Fig. 2: MMP-9+ macrophages located along the periphery of the angiogenic islet.Macrophages inside the islet were MMP-9- (Adapted from Nozawa et. al, 2006)
Along similar lines, an antibody against the "7/4" (a neutrophil marker) was used to localize neutrophils. Suprisingly, the situation, this time, was the opposite. 7/4+ cells inside the lesions were also MMP-9+ while 7/4+ cells along the periphery were not (see Fig. 3). All  7/4+ cells also displayed polymorphic nuclei, strongly indicating that these cells were neutrophils.

Fig. 3: MMP-9+ neutrophils located inside the angiogenic islet. Neutrophils along the periphery of the islet were MMP-9- (Adapted from Nozawa et. al, 2006)

Neutrophils (7/4+ and Gr-1+) represented only 0.4% of the total tumor cells and expressed high levels of MMP-9. In contrast, macrophages (CD68+) represented 2% of the total tumor cells and expressed low levels of MMP-9.

The researchers then tried to determine the role of these MMP-9+ Gr-1+ cells that infiltrate angiogenic islets and tumors. An experimental regimen involving daily inoculation of anti-Gr-1 at 7 weeks (when hyperplastic islets start to undergo angiogenesis) was followed.

After 1 week of injection, most neutrophils disappeared from the pancreatic islets of the transgenic mice (see Fig.4)

Fig. 4: Left: Control; Right: Following 1 week of treatment with anti-Gr-1, MMP-9+ neutrophils located inside the angiogenic islet disappeared (Adapted from Nozawa et. al, 2006)

After two weeks of injection, the neutrophil population rebounded in neoplastic islets. Incredibly, none of the rebound neutrophils were MMP-9+ (see Fig. 5)!

Fig. 5: Left: Control; Right: Following 2 weeks of treatment with anti-Gr-1, neutrophils rebounded back into the islets. However, none of the rebound neutrophils were MMP-9+  (Adapted from Nozawa et. al, 2006)

In a short 2 week prevention trial (week7-week9), carried out to assess angiogenic switching frequency, the anti-Gr-1 antibody regimen, reduced the number of angiogenic islets by 57%!
Furthermore, immunostaining for VEGF:VEGF-R2 complex with GVM39 (red) and for endothelial cells with Meca-32 (green) showed a decrease in bioactive VEGF:VEGF-R2 interaction, consequent to the depletion of infiltrating MMP-9+ neutrophils (see Fig.6)

Fig. 6: Left: Control; Right: Short intervention trials lead to reduced VEGF:VEGF-R2 interactions. Endothelial cells are stained with an antibody directed against Meca-32 (a pan-endothelial cell marker)  (Adapted from Nozawa et. al, 2006)

Taken together, the results from this paper indicate that subtle infiltration by innate immune cells (such as neutrophils) may play a role in the progression of neoplasias towards angiogenic tumors.


Nozawa H, Chiu C, & Hanahan D (2006). Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America, 103 (33), 12493-8 PMID: 16891410

Monday, 14 September 2009

Alan Turing-May He Finally Rest in Peace

Gordon Brown's official statement on Alan Turing

2009 has been a year of deep reflection - a chance for Britain, as a nation, to commemorate the profound debts we owe to those who came before. A unique combination of anniversaries and events have stirred in us that sense of pride and gratitude which characterise the British experience. Earlier this year I stood with Presidents Sarkozy and Obama to honour the service and the sacrifice of the heroes who stormed the beaches of Normandy 65 years ago. And just last week, we marked the 70 years which have passed since the British government declared its willingness to take up arms against Fascism and declared the outbreak of World War Two. So I am both pleased and proud that, thanks to a coalition of computer scientists, historians and LGBT activists, we have this year a chance to mark and celebrate another contribution to Britain’s fight against the darkness of dictatorship; that of code-breaker Alan Turing.

Turing was a quite brilliant mathematician, most famous for his work on breaking the German Enigma codes. It is no exaggeration to say that, without his outstanding contribution, the history of World War Two could well have been very different. He truly was one of those individuals we can point to whose unique contribution helped to turn the tide of war. The debt of gratitude he is owed makes it all the more horrifying, therefore, that he was treated so inhumanely. In 1952, he was convicted of ‘gross indecency’ - in effect, tried for being gay. His sentence - and he was faced with the miserable choice of this or prison - was chemical castration by a series of injections of female hormones. He took his own life just two years later.

Thousands of people have come together to demand justice for Alan Turing and recognition of the appalling way he was treated. While Turing was dealt with under the law of the time and we can’t put the clock back, his treatment was of course utterly unfair and I am pleased to have the chance to say how deeply sorry I and we all are for what happened to him. Alan and the many thousands of other gay men who were convicted as he was convicted under homophobic laws were treated terribly. Over the years millions more lived in fear of conviction.

I am proud that those days are gone and that in the last 12 years this government has done so much to make life fairer and more equal for our LGBT community. This recognition of Alan’s status as one of Britain’s most famous victims of homophobia is another step towards equality and long overdue.

But even more than that, Alan deserves recognition for his contribution to humankind. For those of us born after 1945, into a Europe which is united, democratic and at peace, it is hard to imagine that our continent was once the theatre of mankind’s darkest hour. It is difficult to believe that in living memory, people could become so consumed by hate - by anti-Semitism, by homophobia, by xenophobia and other murderous prejudices - that the gas chambers and crematoria became a piece of the European landscape as surely as the galleries and universities and concert halls which had marked out the European civilisation for hundreds of years. It is thanks to men and women who were totally committed to fighting fascism, people like Alan Turing, that the horrors of the Holocaust and of total war are part of Europe’s history and not Europe’s present.

So on behalf of the British government, and all those who live freely thanks to Alan’s work I am very proud to say: we’re sorry, you deserved so much better.

Gordon Brown

Sunday, 13 September 2009

Aging by Epigenetics

ResearchBlogging.orgWe know that organismal longevity and aging is caused by a lot of interacting factors such as nuclear and mitochondrial genome mutations, shortened telomeres, oxidative damage to DNA and other macromolecules, senescence, apoptosis and many more. This review discusses another possible determinant of aging that is 'epigenetics'. We have seen in the earlier post that epigenetics refers to changes in the DNA and histones which are heritable through cell divisions, but do not involve any change in the sequence of the DNA. 

Chromatin is broadly divided into two types, euchromatin and heterochromatin. Euchromatin is decondensed during interphase and is relatively transcriptionally active. Heterochromatin on the other hand remains compact and condensed and is transcriptionally inactive. It is further divided into constitutive and facultative. Constitutive heterochromatin is present in the telomer and centromere and appears to be fixed or irreversible throughout the life time of an organism. Facultative heterochromatin on the other hand, is made as a part of regulated cell differentiation process or other changes in cell phenotype. For example, a single X chromosome is silenced in female mammalian cells for dosage compensation.

However, despite this apparent clear distinction between euchromatin and heterochromatin, it is now being understood that chromatin structure is highly dynamic and stochastic. Essential processes, such as DNA replication, transcription and repair all involve disruption of the very compact structure of DNA. The proteins bound to the chromatin are also not static but exhibit relatively high 'on' and 'off' binding states even in the 'fixed' heterochromatin. It has also been showed that, formation of heterochromatin depends on a degree of transcription, which contributes to heterochromatinization through the RNAi pathway. Thus the telomeric heterochromatin is also shown to be transcribed. Thus heterochromatin is not a static entity.

Is aging associated with epigenetic changes?

The enzymes Histone acetyl teransferases (HATs) and Histone deacetylases (HDACs) respectively determine the steady-state level of histone acetylation. In S.cerevisiae, inactivation of a HDAC, Sir2, decreases replicative lifespan while activation extends it. The anti aging effects of Sir2 in yeast are due to translocation of a Sir2 containing protein complex from telomeres to ribosomal DNA (rDNA) repeats. These repeats are prone to recombination to form extrachromosomal rDNa circles (ERCs), which curtail yeast lifespan. However, Sir2 mediated histone deactylation and heterochromatization, prevents formation of ERCs and thus extends lifespan of yeast. Thus, this epigenetic redistribution counteracts organismal aging. Orthologs of Sir2 have been found in many species like nematodes, flies and even mice. Thus its anti aging role seems to have been conserved throughout evolution.

In mammals, it has been seen that there is a reduction in genomic DNA methylation, with age. It occurs mostly at repetitive DNA sequences, predominantly in regions of constitutive heterochromatin. Since methylation induces silencing of genes, this change will promote deheterochromatinization of these regions. However DNA methylation increases at specific sites called the CpG islands. These are CG rich sequences, some of them present in the promoter regions, which can get methylated. Methylation also increases in the histone 4 on the lysine 20 residue (H4K20) in rat liver and kidney, with age. Like DNA methylation H4K20 methylation is also linked to gene repression, supporting the notion that heterochromatin accumulates in some sites atleast with aging.
One of the histone chaperones, HIRA, shows increased levels of expression in aging baboon skin. This is shown to have a evolutionary conserved role in formation of heterochromatin.
These observations suggest that mammalian aging is associated with chromatin remodelling. In particular, there is a global decrease in DNA methylation, but an increase at specific sites on the genome.

Cellular senescence, is characterized by irreversible proliferation arrest. This may arise due to excessive cell divisions and shortening of the telomere length. Due to this, most human cells have a finite proliferative lifespan. Senescent cells or molecular markers of senescent phenotype increase during aging. Cellular senescence is also well established tumor suppression process, because it can prevent proliferation and neoplastic progression of cells harboring neoplastic lesions. Senescent cells also show chromatin remodeling. Many senescent cells form domains of facultative heterochromatin, called Senescence Associated Heterochromatin Foci (SAHF), which are visibly more condensed that interphase chromatin. These foci have been proposed to silence proliferation promoting genes. Accumulation of SAHF has been associated with aging. Formation of SAHF requires presence of HIRA, which has been shown to be upregulated in aging baboon skin. Also it seems that in cellular senescence too, the constitutive heterochromatin regions are deheterochromatinized. Thus like tissue aging, cellular senescence also is accompanied by redistribution of heterochromatin, from constitutive heterochromatin to other normally euchromatic sites.

Consequences of age-associated epigenetic changes

Studies going back to 1960s indicate that aging is associated with cell aneuploidy. Proper chromosome segregation is dependent on pericentromeric heterochromatin sturcture. Hence cecreased methylation and deheterochromatinization may lead to faulty chromosome segregation and associated aneuploidy. Aneuploidy confers various altered cell phenotypes including a proliferative impairment, which might contribute to decreased tissue renewal capacity with age. It may also give rise to cancer, for which age is the biggest risk factor. Some of the age associated changes in gene expression may also occur due to epigenetics. Methylation of CpG islands is a well described mode of silencing some tumor suppressor genes. A tissue wide age associated methylation of CpG may be an early causative event in the development of neoplasms.

From the discussion it is apparent that chromatin does undergo change with aging in organisms as diverse as yeast and mammals. However with the exception of Sir2 in yeast, the extent to which this impacts the aging process is not yet defined. Some age associated epigenetic alterations in mammals like formation of SAHF, might extend life span by suppressing age associated diseases like cancer. In sum the effects of chromatin on aging are likely to be complex. A pre requisite to properly understanding the contribution of epigenetics to aging is to better understand the specific cell, tissue and system wide malfunctions that are responsible for aging phenotypes like osteoporosis, sarcopenia, cancer and many others. Then it will be feasible to dissect out the contribution to each phenotype of each candidate epigenetic determinant, like global methylation, CpG island methylation and SAHF.


Sedivy JM, Banumathy G, & Adams PD (2008). Aging by epigenetics--a consequence of chromatin damage? Experimental cell research, 314 (9), 1909-17 PMID: 18423606