Tag Archives: cells

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Fundraiser by Lifespan.io & CellAge: Targeting Senescent Cells With Synthetic Biology

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Categories: Announcements, Science, Transhumanism, Tags: , , , , , , , , , , , , ,

The New Renaissance HatCellAge
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Editor’s Note: The Rational Argumentator and the U.S. Transhumanist Party support Lifespan.io and CellAge in their work towards groundbreaking scientific life-extension research. Finding a way to repair age-related damage to senescent cells would be a fundamental breakthrough for transhumanism, and we offer our best wishes and support for those striving towards these new technologies.

               ~ Gennady Stolyarov II, Editor-in-Chief, The Rational Argumentator, December 11, 2016

From Lifespan.io and CellAge:

Our society has never aged more rapidly – one of the most visible symptoms of the changing demographics is the exponential increase in the incidence of age-related diseases, including cancer, cardiovascular diseases and osteoarthritis. Not only does aging have a negative effect on the quality of life among the elderly but it also causes a significant financial strain on both private and public sectors. As the proportion of older people is increasing so is health care spending. According to a WHO analysis, the annual number of new cancer cases is projected to rise to 17 million by 2020, and reach 27 million by 2030. Similar trends are clearly visible in other age-related diseases such as cardiovascular disease. Few effective treatments addressing these challenges are currently available and most of them focus on a single disease rather than adopting a more holistic approach to aging.

Recently a new approach which has the potential of significantly alleviating these problems has been validated by a number of in vivo and in vitro studies. It has been demonstrated that senescent cells (cells which have ceased to replicate due to stress or replicative capacity exhaustion) are linked to many age-related diseases. Furthermore, removing senescent cells from mice has been recently shown to drastically increase mouse healthspan (a period of life free of serious diseases).

Here at CellAge we are working hard to help translate these findings into humans!

CellAge, together with a leading synthetic biology partner, Synpromics, are poised to develop a technology allowing for the identification and removal of harmful senescent cells. Our breakthrough technology will benefit both the scientific community and the general public.

In short, CellAge is going to develop synthetic promoters which are specific to senescent cells, as promoters that are currently being used to track senescent cells are simply not good enough to be used in therapies. The most prominently used p16 gene promoter has a number of limitations, for example. First, it is involved in cell cycle regulation, which poses a danger in targeting cells which are not diving but not senescent either, such as quiescent stem cells. Second, organism-wide administration of gene therapy might at present be too dangerous. This means senescent cells only in specific organs might need to be targeted and p16 promoter does not provide this level of specificity. Third, the p16 promoter is not active in all senescent cells. Thus, after therapies utilizing this promoter, a proportion of senescent cells would still remain. Moreover, the p16 promoter is relatively large (2.1kb), making it difficult to incorporate in present gene therapy vehicles. Lastly, to achieve the intended therapeutic effect the strength of p16 promoter to drive therapeutic effect might not be high enough.

CellAge will be constructing a synthetic promoter which has a potential to overcome all of the mentioned limitations. A number of gene therapy companies, including uniQure, AGTC and Avalanche Biotech have successfully targeted other types of cells using this technology. With your help, we will be able to use same technology to develop tools and therapies for accurate senescent cell targeting.

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The Two Faces of Aging: Cancer and Cellular Senescence – Article by Adam Alonzi

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Categories: Science, Transhumanism, Tags: , , , , , , , , , , , , , , , , , , , , , , ,

The New Renaissance Hat
Adam Alonzi
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This article is republished with the author’s permission. It was originally posted on Radical Science News.

hELA-400x300Multiphoton fluorescence image of HeLa cells.

Aging, inflammation, cancer, and cellular senescence are all intimately interconnected. Deciphering the nature of each thread is a tremendous task, but must be done if preventative and geriatric medicine ever hope to advance. A one-dimensional analysis simply will not suffice. Without a strong understanding of the genetic, epigenetic, intercellular, and intracellular factors at work, only an incomplete picture can be formed. However, even with an incomplete picture, useful therapeutics can be and are being developed. One face is cancer, in reality a number of diseases characterized by uncontrolled cell division. The other is degradation, which causes a slue of degenerative disorders stemming from deterioration in regenerative capacity.

Now there is a new focus on making geroprotectors, which are a diverse and growing family of compounds that assist in preventing and reversing the unwanted side effects of aging. Senolytics, a subset of this broad group, accomplish this feat by encouraging the removal of decrepit cells. A few examples include dasatinib, quercetin, and ABT263. Although more research must be done, there are a precious handful of studies accessible to anyone with the inclination to scroll to the works cited section of this article. Those within the life-extension community and a few enlightened souls outside of it already know this, but it bears repeating: in the developed world all major diseases are the direct result of the aging process. Accepting this rather simple premise, and you really ought to, should stoke your enthusiasm for the first generation of anti-aging elixirs and treatments. Before diving into the details of these promising new pharmaceuticals, nanotechnology, and gene therapies we must ask what is cellular senescence? What causes it? What purpose does it serve?

Depending on the context in which it is operating, a single gene can have positive or negative effects on an organism’s phenotype. Often the gene is exerting both desirable and undesirable influences at the same time. This is called antagonistic pleiotropy. For example, high levels of testosterone can confer several reproductive advantages in youth, but in elderly men can increase their likelihood of developing prostate cancer. Cellular senescence is a protective measure; it is a response to damage that could potentially turn a healthy cell into a malignant one. Understandably, this becomes considerably more complex when one is examining multiple genes and multiple pathways. Identifying all of the players involved is difficult enough. Conboy’s famous parabiosis experiment, where a young mouse’s system revived an old ones, shows that alterations in the microenviornment, in this case identified and unidentified factors in the blood of young mice, can be very beneficial to their elders. Conversely, there is a solid body of evidence that shows senescent cells can have a bad influence on their neighbors. How can something similar be achieved in humans without having to surgically attach a senior citizen to a college freshman?

By halting its own division, a senescent cell removes itself as an immediate tumorigenic threat. Yet the accumulation of nondividing cells is implicated in a host of pathologies, including, somewhat paradoxically, cancer, which, as any life actuary’s mortality table will show, is yet another bedfellow of the second half of life. The single greatest risk factor for developing cancer is age. The Hayflick Limit is well known to most people who have ever excitedly watched the drama of a freshly inoculated petri dish. After exhausting their telomeres, cells stop dividing. Hayflick et al. astutely noted that “the [cessation of cell growth] in culture may be related to senescence in vivo.” Although cellular senescnece is considered irreversible, a select few cells can resume normal growth after the inactivation of the p53 tumor suppressor. The removal of p16, a related gene, resulted in the elimination of the progeroid phenotype in mice. There are several important p’s at play here, but two are enough for now.

Our bodies are bombarded by insults to their resilient but woefully vincible microscopic machinery. Oxidative stress, DNA damage, telomeric dysfunction, carcinogens, assorted mutations from assorted causes, necessary or unnecessary immunological responses to internal or external factors, all take their toll. In response cells may repair themselves, they may activate an apoptotic pathway to kill themselves, or just stop proliferating. After suffering these slings and arrows, p53 is activated. Not surprisingly, mice carrying a hyperactive form of p53 display high levels of cellular senescence. To quote Campisi, abnormalities in p53 and p15 are found in “most, if not all, cancers.” Knocking p53 out altogether produced mice unusually free of tumors, but those mice find themselves prematurely past their prime. There is a clear trade-off here.

In a later experiment Garcia-Cao modified p53 to only express itself when activated. The mice exhibited normal longevity as well as an“unusual resistance to cancer.” Though it may seem so, these two cellular states are most certainly not opposing fates. As it is with oxidative stress and nutrient sensing, two other components of senescence or lack thereof, the goal is not to increase or decrease one side disproportionately, but to find the correct balance between many competing entities to maintain healthy homeostasis. As mentioned earlier, telomeres play an important role in geroconversion, the transformation of quiescent cells into senescent ones. Meta-analyses have shown a strong relationship between short telomeres and mortality risk, especially in younger people. Although cancer cells activate telomerase to overcome the Hayflick Limit, it is not entirely certain if the activation of telomerase is oncogenic.

majormouse

SASP (senescence-associated secretory phenotype) is associated with chronic inflammation, which itself is implicated in a growing list of common infirmities. Many SASP factors are known to stimulate phenotypes similar to those displayed by aggressive cancer cells. The simultaneous injection of senescent fibroblasts with premalignant epithelial cells into mice results in malignancy. On the other hand, senescent human melanocytes secrete a protein that induces replicative arrest in a fair percentage of melanoma cells. In all experiments tissue types must be taken into account, of course. Some of the hallmarks of inflammation are elevated levels of IL-6, IL-8, and TNF-α. Inflammatory oxidative damage is carcinogenic and an inflammatory microenvironment is a good breeding ground for malignancies.

Caloric restriction extends lifespan in part by inhibiting TOR/mTOR (target of rapamycin/mechanistic target of rapamycin, also called  the mammalian target of rapamycin). TOR is a sort of metabolic manager, it receives inputs regarding the availability of nutrients and stress levels and then acts accordingly. Metformin is also a TOR inhibitor, which is why it is being investigated as a cancer shield and a longevity aid. Rapamycin has extended average lifespans in all species tested thus far and reduces geroconversion. It also restores the self-renewal and differentiation capacities of haemopoietic stem cells. For these reasons the Major Mouse Testing Program is using rapamycin as its positive control. mTOR and p53 dance (or battle) with each other beautifully in what Hasty calls the “Clash of the Gods.” While p53 inhibits mTOR1 activity, mTOR1 increases p53 activity. Since neither metformin nor rapamycin are without their share of unwanted side effects, more senolytics must be explored in greater detail.

Starting with a simple premise, namely that senescent cells rely on anti-apoptotic and pro-survival defenses more than their actively replicating counterparts, Campisi and her colleagues created a series of experiments to find the “Achilles’ Heel” of senescent cells. After comparing the two different cell states, they designed senolytic siRNAs. 39 transcripts were selected for knockdown by siRNA transfection, and 17 affected the viability of their target more than healthy cells. Dasatinib, a cancer drug, and quercitin, a common flavonoid found in common foods, have senolytic properties. The former has a proven proclivity for fat-cell progenitors, and the latter is more effective against endothelial cells. Delivered together, they they remove senescent mouse embryonic fibroblasts. Administration into elderly mice resulted in favorable changes in SA-BetaGAL (a molecule closely associated with SASP) and reduced p16 RNA. Single doses of D+Q together resulted in significant improvements in progeroid mice.

If you are not titillated yet, please embark on your own journey through the gallery of encroaching options for those who would prefer not to become chronically ill, suffer immensely, and, of course, die miserably in a hospital bed soaked with several types of their own excretions―presumably, hopefully, those who claim to be unafraid of death have never seen this image or naively assume they will never be the star of such a dismal and lamentably “normal” final act. There is nothing vain about wanting to avoid all the complications that come with time. This research is quickly becoming an economic and humanitarian necessity. The trailblazers who move this research forward will not only find wealth at the end of their path, but the undying gratitude of all life on earth.

Adam Alonzi is a writer, biotechnologist, documentary maker, futurist, inventor, programmer, and author of the novels “A Plank in Reason” and “Praying for Death: Mocking the Apocalypse”. He is an analyst for the Millennium Project, the Head Media Director for BioViva Sciences, and Editor-in-Chief of Radical Science News. Listen to his podcasts here. Read his blog here.

References

Blagosklonny, M. V. (2013). Rapamycin extends life-and health span because it slows aging. Aging (Albany NY), 5(8), 592.

Campisi, Judith, and Fabrizio d’Adda di Fagagna. “Cellular senescence: when bad things happen to good cells.” Nature reviews Molecular cell biology 8.9 (2007): 729-740.

Campisi, Judith. “Aging, cellular senescence, and cancer.” Annual review of physiology 75 (2013): 685.

Hasty, Paul, et al. “mTORC1 and p53: clash of the gods?.” Cell Cycle 12.1 (2013): 20-25.

Kirkland, James L. “Translating advances from the basic biology of aging into clinical application.” Experimental gerontology 48.1 (2013): 1-5.

Lamming, Dudley W., et al. “Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity.” Science 335.6076 (2012): 1638-1643.

LaPak, Kyle M., and Christin E. Burd. “The molecular balancing act of p16INK4a in cancer and aging.” Molecular Cancer Research 12.2 (2014): 167-183.

Malavolta, Marco, et al. “Pleiotropic effects of tocotrienols and quercetin on cellular senescence: introducing the perspective of senolytic effects of phytochemicals.” Current drug targets (2015).

Rodier, Francis, Judith Campisi, and Dipa Bhaumik. “Two faces of p53: aging and tumor suppression.” Nucleic acids research 35.22 (2007): 7475-7484.

Rodier, Francis, and Judith Campisi. “Four faces of cellular senescence.” The Journal of cell biology 192.4 (2011): 547-556.

Salama, Rafik, et al. “Cellular senescence and its effector programs.” Genes & development 28.2 (2014): 99-114.

Tchkonia, Tamara, et al. “Cellular senescence and the senescent secretory phenotype: therapeutic opportunities.” The Journal of clinical investigation 123.123 (3) (2013): 966-972.

Zhu, Yi, et al. “The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.” Aging cell (2015).

 

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Our Cells Will Be Guided and Protected by Machines – Article by Reason

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Categories: Science, Technology, Transhumanism, Tags: , , , , , , , , , , , , , , ,

The New Renaissance Hat
Reason
September 21, 2014
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A gulf presently lies between the nanoscale engineering of materials science on the one hand and the manipulation and understanding of evolved biological machinery on the other. In time that gulf will close: future industries will be capable of producing and controlling entirely artificial machines that integrate with, enhance, or replace our natural biological machines. Meanwhile biologists will be manufacturing ever more artificial and enhanced versions of cellular components, finding ways to make them better: evolution has rarely produced the best design possible for any given circumstance. Both sides will work towards one another and eventually meet in the middle.

Insofar as aging goes, a process of accumulating damage and malfunction in our biology, it is likely that this will first be successfully addressed and brought under medical control by producing various clearly envisaged ways to repair and maintain our cells just as they are: remove the damage, restore youthful function, and repeat as necessary. We stand much closer to that goal than the far more ambitious undertaking of building a better, more resilient, more easily repaired cell – a biology 2.0 if you like. That will happen, however. Our near descendants will be as much artificial as natural, and more capable and healthier for it.

The introduction of machinery to form a new human biology won’t happen all at once, however, and it isn’t entirely a far future prospect. There will be early gains and prototypes, the insertion of simpler types of machine into our cells for specific narrow purposes: sequestering specific proteins or wastes, or as drug factories to produce a compound in response to circumstances, or any one of a number of other similar tasks. If you want to consider nanoparticles or engineered assemblies of proteins capable of simple decision tree operations as machines then this has already happened in the lab:

Researchers Make Important Step Towards Creating Medical Nanorobots

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Researchers [have] have made an important step towards creating medical nanorobots. They discovered a way of enabling nano- and microparticles to produce logical calculations using a variety of biochemical reactions. Many scientists believe logical operations inside cells or in artificial biomolecular systems to be a way of controlling biological processes and creating full-fledged micro-and nano-robots, which can, for example, deliver drugs on schedule to those tissues where they are needed.

Further, there is a whole branch of cell research that involves finding ways to safely introduce ever larger objects into living cells, such as micrometer-scale constructs. In an age in which the state of the art for engineering computational devices is the creation of 14 nanometer features, there is a lot that might be accomplished in the years ahead with the space contained within a 1000 nanometer diameter sphere.

Introducing Micrometer-Sized Artificial Objects into Live Cells: A Method for Cell-Giant Unilamellar Vesicle Electrofusion

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Direct introduction of functional objects into living cells is a major topic in biology, medicine, and engineering studies, since such techniques facilitate manipulation of cells and allows one to change their functional properties arbitrarily. In order to introduce various objects into cells, several methods have been developed, for example, endocytosis and macropinocytosis. Nonetheless, the sizes of introducible objects are largely limited: up to several hundred nanometers and a few micrometers in diameter. In addition, the uptake of objects is dependent on cell type, and neither endocytosis nor macropinocytosis occur, for example, in lymphocytes. Even after successful endocytosis, incorporated objects are transported to the endosomes; they are then eventually transferred to the lysosome, in which acidic hydrolases degrade the materials. Hence, these two systems are not particularly suitable for introduction of functionally active molecules and objects.To overcome these obstacles, novel delivery systems have been contrived, such as cationic liposomes and nanomicelles, that are used for gene transfer; yet, only nucleic acids that are limited to a few hundred nanometers in size can be introduced. By employing peptide vectors, comparatively larger materials can be introduced into cells, although the size limit of peptides and beads is approximately 50nm, which is again insufficient for delivery of objects, such as DNA origami and larger functional beads.

Here, we report a method for introducing large objects of up to a micrometer in diameter into cultured mammalian cells by electrofusion of giant unilamellar vesicles (GUVs). We prepared GUVs containing various artificial objects using a water-in-oil emulsion centrifugation method. GUVs and dispersed HeLa cells were exposed to an alternating current (AC) field to induce a linear cell-GUV alignment, and then a direct current (DC) pulse was applied to facilitate transient electrofusion.

With uniformly sized fluorescent beads as size indexes, we successfully and efficiently introduced beads of 1 µm in diameter into living cells along with a plasmid mammalian expression vector. Our electrofusion did not affect cell viability. After the electrofusion, cells proliferated normally until confluence was reached, and the introduced fluorescent beads were inherited during cell division. Analysis by both confocal microscopy and flow cytometry supported these findings. As an alternative approach, we also introduced a designed nanostructure (DNA origami) into live cells. The results we report here represent a milestone for designing artificial symbiosis of functionally active objects (such as micro-machines) in living cells. Moreover, our technique can be used for drug delivery, tissue engineering, and cell manipulation.

Cell machinery will be a burgeoning medical industry of the 2030s, I imagine. To my eyes the greatest challenge in all of this is less the mass production of useful machines per se, and more the coordination and control of a body full of tens of trillions of such machines, perhaps from varied manufacturers, introduced for different goals, and over timescales long in comparison to business cycles and technological progress. That isn’t insurmountable, but it sounds like a much harder problem than those inherent in designing these machines and demonstrating them to be useful in cell cultures. It is a challenge on a scale of complexity that exceeds that of managing our present global communications network by many orders of magnitude. If you’ve been wondering what exactly it is we’ll be doing with the vast computational power available to us in the decades ahead, given that this metric continues to double every 18 months or so, here is one candidate.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 
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This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

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An Overview of Involuntary Bodily Functions and Cellular Regeneration (2004) – Article by G. Stolyarov II

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Categories: Science, Transhumanism, Tags: , , , , , , , , , , , ,

The New Renaissance Hat
G. Stolyarov II
July 26, 2014
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Note from the Author: This essay was originally written in 2004 and published on Associated Content (subsequently, Yahoo! Voices) in 2007.  The essay earned over 4,700 page views on Associated Content/Yahoo! Voices, and I seek to preserve it as a valuable resource for readers, subsequent to the imminent closure of Yahoo! Voices. Therefore, this essay is being published directly on The Rational Argumentator for the first time.  
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~ G. Stolyarov II, July 26, 2014
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Two of the mechanisms essential to sustaining human life as we know it are the brain’s coordination of involuntary bodily activities and cellular regeneration. This paper explores such phenomena.
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The brain is responsible for coordinating all involuntary bodily mechanisms, which, in themselves, occupy a far greater amount of the body’s functions than conscious activities. This involuntary activity includes facilitating digestion of food, the movement of muscles, and the reception of sensory signals, and responses such as pain, hunger, or the adrenaline rush.

At present, my brain is facilitating my capacity to see, though the specific items I concentrate are determined by my personal choice. I may choose to touch the keyboard, but the sensation this creates on the tips of my fingers is engineered by the brain without my consent. My heart beats involuntarily; I would not be able to engage in many other activities if I were forced to consciously guide it through its every motion.

The majority of human cells regenerate both to repair damage to a given tissue and to ensure a lifespan beyond that of the given cells. Since human beings will inevitably suffer from a wide variety of minor harms and accidents throughout their lives, it is useful for the body to possess the ability to partially repair itself.

The walls of the stomach, after being eroded by stomach acid, can grow back to their former thickness. A cut can heal by the generation of new skin cells. In the event that white blood cells suffer heavy casualties when resisting microbes, new ones can take their place. These cells are generally short-lived and last for a few years at the most. They must be replaced in order for the human organism to continue existing for decades.

If heart and nerve cells possessed the ability to regenerate, two of the leading causes of “natural” death, brain atrophy and heart failure, would be eliminated, as new vitality would be imparted upon these organs by successive creation of new cells to take the place of old and declining ones.

There are no apparent negative drawbacks to the regeneration of heart cells, but the regeneration of nerve cells may hold the potential of memory loss. If a particular neuron in the brain were responsible for storing a particular datum of information, that datum might be lost once that cell atrophied, though the organism could continue functioning and acquiring new information by the use of the fresh neuron that would arise in the old one’s place.

Of course, in a technological society, where forgotten information can quickly be recalled by the reading of books or the viewing of audiovisual records of multiple varieties, this drawback would not be substantial to bring about complete amnesia or loss of personality within the individual.

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A Simpler Path to Creating Pluripotent Stem Cells – Article by Reason

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Categories: Science, Tags: , , , , , , , , , , ,

The New Renaissance Hat
Reason
January 31, 2014
Recommend this page.
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An improvement on current methods of creating pluripotent stem cells has been in the news the past few days. It involves stressing cells with simple mechanisms, and is straightforward enough that I hear numerous laboratories and individual researchers have started in on trying it out immediately, as well as revisiting other variants of stressing cells to see what the outcome might be. The methodology is something that DIYbio enthusiasts could carry out as a weekend project with minimal cost and equipment, which is a great improvement over prior standard methods involving delivery of genes or similar operations.

As with all such potential infrastructure improvements, one pillar of importance is the reduction in cost and difficulty of research. When someone figures out a much cheaper way of achieving any particular goal, all further work that builds on that goal moves more rapidly: existing groups can do more, and new groups that previously couldn’t afford to join in now start work. Cell pluripotency is near the base of regenerative medicine and tissue engineering: ways to better achieve it accelerate the whole field.

As you can see, there are also other ramifications, however, such as for persistent reports of pluripotent stem cells isolated from adult tissues – VSELs and others – and the debate over difficulties in replicating that research.

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In 2006, Japanese researchers reported a technique for creating cells that have the embryonic ability to turn into almost any cell type in the mammalian body – the now-famous induced pluripotent stem (iPS) cells. In papers published this week, another Japanese team says that it has come up with a surprisingly simple method – exposure to stress, including a low pH – that can make cells that are even more malleable than iPS cells, and do it faster and more efficiently.

“It’s amazing. I would have never thought external stress could have this effect,” says Yoshiki Sasai. It took Haruko Obokata, a young stem-cell biologist at the same centre, five years to develop the method and persuade Sasai and others that it works. “Everyone said it was an artefact – there were some really hard days.”

The results could fuel a long-running debate. For years, various groups of scientists have reported finding pluripotent cells in the mammalian body. But others have had difficulty reproducing such findings. Obokata started the current project by looking at cells thought to be pluripotent cells isolated from the body. But her results suggested a different explanation: that pluripotent cells are created when the body’s cells endure physical stress.

Obokata has already reprogrammed a dozen cell types, including those from the brain, skin, lung and liver, hinting that the method will work with most, if not all, cell types. On average, she says, 25% of the cells survive the stress and 30% of those convert to pluripotent cells – already a higher proportion than the roughly 1% conversion rate of iPS cells.

Link: http://www.nature.com/news/acid-bath-offers-easy-path-to-stem-cells-1.14600

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 

This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

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A Brace of Papers from the Longevity Genetics Community – Article by Reason

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The New Renaissance Hat
Reason
December 29, 2013
Recommend this page.
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You’ll find quite a few papers on longevity and genetics in the preprint queue of Current Vascular Phamacology at the moment. This is a portion of the output of that part of the research community focused on developing a full understanding of the molecular biology of how aging progresses and varies between individuals and species. Biology is fantastically complex, and obtaining that full understanding will be a much, much more challenging endeavor than merely successfully treating or reversing aging.

Treating and even curing aging are goals that might be achieved without a full understanding of exactly how aging progresses. Consider this: you don’t need anything even close to a full molecular model of the progression of rust to greatly extend the life of metal equipment through scrubbing and protective coating. Exactly the same argument about knowledge and action can be applied to biology and medicine. Knowing what the damage is and having a complete understanding of how that damage progresses to cause the visible symptoms of aging are two very different things, the latter much more complex than the former, and only the former actually needed to produce useful therapies.

Nonetheless, most of the present work and funding in the aging science community is focused on developing an understanding of how degenerative aging progresses, not on damage repair and treatment of aging. So most of the output of the research community looks much along the lines of these first few papers I’m going to point out today.

The Challenges in Moving from Ageing to Successful Longevity

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During the last decades survival has significantly improved and centenarians are becoming a fast-growing group of the population. Genetic factors contribute to the variation of human life span by around 25%, which is believed to be more profound after 85 years of age. It is likely that multiple factors influence life span and we need answers to questions such as: 1) What does it take to reach 100?, 2) Do centenarians have better health during their lifespan compared with contemporaries who died at a younger age?, 3) Do centenarians have protective modifications of body composition, fat distribution and energy expenditure, maintain high physical and cognitive function, and sustained engagement in social and productive activities?, 4) Do centenarians have genes which contribute to longevity?, 5) Do centenarians benefit from epigenetic phenomena?, 6). Is it possible to influence the transgenerational epigenetic inheritance (epigenetic memory) which leads to longevity?, 7) Is the influence of nutrigenomics important for longevity?, 8) Do centenarians benefit more from drug treatment, particularly in primary prevention?, and, 9) Are there any potential goals for drug research?

Genes Of Human Longevity: An Endless Quest?

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Human longevity is a complex trait which genetics, epigenetics, environmental and stochasticity differently contribute to. To disentangle the complexity, our studies on genetics of longevity were, at the beginning, mainly focused on the extreme phenotypes, i.e. centenarians who escaped the major age-related diseases compared with cross sectional cohorts.

In association studies on candidate genes many SNPs, positively or negatively correlated with longevity have been identified. On the other hand, the identification of longevity-related genes does not explain the mechanisms of healthy aging and longevity, but it opens a huge amount of questions on epigenetic contribution, gene regulation and the interactions with essential genomes, i.e. mitochondrial DNA and microbiota.

Centenarian Offspring: a model for Understanding Longevity

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A main objective of current medical research is the improving of life quality of elderly people as priority of the continuous increase of ageing population. Accordingly, the research interest is focused on understanding the biological mechanisms involved in determining the positive ageing phenotype, i.e. the centenarian phenotype. Centenarians have been used as an optimal model for successful ageing. However, it is characterized by several limitations, i.e. the selection of appropriate controls for centenarians and the use itself of the centenarians as a suitable model for healthy ageing. Thus, the interest has been centered on centenarian offspring, healthy elderly people. They may represent a model for understanding exceptional longevity for the following reasons: to exhibit a protective genetic background, cardiovascular and immunological profile as well as a reduced rate of cognitive decline than age-matched people without centenarian relatives.

Phenotypes and Genotypes of High Density Lipoprotein Cholesterol in Exceptional Longevity

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A change in the lipoprotein profile is a metabolic hallmark of aging and has been the target for modern medical developments. Although pharmaceutical interventions aimed at lipid lowering substantially decrease the risk of cardiovascular disease, they have much less impact on mortality and longevity. Moreover, they have not affected death from other age-related diseases.

In this review we focus on high density lipoprotein (HDL) cholesterol, the levels of which are either elevated or do not decrease as would be expected with aging in centenarians, and which are associated with lower prevalence of numerous age-related diseases; thereby, suggesting a potential HDL-mediated mechanism for extended survival. We also provide an update on the progress of identifying longevity-mediating lipid genes, describe approaches to discover longevity genes, and discuss possible limitations. Implicating lipid genes in exceptional longevity may lead to drug therapies that prevent several age-related diseases, with such efforts already on the way.

It has to be said, however, that some areas of research are close enough to the development of actual rejuvenation treatments – those addressing at least some of the root cause damage of aging rather than downstream consequences – that even the scientific mainstream is coming around to the idea. The impact of cellular senescence on aging is one such field, as several obvious and existing applications of medical technology may aid in removal of the senescent cells that accumulate with age, and early work in mice confirms that such treatments should prove helpful:

Cellular Senescence in Ageing, Age-Related Disease and Longevity

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Cellular senescence is the state of permanent inhibition of cell proliferation. There is mounting evidence that senescent cells contribute to ageing and age-related disease by generating a low grade inflammation state (senescence-associated secretory phenotype-SASP). Even though cellular senescence is a barrier for cancer it can, paradoxically, stimulate development of cancer via proinflammatory cytokines. There is evidence that senescent vascular cells, both endothelial and smooth muscle cells, participate in atherosclerosis and senescent preadipocytes and adipocytes have been shown to lead to insulin resistance.

Thus, modulation of cellular senescence is considered as a potential pro-longevity strategy. It can be achieved in several ways like: elimination of selected senescent cells, epigenetic reprogramming of senescent cells, preventing cellular senescence or influencing the secretory phenotype. Some pharmacological interventions have already been shown to have promising activity in this field.

 

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 

This work is reproduced here in accord with a Creative Commons Attribution license.  It was originally published on FightAging.org.

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Mitochondrially Targeted Antioxidant SS-31 Reverses Some Measures of Aging in Muscle – Article by Reason

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The New Renaissance Hat
Reason
May 26, 2013
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Originally published on the Fight Aging! website.

Antioxidants of the sort you can buy at the store and consume are pretty much useless: the evidence shows us that they do nothing for health, and may even work to block some beneficial mechanisms. Targeting antioxidant compounds to the mitochondria in our cells is a whole different story, however. Mitochondria are swarming bacteria-like entities that produce the chemical energy stores used to power cellular processes. This involves chemical reactions that necessarily generate reactive oxygen species (ROS) as a byproduct, and these tend to react with and damage protein machinery in the cell. The machinery that gets damaged the most is that inside the mitochondria, of course, right at ground zero for ROS production. There are some natural antioxidants present in mitochondria, but adding more appears to make a substantial difference to the proportion of ROS that are soaked up versus let loose to cause harm.

If mitochondria were only trivially relevant to health and longevity, this wouldn’t be a terribly interesting topic, and I wouldn’t be talking about it. The evidence strongly favors mitochondrial damage as an important contribution to degenerative aging, however. Most damage in cells is repaired pretty quickly, and mitochondria are regularly destroyed and replaced by a process of division – again, like bacteria. Some rare forms of mitochondrial damage persist, however, eluding quality-control mechanisms and spreading through the mitochondrial population in a cell. This causes cells to fall into a malfunctioning state in which they export massive quantities of ROS out into surrounding tissue and the body at large. As you age, ever more of your cells suffer this fate.

In recent years a number of research groups have been working on ways to deliver antioxidants to the mitochondria, some of which are more relevant to future therapies than others. For example gene therapies to boost levels of natural mitochondrial antioxidants like catalase are unlikely to arrive in the clinic any time soon, but they serve to demonstrate significance by extending healthy life in mice. A Russian research group has been working with plastinquinone compounds that can be ingested and then localize to the mitochondria, and have shown numerous benefits to result in animal studies of the SkQ series of drug candidates.

US-based researchers have been working on a different set of mitochondrially targeted antioxidant compounds, with a focus on burn treatment. However, they recently published a paper claiming reversal of some age-related changes in muscle tissue in mice using their drug candidate SS-31. Note that this is injected, unlike SkQ compounds:

Mitochondrial targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice

Quote:

Mitochondrial dysfunction plays a key pathogenic role in aging skeletal muscle resulting in significant healthcare costs in the developed world. However, there is no pharmacologic treatment to rapidly reverse mitochondrial deficits in the elderly. Here we demonstrate that a single treatment with the mitochondrial targeted peptide SS-31 restores in vivo mitochondrial energetics to young levels in aged mice after only one hour.

Young (5 month old) and old (27 month old) mice were injected intraperitoneally with either saline or 3 mg/kg of SS-31. Skeletal muscle mitochondrial energetics were measured in vivo one hour after injection using a unique combination of optical and 31 P magnetic resonance spectroscopy. Age-related declines in resting and maximal mitochondrial ATP production, coupling of oxidative phosphorylation (P/O), and cell energy state (PCr/ATP) were rapidly reversed after SS-31 treatment, while SS-31 had no observable effect on young muscle.

These effects of SS-31 on mitochondrial energetics in aged muscle were also associated with a more reduced glutathione redox status and lower mitochondrial [ROS] emission. Skeletal muscle of aged mice was more fatigue resistant in situ one hour after SS-31 treatment and eight days of SS-31 treatment led to increased whole animal endurance capacity. These data demonstrate that SS-31 represents a new strategy for reversing age-related deficits in skeletal muscle with potential for translation into human use.

So what is SS-31? If look at the publication history for these authors you’ll find a burn-treatment-focused open-access paper that goes into a little more detail and a 2008 review paper that covers the pharmacology of the SS compounds:

Quote:

The SS peptides, so called because they were designed by Hazel H. Sezto and Peter W. Schiler, are small cell-permeable peptides of less than ten amino acid residues that specifically target to inner mitochondrial membrane and possess mitoprotective properties. There have been a series of SS peptides synthesized and characterized, but for our study, we decided to use SS-31 peptide (H-D-Arg-Dimethyl Tyr-Lys-Phe-NH2) for its well-documented efficacy.

Studies with isolated mitochondrial preparations and cell cultures show that these SS peptides can scavenge ROS, reduce mitochondrial ROS production, and inhibit mitochondrial permeability transition. They are very potent in preventing apoptosis and necrosis induced by oxidative stress or inhibition of the mitochondrial electron transport chain. These peptides have demonstrated excellent efficacy in animal models of ischemia-reperfusion, neurodegeneration, and renal fibrosis, and they are remarkably free of toxicity.

Given the existence of a range of different types of mitochondrial antioxidant and research groups working on them, it seems that we should expect to see therapies emerge into the clinic over the next decade. As ever, the regulatory regime will ensure that they are only approved for use in treatment of specific named diseases and injuries such as burns, however. It’s still impossible to obtain approval for a therapy to treat aging in otherwise healthy individuals in the US, as the FDA doesn’t recognize degenerative aging as a disease. The greatest use of these compounds will therefore occur via medical tourism and in a growing black market for easily synthesized compounds of this sort.

In fact, any dedicated and sufficiently knowledgeable individual could already set up a home chemistry lab, download the relevant papers, and synthesize SkQ or SS compounds. That we don’t see this happening is, I think, more of a measure of the present immaturity of the global medical tourism market than anything else. It lacks an ecosystem of marketplaces and review organizations that would allow chemists to safely participate in and profit from regulatory arbitrage of the sort that is ubiquitous in recreational chemistry.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.  

This work is reproduced here in accord with a Creative Commons Attribution license.  It was originally published on FightAging.org.