Fight Aging! Newsletter, October 7th 2013

October 7th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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  • Naked Mole Rats Have Unusual and Efficient Ribosomes
  • October 1st is International Longevity Day
  • Articles From Cryonics Magazine
  • Measuring Mitochondrial Mutations and Their Causes
  • SENS Research Foundation Videos, First SENS6 Videos
  • Latest Headlines from Fight Aging!
    • Cryonics Magazine: An Interview With Aubrey de Grey
    • Mitochondrial DNA Variants and Heart Disease Risk
    • Three Specters of Immortality
    • Investigating the Mechanisms of Mitophagy
    • Considering Mineralization in Aging
    • Linking Sirtuin 1 to Methylation of Nicotinamide
    • In Search of MicroRNAs Related to Aging
    • Speculation on Google's Calico Initiative
    • Radical Life Extension Won't Cause Resource Shortages
    • Trials for Rejuvenation Biotechnology Targeting α-Synuclein


Naked mole rats live as much as nine times longer than the members of other similarly-sized rodent species and are essentially immune to cancer, traits that may be side-effects of evolutionary adaptation to life in oxygen-poor underground burrows. Insofar as there is any consensus on the mechanisms driving naked mole rat longevity, it centers around the membrane pacemaker hypothesis: that the composition of important cell membranes in this species, such as those in mitochondria, makes them more resistant to oxidative damage. That in theory cuts down on some of the forms of stochastic damage that lead to degenerative aging.

Here researchers identify another novel feature in the low-level molecular biology of naked mole rats. This most likely indicates the opening of another line of research into the roots of their longevity:

Why Do Naked Mole Rats Live So Long?

In recent years, Gorbunova and her husband Andrei Seluanov have looked closely at the species, which lives in underground colonies in East Africa, hoping to figure out how exactly it manages to survive so long. As revealed in new research her team published today in Proceedings of the National Academy of Sciences, their team thinks they've found at least part of the answer: naked mole rats have strange ribosomes.

Every one of our cells (and, for that matter, every living organism's cells) converts the genetic instructions present in our DNA into proteins - which control a cell's overall operation - through a process called translation. Tiny microscopic structures called ribosomes handle this translation, reading genetic instructions that specify a particular recipe and churning out the protein accordingly.

The ribosomes in almost every multicellular organism on the planet is made up of two large pieces of RNA, a genetic substance similar to DNA. But last year, one of the Rochester lab's students was isolating RNA from cells taken from the naked mole rats when he noticed something unusual. When he separated the RNA pieces, instead of seeing two distinct pieces of ribosomal RNA, he saw three.

After a variety of testing confirmed that it wasn't an experimental error, they decided to look more closely at the potential effects of this unusual structure. It turned out that, compared to mouse ribosomes, these three-part structures made between four and forty times fewer errors during the translation process. At this point, it's unclear how exactly that might lead to longer lifespans, but the researchers believe it plays a key role.

Naked mole-rat has increased translational fidelity compared with the mouse, as well as a unique 28S ribosomal RNA cleavage

Molecular mechanisms responsible for differences in longevity between animal species are largely unknown. Here we show that the longest-lived rodent, the naked mole-rat, has more accurate protein translation than the mouse. Furthermore, we show that the naked mole-rat has a unique fragmented ribosomal RNA structure. Such cleaved ribosomal RNA has been reported for only one other species of mammal.

Although we cannot directly test whether the unique 28S rRNA structure contributes to the increased fidelity of translation, we speculate that it may change the folding or dynamics of the large ribosomal subunit, altering the rate of GTP hydrolysis and/or interaction of the large subunit with tRNA during accommodation, thus affecting the fidelity of protein synthesis. In summary, our results show that naked mole-rat cells produce fewer aberrant proteins, supporting the hypothesis that the more stable proteome of the naked mole-rat contributes to its longevity.

The first thing I would do with this new finding, if I had a laboratory and time to burn, is to look at the ribosomes of blind mole rats, a similar species that seems to have evolved its own mechanism for cancer resistance that is conceptually similar to that of the naked mole rat but different in detail. It would be interesting to see if they also have unusual ribosomes, with the most beneficial outcome being that they do not, meaning there may be a good opportunity for comparison studies.


You might recall that the advocates of the International Longevity Alliance have declared October 1st to be International Longevity Day. They hope to gather official recognition and use this yearly event to raise awareness of longevity science, the need for greater funding of rejuvenation research, and the moral imperative to lengthen the healthy human life span, eliminate frailty, and defeat age-related disease:

International Longevity Day

Some time ago the idea was raised to celebrate a special day by the longevity movement - the LONGEVITY DAY. Now an excellent opportunity to do this is coming the 1st of October, the official United Nations International Day of Older Persons. Let us make the Longevity Day on that day - the 1st of October this year! Let us hold meetings and other events globally!

Longevity Day

Making the Longevity Day on October 1: So far, people in about 30 countries have expressed their willingness to hold dedicated meetings and other events on that day. The day is especially significant as, on that day, we have an excellent opportunity to link in the public mind the issue of AGING with the issue of ANTI-AGING research that is probably the only means to truly address and ameliorate the problem of aging.

Longevity Day Appeal - October 1

An additional way of promotion is: Support our petition to celebrate the International Longevity Day during the International Day of Older Persons. This can be done in several ways:

1) Sign the online petition and spread it among your friends and on social media. The petition is also featured on the newly established Longevity Intelligence Communications (LIC) site dedicated to promoting petitions related to longevity.

2) Participate in the physical signing and mailing of the petition (to be sent to International Organizations, Governmental Offices, Associations of the Elderly, Scientific Societies, etc.) As a first option, the petition will be sent to the UN (the authors of the "International Day of Older Persons"). If you are interested in doing so, please contact us.

3) Download a template of a flyer containing a short version of the petition. You can modify it as you see fit: change the text, affiliation, country, logo, slogan, links, etc. - as long as the spirit of support for Longevity and Longevity Research is maintained. Or print it out as it is and distribute it among friends, at your school, health club, etc. Engage people in the topic. Or upload it and spread it online.

You can download the flyer template from the Longevity Day Facebook page.

Please consider spreading this message. With some minimal effort we can create a series of highly influential and positive events, promoting the advancement of Healthy Longevity for All through Support of Scientific Research directed toward that goal!


Cryonics Magazine is the in-house publication of cryonics service provider Alcor, available to members of the organization. Articles from recently issues sometimes make their way online to the magazine site, and are usually well worth reading.

What is cryonics? It is the provision of indefinite low-temperature storage for the body and brain immediately following death. For so long as the pattern of fine tissue structures that encode your mind survive intact, there is the chance that future technologies can restore you to life. This should be within the capabilities of a mature molecular nanotechnology industry, able to build sophisticated molecular machines to repair cells, remove cryoprotectant chemicals, and perform all the other myriad tasks needed to restore a cryopreserved individual to life. How long until that industry arrives? The answer to that question doesn't really matter when you are preserved: you have all the time in the world, for so long as the cryonics industry continues forward robustly.

Cryopreserved individuals are vitrified, not frozen, these days. Freezing tends to produce significant ice-crystal damage, while vitrification does not: tissues turn to a glass-like state, suffused by cryoprotectant chemicals, the structure well preserved at all levels. There is still the issue of potential fracturing, but that too can be addressed. Vitrification is under development in the broader cryobiology industry for use in long-term storage of organs for transplant, and reversible vitrification for that use isn't too far from prime time. Undoing vitrification for a human brain in the field is obviously a little way beyond doing so for blood vessels or an animal kidney under laboratory conditions - but it's just an advance.

One of the underlying assumptions in cryonics is that any future society capable of restoring a vitrified individual should have absolutely no problem with building a new body and rejuvenating old tissues - that being a much easier challenge. If you can mass-precision-engineer molecules and molecular robots to the degree needed to undo cryopreservation, then rearranging molecules to undo mere damage to cells is no great issue. That seems reasonable given what we expect to see in the next fifty years of development in medicine, nanotechnology, and related fields. Beyond that, of course, the sky is the limit.

Here are a few recent pieces from Cryonics Magazine, in no particular order. I think that you'll find them interesting:

Resuscitation Research Can Start Now!

A major obstacle to strengthening the case for cryonics is the perception that meaningful research aimed at resuscitation of cryonics patients cannot be done today. Attempts to be more specific than evoking the need for a technology that can manipulate matter at the molecular level are considered to be vague and unproductive. Clearly, such a stance is an open invitation for skeptics to claim that cryonics advocates have not much more to offer than hope and optimism. Nothing could be further from the truth. Not only is there a lot of relevant empirical research that can be conducted today, a focused investigation into the technical and logistical challenges of resuscitation can also define cryonics research priorities and refine the stabilization and cryopreservation procedures that we use today.

[Of interest] is the 1991 article "'Realistic' Scenario for Nanotechnological Repair of the Frozen Human Brain" where the individual forms of mechanical and biochemical damage (ice formation, protein denaturation, osmotic damage, etc.) are catalogued and repair strategies are discussed in biological terms. Describing the various forms of damage at such a detailed level provides a meaningful context within which to discuss the technical feasibility of cryonics in rather specific terms.

Effects of Temperature on Preservation and Restoration of Cryonics Patients

An understanding of probable future repair requirements for cryonics patients could affect current cryostorage temperature practices. I believe that molecular nanotechnology at cryogenic temperatures will probably be required for repair and revival of all cryonics patients in cryo-storage now and in the foreseeable future. Current nanotechnology is far from being adequate for that task. I believe that warming cryonics patients to temperatures where diffusion-based devices could operate would result in dissolution of structure by hydrolysis and similar molecular motion before repair could be achieved. I believe that the technologies for scanning the brain/mind of a cryonics patient, and reconstructing a patient from the scan are much more remote in the future than cryogenic nanotechnology.

Cryonicists face a credibility problem. It is important to show that resuscitation technology is possible (or not impossible) if cryonicists are to convince ourselves or convince others that current cryonics practice is not a waste of money and effort. For some people it is adequate to know that the anatomical basis of the mind is being preserved well enough - even if in a very fragmented form - that some unspecified future technology could repair and restore memory and personal identity. Other people want more detailed elaboration.

What Do We Really Know About Fracturing?

The goal of any credible cryonics organization is to develop reversible cryopreservation to avoid passing on problems with the cryopreservation process itself to the next generation. While there is a lot of recognition for the need to eliminate cryoprotectant toxicity, it is rather obvious that it will not be possible to restore integrated function in a fractured brain. Despite all the articles and discussions that have been devoted to the topic of intermediate temperature storage, we do not seem to know much yet about fracturing in (large) tissues that are well equilibrated with a vitrification solution and subjected to a responsible cooling protocol. While [the] data seem to support the use of the newer vitrification solutions for reducing fracturing, controlled studies of fracturing in vitrified tissues will need to be conducted in a lab to really understand what we can expect under ideal (non-ischemic) circumstances.


Mutations in mitochondrial DNA (mtDNA) are at the center of the mitochondrial free radical theory of aging. Every cell has its herd of bacteria-like mitochondria, toiling to generate chemical energy stores and emitting reactive free radicals as a result of this activity. Each mitochondrion has its own copy of mitochondrial DNA, separate from the DNA in the nucleus of the cell. If mutations change or remove any one of a dozen or so of the most vital genes in a mitochondrion then it will malfunction in ways that can evade the cell's quality control mechanisms. That mitochondrion will divide to create more broken copies, and ultimately all the mitochondria in that cell and all its descendants will become defective. This creates malfunctioning, abnormal cells that export streams of harmful, reactive molecules into the surrounding tissues. This process is one of the root causes of aging, and is why you'll see a fair number of posts here on the repair of mitochondrial DNA as a part of any future toolkit of rejuvenation therapies.

There is some debate over the different types of mutational damage in mitochondrial DNA and their significance, however. Damage ranges all the way from comparatively minor point mutations, in which a single base is substituted, all the way up to catastrophic double strand breaks that require major intervention to restore correctly. To pick one example from past research, scientists have shown that mice loaded up with many more mitochondrial point mutations than usual don't seem to suffer for it. So are point mutations unimportant in mitochondrial function and we should focus more on deletions, in which breaks are poorly repaired or replication failed? Perhaps.

Here is a recent open access paper on this topic. These researchers speculate that it's not damage from free radicals at fault, but rather replication issues as mitochondria reproduce inside the cell. This is an interesting challenge to the prevailing paradigm, but the researchers would then have to explain how genetic changes that alter the levels of free radicals produced by mitochondrial can shift life span so readily in laboratory species. Where is the connection to replication rate and efficiency there? Again, it is worth noting that these researchers are predominantly looking at point mutations (and transitions, a form of point mutation) - and this might not be where the action is in the case of mitochondrial DNA and aging.

Ultra-Sensitive Sequencing Reveals an Age-Related Increase in Somatic Mitochondrial Mutations That Are Inconsistent with Oxidative Damage

Owing to their evolutionary history, mitochondria harbor independently replicating genomes. Failure to faithfully transmit the genetic information of mtDNA during replication can lead to the production of dysfunctional electron transport proteins and a subsequent decline in energy production. Cellularly-derived reactive oxygen species (ROS) and environmental agents preferentially damage mtDNA compared to nuclear DNA. However, little is known about the consequences of mtDNA damage for mutagenesis. This lack of knowledge stems, in part, from an absence of methods capable of accurately detecting these mutations throughout the mitochondrial genome.

Using a new, highly sensitive DNA sequencing strategy, we find that the frequency of point mutations is 10-100-fold lower than what has been previously reported using less precise means. Moreover, the frequency increases 5-fold over an 80 year lifespan. We also find that it is predominantly transition mutations, rather than mutations commonly associated with oxidative damage to mtDNA, that increase with age. This finding is inconsistent with free radical theories of aging.

The bottom line for the prospective longevity engineer is that the outcome of this sort of debate is probably moot. Mitochondrial DNA is getting damaged, this is a definite, well-established difference between old tissue and young tissue, and the prospective mechanisms for repair or replacement of mitochondrial DNA will revert the entirety of that difference regardless of how important or unimportant different forms of mutation happen to be. So the order of the day is to carry on building mitochondrial repair therapies: at this point it would be faster to create them and try them out to settle any debate over effectiveness than to do more research and measurement of mitochondrial mutation types and rates.


The SENS Research Foundation funds and coordinates much-needed research into the foundation biotechnologies for human rejuvenation, as well as advocacy programs to encourage greater funding and progress in areas of longevity science that are presently neglected. This, sadly, is most of the list beyond cancer and stem cell medicine.

Among their many other activities, the Foundation staff are engaged in building a video library that will in time include a full lecture course from noted researchers aimed at students and young scientists, profiles of researchers and postgraduate interns working on rejuvenation biotechnology, and records of the SENS conference series at which new advances are presented in fields of research relevant to engineering greater human longevity.

The SENS6 conference was held last month, and some of the first few presentation videos are being posted to the SENS Research Foundation YouTube channel. Here, for example, is the keynote from George Church:

In the SENS6 Conference's keynote address, Harvard University's Dr. George Church describes recent advances in genomics and in the reading, writing, and interpretation of -omes fields. He also discusses, his initiative to glean new medical insights by gathering data on the genotypes, microbiomes, environments, traits, and stem cells of participants. He proceeds to cover various methods of improving RNA sequencing to gather data on transcriptomes, then provides additional detail on engineering therapeutics for individual patients. Before concluding, Dr. Church discusses protective alleles and offers a broad overview of genomic engineering strategies. In particular, he notes the considerable promise the CRISPR approach holds for the field.


Monday, September 30, 2013

Cryonics Magazine is published by Alcor, a cryonics service provider. Aubrey de Grey is a noted biogerontologist, advocate for research into human rejuvenation, and co-founder of the SENS Research Foundation:

Cryonics Magazine: At what age, currently, should someone feel that there is very little chance of life extension research benefiting him before the end of his (current, average projected) life expectancy?

Aubrey de Grey: There's no way to answer that in terms of chronological age, because different people aged (say) 60 have such different states of health and chances of living another (say) 30 years. All we can say is that there seems to be a good chance - I'd say at least 50% - that we will be able to control aging pretty comprehensively within 20-25 years from now, allowing those who are not too frail to be treated to benefit greatly. I think anyone who is in a good enough state of health that they can reasonably expect to avoid serious age-related disease or disability for another 10 years has a non-negligible chance of benefiting. But I should point out that the humanitarian motivation for striving to hasten the defeat of aging is much the most powerful in my view - much more powerful than the desire to benefit oneself, or to benefit any particular other person.

Cryonics Magazine: What advice can you give to cryonics organizations and activists to improve the public's perception of cryonics?

Aubrey de Grey: That's pretty hard: very smart people have been trying to perfect a pitch that works for a long time, so I'm unlikely to have any ideas that are really new. The only thing I think might be more effective is to promote certain aspects of the logic of cryonics a bit more aggressively, and especially to educate the public better concerning aspects of that logic that are already mainstream. For example, I think it would be useful if the public knew that mainstream cryobiologists, the type who publicly deride cryonics with great vigor, nevertheless typically have a very positive view of research aimed at vitrifying organs and reviving them for transplant purposes. If this were better known, the question of what makes the brain any less revivable in principle than a kidney becomes rather obvious, and the absence of any good answer from the mainstream critics of cryonics becomes rather conspicuous.

Monday, September 30, 2013

Mitochondria are the power plants of the cell, known to be important in aging. They have their own DNA, inherited from the mother, and genetic variations lead to different levels of mitochondrial efficiency. This DNA becomes damaged in the course of aging, and in recent years researchers have been investigating ways to replace mitochondria and their DNA, the basis for therapies to treat this contribution to degenerative aging.

Of related interest, researchers here show that mitochondrial DNA variations impact heart disease risk. This is another incentive to complete the development of technologies that will allow replacement of mitochondrial DNA with some more optimal form, not just to repair damage that occurs over a lifetime.

"Having been in this field for decades, I remember when mitochondrial DNA variations were thought to play a role only in the rarest of genetic syndromes. Today, there is a growing consensus that variations in mitochondrial DNA alone make a substantial contribution to each person's risk for heart disease, and ours is the first study to directly confirm it in a living mammal."

The research team started with two varieties of mice; the C57 mouse known to be vulnerable to diseases associated with diet, and the C3H mouse, which is resistant. The study authors then used a technique called nuclear transfer to remove the nucleus from an embryo in each mouse line and switch them. Because mitochondria reside in the cytoplasm (not in the switched nuclei), the new embryos grew into mice whose cells had their own mitochondrial DNA and the nuclear DNA from the other line. That enabled researchers to compare mice with the same nuclear DNA, but different mitochondrial DNA, isolating the latter's distinct contribution to risk.

In general, the data showed that replacing mitochondrial DNA alone could increase or decrease a given mouse's susceptibility to a model of heart failure. Mice with efficient C57 mitochondrial DNA also generated 200 percent more oxidants than their disease-resistant counterparts with C3H mitochondrial DNA.

Another study underway [is] comparing mitochondrial DNA variations in people of African versus northern European ancestry. Evidence suggests that mitochondria carrying African mitochondrial DNA get more energy from the same amount of oxygen and sugar, perhaps reflecting an evolutionary history of food scarcity. Early migrating humans may have found more food in Europe, but would also have had to brave the cold. Thus, Euro mitochondria appear to be less efficient, perhaps because a byproduct of such inefficiency is the increased generation of body heat. More efficient mitochondria, with their greater oxidant production, may explain, in part, higher incidents of heart disease and diabetes among those of African ancestry in the face of modern, high-calorie diets.

Tuesday, October 1, 2013

A long-form essay on priorities in advocacy and fundraising for longevity science:

I would like to address what I consider to be three common criticisms against the desirability and ethicacy of life-extension I come across all too often - three specters of immortality, if you will. These will be Overpopulation (the criticism that widely-available life-extension therapies will cause unmanageable overpopulation), Naturality (the criticism that life-extension if wrong because it is unnatural), and Selfishness (the criticism that life-extension researchers, activists and supporters are motivated by a desire to increase their own, personal lifespans than by a desire to decrease involuntary suffering in the world at large).

What makes them worrying is the fact that they deter widespread support of life-extension from the general public, because they stop many people from seeing the advantage and desirability of life-extension today. Just what is considered worthy of scientific study is to a very large extent out of the hands of the average scientist. The large majority of working-day scientists don't have as much creative license and choice over what they research as we would like to think they do.

Scientists have to make their studies conform to the kinds of research that are getting funded. In order to get funding, more often than not they have to do research on what the scientific community considers important or interesting, rather than on what they personally might find the most important or interesting. And what the scientific community considers important and worthy of research is, by and large, determined by what the wider public considers important.

Thus if we want to increase the funding available to academic projects pertaining to life-extension, we should be increasing public support for it first and foremost. We should be catalyzing popular interest in and knowledge of life-extension. Strangely enough, the objective of increased funding can be more successfully and efficiently achieved, per unit of time or effort, by increasing public support and demand via activism, advocacy and lobbying than by say direct funding, period. Thus, even if most of these criticisms, these specters of immortality, are to some extent baseless, refuting them is still important insofar as it increases public support for life-extension, thereby hastening progress in the field.

Tuesday, October 1, 2013

Mitochondria are the cell's roving herd of power plants, producing chemical energy stores to power cellular processes, and mitophagy is the process by which damaged mitochondria are recycled for parts. If allowed to continue functioning and dividing like bacteria, damaged mitochondria can harm the cell - and in fact forms of damage that allow mitochondria to evade mitophagy are one of the root causes of degenerative aging. In older individuals many cells are overtaken by malfunctioning mitochondria, forcing them to operate abnormally and export damaging reactive molecules into surrounding tissues.

Here, researchers make inroads into understanding more of the mechanisms by which mitophagy operates, which may open the door to correcting failures in this process. This presents another potential avenue for treatments for aging based on mitochondrial repair to add to those that already exist and are under development.

Cardiolipins, named because they were first found in heart tissue, are a component on the inner membrane of mitochondria. When a mitochondrion is damaged, the cardiolipins move from its inner membrane to its outer membrane, where they encourage the cell to destroy the entire mitochondrion. "It's a survival process. Cells activate to get rid of bad mitochondria and consolidate good mitochondria. If this process succeeds, then the good ones can proliferate and the cells thrive."

[The newly identified part of this mechanism] turns out to be a protein called LC3. One part of LC3 binds to cardiolipin, and LC3 causes a specialized structure to form around the mitochondrion to carry it to the digestive centers of the cell. "There are so many follow-up questions. What is the process that triggers the cardiolipin to move outside the mitochondria? How does this pathway fit in with other pathways that affect onset of diseases like Parkinson's? Interestingly, two familial Parkinson's disease genes also are linked to mitochondrial removal." While this process may happen in all cells with mitochondria, it is particularly important that it functions correctly in neuronal cells because these cells do not divide and regenerate as readily as cells in other parts of the body.

"I think these findings have huge implications for brain injury patients. The mitochondrial 'eat me' signaling process could be a therapeutic target in the sense that you need a certain level of clearance of damaged mitochondria. But, on the other hand, you don't want the clearing process to go on unchecked. You must have a level of balance, which is something we could seek to achieve with medications or therapy if the body is not able to find that balance itself."

Wednesday, October 2, 2013

Is the mineralization of connective tissue important in aging and something that should be addressed separately from other forms of change that occur in old tissues? These researchers think so:

When you open a 70-year old patient on the operating table and touch the aorta, the feeling may resemble touching an eggshell or sand paper. It is stiffer than the heart of a young person and the key reasons for this are the abundant calcium deposits in the connective tissue that accumulate with age. The many factors leading to mineralization of the connective tissue include genetic and acquired diseases, inflammation, reactive oxygen species, but the major problem is that it occurs spontaneously during aging as calcium-containing molecules are trapped in the extracellular matrix and develop into apatite over time.

"Aging inevitably leads to the loss of function on many levels. Mineralization of the connective tissue is one of the causes and consequences of aging and is a complex multifactorial process. Metabolic activity, diseases and external stress factors may cause calcification, but most importantly, it occurs spontaneously. Our goal is to identify least toxic ways to both prevent calcification and to repair the accumulated aggregates. Mineralization of connective tissue with age is one of the many aspects of aging that are examples of 'accumulation of eventually pathogenic extracellular material', an issue that attracts too little attention within the academic community. The accumulation of advanced glycation endproducts (AGEs) and of mineral deposits both result in increased stiffness of connective tissue, impair homeostasis and contribute to a broad range of age-related diseases."

Wednesday, October 2, 2013

The shine has worn off sirtuin research, as extension of life span resulting from manipulation of sirtuin 1 has been hard to reproduce in mammals. Sirtuin 3 is looking more interesting, however, and there is a still a great deal of funding for investigative work on sirtuin 1 and its role in the extended longevity produced by calorie restriction:

Sirtuins, a family of histone deacetylases, have a fiercely debated role in regulating lifespan. In contrast with recent observations, here we find that overexpression of sir-2.1, the ortholog of mammalian SirT1, does extend Caenorhabditis elegans lifespan. Sirtuins mandatorily convert NAD+ into nicotinamide (NAM). We here find that NAM and its metabolite, 1-methylnicotinamide (MNA), extend C. elegans lifespan, even in the absence of sir-2.1.

We identify a previously unknown C. elegans nicotinamide-N-methyltransferase, encoded by a gene now named anmt-1, to generate MNA from NAM. Disruption and overexpression of anmt-1 have opposing effects on lifespan independent of sirtuins, with loss of anmt-1 fully inhibiting sir-2.1-mediated lifespan extension. MNA serves as a substrate for a newly identified aldehyde oxidase, GAD-3, to generate hydrogen peroxide, which acts as a mitohormetic reactive oxygen species signal to promote C. elegans longevity.

Taken together, sirtuin-mediated lifespan extension depends on methylation of NAM, providing an unexpected mechanistic role for sirtuins beyond histone deacetylation.

Thursday, October 3, 2013

Gene expression, the process by which a protein is produced from the specification of a gene, is complicated and the early steps involve dynamic interactions between RNA sequences. MicroRNAs (miRNAs), for example, are small RNA sequences that regulate gene expression by targeting specific messenger RNAs (mRNAs), sequences that transfer information on the gene into the ribosome where the protein will be built.

A lot of work has gone into looking for genes and gene product proteins relating to aging or longevity, but work on finding microRNAs with the same associations has really only just started in comparison - there are few results to see so far. Here, researchers identify some microRNAs whose levels vary with age:

Altered expression of circulating miRNAs have been associated with age-related diseases including cancer and cardiovascular disease. Although we and others have found an age-dependent decrease in miRNA expression in peripheral blood mononuclear cells (PBMCs), little is known about the role of circulating miRNAs in human aging.

Here, we examined miRNA expression in human serum from young (mean age 30 years) and old (mean age 64 years) individuals using next generation sequencing technology and real-time quantitative PCR. Of the miRNAs that we found to be present in serum, three were significantly decreased in 20 older individuals compared to 20 younger individuals: miR-151a-5p, miR-181a-5p and miR-1248. Consistent with our data in humans, these miRNAs are also present at lower levels in the serum of elderly rhesus monkeys.

In humans, miR-1248 was found to regulate the expression of mRNAs involved in inflammatory pathways and miR-181a was found to correlate negatively with the pro-inflammatory cytokines IL-6 and TNFα and to correlate positively with the anti-inflammatory cytokines TGFβ and IL-10. These results suggest that circulating miRNAs may be a biological marker of aging and could also be important for regulating longevity. Identification of stable miRNA biomarkers in serum could have great potential as a noninvasive diagnostic tool as well as enhance our understanding of physiological changes that occur with age.

Thursday, October 3, 2013

This article is pure speculation in absence of data, but it certainly can't hurt to have more serious discussions of longevity science appearing in the mainstream media:

But the question is, what will Calico actually do? At the moment the company isn't giving much detail away [and] repeated requests [to] interview either Page or Levinson were politely declined. In the absence of any real information, many commentators have speculated that Calico will pursue a 'big-data' approach to health: gathering massive amounts of information from patients and 'crunching it' to help speed the way to health care discoveries. Some have suggested that Calico's new CEO will take the view that the best way to tackle aging is to focus on preventing diseases.

Aubrey de Grey, an expert in the field of regenerative medicine, [says] that it is too soon to speculate on what Google's approach will be: "in relation to Calico, I think it's vital to keep in mind that there is essentially no concrete information about their planned direction and emphasis, and any guess that they will take a heavily data-driven approach is no more than a guess." However, he does think that Calico will not limit its focus to a single disease: "The statements from Page and Levinson thus far indicate quite strongly that the emphasis will not be just cancer, or even just a range of specific diseases, but will be 'aging itself': Page in particular has highlighted the paltry longevity gains that would arise even from totally eliminating cancer."

João Pedro de Magalhães, a Portuguese biologist who leads the Integrative Genomics of Aging group at the University of Liverpool, agrees: "From what I've read, I don't think the company will mostly focus on cancer. In the Time interview Larry Page clearly states that solving cancer is 'not as big an advance as you might think'. This is reminiscent of what experts studying aging have been saying for a while, which is that to really make a difference in human health and longevity you need to tackle the aging process rather than individual age-related diseases."

Friday, October 4, 2013

That overpopulation exists at all is one of the most prevalent delusions in the modern world: thanks to the environmentalist movement, a cause that has ascended near to the status of civic religion, the average fellow in the street thinks that there are too many people alive today, that resources are stretched to breaking point, that the future is one of Malthusian decline, and that horrible poverty in the third world is caused by the existence of too many people. All of these points are flat-out wrong. Humanity is wealthier and has greater access to resources today than at any time in history, the variety and amounts of available resources are growing at an accelerating pace due to technological progress, the earth could support many times more people than are alive today, and where there is poverty it exists due to terrible, predatory governance and the inhumanity of man - it exists due to waste and aggression amidst the potential for plenty.

Even this pro-longevity piece subscribes, as many do, to the false idea that somehow we are consuming too many resources and will run out. This is silly: resources are infinite, because through technological progress we constantly develop new ones. People live in an age of change, with each new decade clearly different from the last, and yet live under the assumption that everything will remain the same going forward. Being worried about running out of anything that we use today is like being worried about running out of candle wax in 1810, or running out of room for horse breeding operations in 1840, or running out of food in 1940. All false concerns, and all false for exactly the same reasons: we are not static consumers of resources, we are net producers of resources.

Make no mistake, it'll take us a long, long time to get there, but we'll eventually find a way to halt the aging process. Owing to advanced medical, regenerative, and cybernetic technologies, future humans will enter into a state of "negligible senescence," a condition marked by the cessation of aging and the onset of everlasting youth. It sounds utopian, but as biogerontologist Aubrey de Grey has repeatedly noted, it's simply an engineering problem - one that's not intractable.

I've been debating this issue for the better part of a decade, and I've heard virtually every argument there is to be said both in favor of and in condemnation of the possibility. I'm not going to go over all of them here. But without a doubt the single most prominent argument set against radical life extension is the issue of overpopulation and environmental sustainability.

As a final note, there's a certain inevitability to radical life extension. It's the logical conclusion to the medical sciences. So rather than futilely argue against it, we should come up with constructive solutions to ensure that it unfolds in the most non-disruptive way possible.

Friday, October 4, 2013α-synuclein.php

A long and detailed piece from the SENS Research Foundation on the relevance of ongoing development of therapies for Parkinson's disease based on targeting α-synuclein, a protein thought to be important in the disease process:

A range of damaged proteinaceous aggregates accumulate intracellularly and extracellularly in the aging brain, with higher burdens of characteristic aggregates associated with diagnosed age-related neurodegenerative disorders. These include beta-amyloid protein (Aβ) and neurofibrillary tangles (NFT) in Alzheimer's disease (AD) and other age-related dementias, and Lewy bodies and other intracellular α-synuclein (AS) aggregates in Parkinson's disease (PD) and other synucleinopathies. Additionally, it is increasingly clear that LB along with other neuronal protein aggregates are key drivers of "normal" cognitive aging.

Multiple lines of evidence from cell culture studies, transgenic model organisms, and genetic epidemiology link a person's steady-state AS levels and accumulation of LB to both clinical PD and subclinical age-related movement disorders. Mutations and genetic variants that increase the production or aggregability of AS are clearly linked to earlier onset and severity of PD.

Buoyed by the strong evidence from AS vaccination studies, an Austrian biotechnology firm with an unique development platform - with support from a major Parkinson's charity - has lept ahead of the pack. As of this writing, they are now in the midst of human clinical trials of a first-in-class immunotherapeutic agent targeting the removal of pathological AS species as a disease-modifying rejuvenation therapy to prevent, arrest, and reverse the ravages of Parkinson's disease.

The degenerative aging process is driven by the accumulation of multiple forms of cellular and molecular damage in the structures of our tissues, leading progressively over time to increasing disease, disability, and ultimately death. PD as a clinical entity emerges when the level of a specific subset of such lesions crosses of a clinical threshold. The key corollary of these facts is that when rejuvenation biotechnology matures to the point that this underlying damage is safely and effectively removed, repaired, replaced, or rendered harmless, then PD and the full spectrum of age-related disease and disability can be prevented, arrested in its course, and ultimately reversed.

AS vaccines will address one key driver of the PD phenotype: the accumulation of aggregated AS species in the brain and peripheral nervous system. But to fully arrest the progression of the disease, multiple rejuvenation biotechnologies will have to be brought to bear, each of them targeting specific cellular and molecular lesions involved in the constellation of pathology underlying PD.

Step by step, the rejuvenation biotechnologies needed to prevent and reverse the disabling neuropathology that drives PD are being developed, tested in rodents, and moved into clinical trials. The rejuvenation biotechnologies that emerge from these trials will initially be indicated for PD, but the lesions that these new therapies target are suffered by all aging people, driving the universal age-related loss of motor control, cognition, and autonomic dysfunction. Whether any individual suffers the obvious gait disturbances, tremors, and "masklike" loss of facial affect - these eventualities are in part a matter of individual variations in how rapidly the age-related lesions most specific to PD symptoms accumulate in our tissues, and in part a matter of the rate at which other aging damage accumulates in our bodies, overshadowing or pre-empting clinical PD with competiting forms of age-related morbidity and mortality.

An end to this, and to the misery of age-related ill health in all its forms, are what drives SENS Research Foundation's work in research, education, outreach, transdisciplinary networking, and advocacy. We are encouraged by the progress being made in clearance of AS aggregates from the aging brain, moving us one step closer to the day when humanity will move free of the mummification of the years.


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