Stem Cells Age as Well
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Today I thought I'd point out an interesting post from the Buck Institute team on the topic of stem cell aging. The good news here is that the characteristic age-related decline of stem cell function is an issue that the research community has to engage with on the way to developing effective treatments based on their work. It is unavoidable: the majority of regenerative medicine based on the use of stem cells is most applicable to age-related diseases, yet the old and damaged tissue environment disrupts stem cell activity.

What happens to adult stem cells as a person ages? Can they always maintain their regenerative capacity? The answer is no. Adult stem cells maintain tissue homeostasis and differentiate into the cell types that make up the tissue in which they reside, however these processes become less efficient over time. Adult stem cell dysfunction caused by aging has been reported in many organ systems including the heart, muscle, and bone marrow. Some adult stem cell populations like neural stem cells in the brain and melanocyte stem cells in hair follicles actually decline with age. Both adult stem cell dysfunction and a decline in number translate to a reduced regenerative response to tissue or age-related damage.

A few of the culprits: DNA damage occurs in aging stem cells over time because of factors present inside and outside of the cells and because of exposure to genotoxic stress (chemical factors that cause genetic mutations). The machinery that repairs DNA in older stem cells does not function as precisely, and this can cause genomic instability, cell death, or even cancer if a person is really unlucky. Cellular senescence is a term that refers to cells that have entered a state where they can no longer proliferate and divide. Senescence occurs in older stem cells because of elevated cellular stress. Senescent stem cells are bad news because they secrete factors that can cause inflammation and stem cell dysfunction, which further exacerbates symptoms of aging and disease. Then there is mitochondrial dysfunction. Mitochondria are the batteries that power our cells. Mitochondria have their own genome, and in aging stem cells, mitochondrial DNA can be damaged, which impairs mitochondrial function and consequently, adult stem cell function.

So how do we solve the problem of aging stem cells? One obvious approach is to rejuvenate adult stem cells by preventing DNA damage, cellular senescence, and mitochondrial dysfunction. Another strategy is to transplant healthy adult stem cells from a donor into a patient with disease or damaged tissue. However, the issue with adult stem cell transplantation is that the environment (called the niche) into which you transplant healthy stem cells may contain toxic factors (caused by disease or damage) that will kill off the newly transplanted stem cells or impair their function. Thus, a better approach would be to fix or reverse aging phenotypes in the surviving stem cells and other mature cells in that niche, and then transplant healthy donor stem cells into a rejuvenated, healthy environment.

One last thing to consider as one addresses the aging adult stem cell issue is when to intervene therapeutically. Trying to restore adult stem cell function in already diseased or older tissue might not be as effective as preventing damage from accumulating in the same stem cells earlier in life. Prevention of stem cell aging would be a promising strategy to fight aging itself, but that would require the ability to predict or diagnose disease onset in healthy people, which is a huge and complicated endeavor.

Link: http://sage.buckinstitute.org/stem-cells-get-old-too/

So: At What Age Do You Want to Become Diseased and Die?
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Here are a few thoughts on the need for advocacy in longevity science from Rejuvenaction:

People don't think that ageing is a disease because they're used to thinking that it's just a stage of life. They will start to finally accept that this is not the case only when a sufficiently large number of other people in positions of authority, scientists and organizations, will come out and say it out loud. That's one sad truth: people accept things far more quickly than they understand them, and if, at some point, news from the anti-ageing world will frequently populate their TV screens, social media feeds, newspaper articles, and even casual discussions, they will stop ignoring the problem of ageing and cease to oppose its resolution. Nobody likes to advocate for an unpopular cause: it doesn't feel good to be the only person in a group to support a certain claim while being fiercely opposed by all the others, but it does feel nice to be on the winning side of an argument.

Unfortunately, with the exception of the SENS Research Foundation and a few others, researchers of the field are quite hesitant about their goals. I don't see anything wrong with looking for a "fountain of youth". Actually, I don't see how can you want to just "increase health span" without looking for a fountain of youth or eternal life. If they want to increase the current health span it's clearly because they think that the current one isn't enough. So they're not okay with getting sick of the diseases of old age at 80. Now just how much do they want to increase this health span? Till you're 100? 120? When is it okay to get age-related diseases? Unless you increase health-span indefinitely, at some point you are going to get age-related diseases, and they will kill you.

And say that one day they manage to extend health span so that you don't start experiencing age-related decay until you're 120. Then some other researchers come along and say that "they just want to extend health span" so that age-related diseases are delayed until you're 140. Are we saying no to that? Extending your health span up to when you're 120 is fine but up to when you're 140 is not? Why? This game is rather silly, particularly when you think about the obvious fact that unless you have a health problem of some sort, you do not die: yes, being shot, poisoned, electrocuted, eaten by a shark and whatever violent death you can think of counts too, because they all cause you health issues that eventually (rather fast, in fact) kill you. So, if you're not looking for eternal life, it means you're explicitly and intentionally leaving around some health problem of which people can die. In the case of age-related diseases, which ones should we leave around? Which age-related diseases are okay to die of? Alzheimer's? Cancer? Cardiovascular disease? Make your pick - I'm okay without any of those, thank you.

I'm willing to concede that, perhaps, the researchers are playing it safe: they know that if you dare saying that you want to get rid of biological ageing altogether then people will jump down your throat, and thus it's better to slowly get them used to anti-ageing research before making bolder claims. However, I disagree: curing ageing is an urgent humanitarian problem, and there's no time to fool around to please the masses. We need to educate people, get them understand that curing ageing and immortality aren't the same thing at all, that age-related diseases are an extremely serious and compelling problem that needs to be addressed right now, before it goes from bad to worse, and that all the objections to the defeat of ageing make no sense whatsoever.

Link: https://rejuvenaction.wordpress.com/2015/06/22/which-age-related-disease-would-you-like-to-die-of/

Cellular Senescence and Parkinson's Disease
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The Buck Institute here provides a popular science look at links between cellular senescence and the development of Parkinson's disease. The proximate cause of the symptoms of Parkinson's is the diminishing numbers and function of a small collection of dopamine generating neurons in the brain. This is a process that happens to all of us with aging, but Parkinson's patients have, for a variety of reasons, suffered more of the cell and tissue damage that leads to cell death and dysfunction in this population of neurons.

Parkinson's Disease (PD) is the second most common age-related neurological disorder in the US. Many genetic factors that contribute to an increased risk of developing PD have been identified over the years. These include mutations in the α-synuclein and Parkin genes. Additionally, epidemiology studies show increased risk of PD after exposure to pesticides and organic pollutants, as well as heavy metals. However, recent research shows that aging is a major player in the development of PD.

The motor issues present in PD patients are primarily caused by loss of dopaminergic neurons in the substantia nigra (SN) of the brain, which is a key regulator of motor movement and reward-seeking behavior. As a result, the most widely available PD treatments focus on replacing the neurotransmitter dopamine, which is produced by dopamingergic neurons, in various ways. These treatments do not halt disease progression, since dopaminergic neurons continue to degenerate even with these treatments. Instead, they only treat the symptoms of PD and make everyday life more manageable for PD patients.

Our brains possess the capability to replace lost cells through a process called neurogenesis, or the formation of new neurons. However, it turns out that the ability of the brain to produce new neurons is reduced both with age and in people who have a mutant version of α-synuclein (a major genetic risk factor for PD). This reduced capacity for neurogenesis extends to stem cell transplants in PD patients. Many groups have reported that healthy transplanted stem cells in PD patient brains show pathological characteristics over time. Thus it seems that there is something about the environment in the brain that causes healthy cells to develop the neurodegenerative characteristics of PD.

Here at the Buck Institute, we have found that cellular senescence may play a large role in the pathological neurodegeneration of PD. Cellular senescence is an anti-cancer mechanism intended to irreversibly prevent cell division when a cell is exposed to stress. Senescent cells show distinct biological markers, such as secretion of inflammatory compounds in a phenomenon also referred to as Senescence Associated Secretory Phenotype (SASP). Data suggests that cellular senescence in astrocytes may alter the brain environment to promote disease progression and inhibit neurogenesis. Astrocytes show increased levels of SASP factors, and manipulations that reduce cellular senescence also reduce Parkinsonian phenotypes in mouse models. Since cellular senescence is associated with age, astrocyte senescence may explain the age-dependency of PD onset. We are currently searching for potential treatments that can inhibit cellular senescence in the brain, thereby halting the progress of PD.

While the field of cellular senescence is relatively young in the larger field of neurobiology, it is becoming more evident that cellular senescence is key to explaining age-related disorders. Cellular senescence in the brain may prove to be one of the underlying factors common to multiple age-related neurodegenerative diseases, which would make it an important therapeutic target to pursue.

Link: http://sage.buckinstitute.org/the-parkinsonian-brain-cellular-senescence-and-neurodegeneration/

The Latest Glenn Foundation Funding for Aging Research
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In past years the Glenn Foundation for Medical Research has reinforced the mainstream of the aging research community with grants of a few million dollars apiece to establish or expand laboratories in many major universities and research centers. Much of this supports work focused on cataloging and then attempting to safely alter the complex details of metabolic operation, such as through potential calorie restriction mimetic drugs, so as to slightly slow the aging process. Here is news of the latest round of grants:

Building on its previous gifts to MIT, the Glenn Foundation for Medical Research has pledged $2 million to establish a new center for the study of aging. The new Paul F. Glenn Center for Science of Aging Research at MIT will be directed by Novartis Professor of Biology Leonard Guarente. "With this generous gift, the Glenn Foundation will enable us to carry out a multitiered approach and leverage the strengths of all three labs to arrive at new and testable conclusions about what pathways and mechanisms govern aging. Behind all of our research is the drive to discover new therapeutic compounds that have the potential to improve the course of the aging process, and hopefully lead the way toward effective treatments for neurodegenerative diseases, like Alzheimer's disease and Parkinson's disease, as well as cancer."

The new center will build upon research that was formerly conducted within the Paul F. Glenn Laboratory for Science of Aging Research, which was established at MIT in 2008 with a $5 million gift from the foundation and expanded with an additional $1 million gift in 2013. These efforts were led by Guarente, a pioneer in the field of aging research who is known for his work to uncover the SIR2 gene, a key regulator of longevity in yeast and worms. Since then, Guarente and his colleagues have continued to explore aging, and key pathways and genes that govern aging in the human brain. A particular focus has been the role of sirtuin activation and nicotinamide adenine dinucleotide supplementation in slowing the aging process and diseases of aging. Their recent work involves the use of bioinformatics to advance their analysis.

Link: http://newsoffice.mit.edu/2015/glenn-foundation-gift-aging-research-initiatives-0625

Population Life Expectancy Inversely Correlated with Childhood Autoimmune Disease Incidence
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A researcher here runs the numbers to demonstrate an inverse correlation between autoimmune disease incidence and life expectancy. It is interesting to speculate on the mechanisms here, which are probably not going to turn out to be a straightforward matter of (a) declining immune function being important in the progression of aging, and (b) more autoimmunity indicating a greater tendency to subclinical immune dysfunction over the course of aging in a population:

The autoimmune diseases are among the ten leading causes of death for women and the number two cause of chronic illness in America. They are a predisposing factor for cardiovascular diseases and cancer. Patients of some autoimmune diseases have shown a shorter lifespan and are a model of accelerated immunosenescence. Centenarians from the other side, are used as a model of successful aging and have shown better preserved several immune parameters and lower levels of autoantibodies. My study is focused on clarifying the connection between longevity and some autoimmune and allergic diseases in 29 developed OECD countries as the multidisciplinary analyses of the accelerated or delayed aging data could show a distinct relation pattern, help to identify common factors and determine new important ones that contribute to longevity and healthy aging.

I have assessed the relations between the mortality rates data of Multiple Sclerosis MS, Rheumatoid arthritis RA, Asthma, the incidence of Type 1 diabetes T1D from one side and Centenarian Rates (two sets) as well as Life Expectancy data from the other side. The obtained data correspond to an inverse linear correlation with different degrees of linearity. I have been the first to observe a clear tendency of diminishing Centenarian Rates or Life Expectancy in countries having higher death rates of Asthma, MS and RA and a higher incidence of T1D in children. I have therefore concluded that most probably there are common mechanistic pathways and factors, affecting the above diseases and in the same time but in the opposite direction the processes of longevity. Further study, comparing genetic data, mechanistic pathways and other factors connected to autoimmune diseases with those of longevity, could clarify the processes involved, in order to promote the longevity and limit the expanding of those diseases in the younger and older population.

Link: http://dx.doi.org/10.1089/rej.2015.1690

The Prospects for Stem Cells to Treat Chronic Wounds
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Based on the evidence to date, stem cell transplants could be used to treat chronic, non-healing wounds that occur in older patients, though work to be accomplished in order to achieve this goal. Here is an open access review paper on that topic:

Wound healing is an elaborate process that occurs in three distinct, yet overlapping, phases: inflammation, cell proliferation, and remodeling. Adult cutaneous wound repair is characterized by a highly evolved fibroproliferative response to injury that quickly restores the skin barrier, thereby reducing the risk of infection and further injury. The inflammatory phase is characterized by influx of polymorphonuclear cells followed by monocytes/macrophages. Macrophages secrete the growth factors and cytokines necessary for wound healing. Stimulated by these growth factors, healing proceeds to the proliferative phase, made up of fibroplasia, matrix deposition, angiogenesis, and reepithelialization. Remodeling is a dynamic phase during which various collagens are continuously deposited and degrade.

Chronic wounds occur when there is a failure of injured skin to proceed through an orderly and timely process to produce anatomic and functional integrity. Causative factors include malnutrition and immunosuppression, and chronic wounds are commonly seen as a consequence of diabetes mellitus and vascular compromise. Current techniques to manage chronic wounds typically focus on modification of controllable causative factors. The advent of skin substitutes has increased our armamentarium for treating this difficult condition, but to date no ideal therapy is available to treat troublesome, chronic wounds.

New therapies in this area are required to optimize outcomes for our patients. Stem cells, with their unique properties to self-renew and undergo differentiation, are emerging as a promising candidate for cell-based therapy for the treatment of chronic wounds. Mesenchymal stem cells (MSC), a progenitor cell population of the mesoderm lineage, have been shown to be significant mediators in inflammatory environments. Preclinical studies of MSC in various animal wound healing models point towards a putative therapy. This review examines the body of evidence suggesting that MSC accelerate wound healing in both clinical and preclinical studies and also the possible mechanisms controlling its efficacy.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461792/

An Early Attempt to Work Around Immunosenescence
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Researchers have recently demonstrated a partial restoration of immune response in aged mice using a combination of existing Toll-like receptor agonists. This might be seen as a first step on the road to ways to reverse those aspects of immune system failure with age that depend more on misconfiguration rather than cellular damage.

The immune system declines with age for a variety of reasons, and this decline accounts for a great deal of the frailty of the elderly, vulnerable to infections that the young shrug off, and less able to eliminate precancerous cells. Some of these reasons involve the rising levels of damage to all tissues and cells that occurs with aging, while others are structural and inevitable due to the way in which the immune system works. Even absent cellular damage it would fail over the course of a lifetime. For example, the slow pace of immune cell replacement in adults means that the population of these cells is effectively limited, and in the adaptive immune system ever more of that population consists of memory T cells devoted to past threats rather than naive T cells needed to meet new threats. Most of those memory T cells are not even particularly helpful, being duplicates of one another that exist because of the recurring presence of viruses that cannot be cleared from the body, such as cytomegalovirus. Some form of targeted cell clearance should be a useful approach here, to free up space for new immune cells, and has in fact been demonstrated to produce benefits in the laboratory for other immune cell types.

At base this sort of thing is a programming and configuration problem. Cells are machines that operate according to their state and the chemical signals they receive. Removing the misconfigured cells is one way to deal with the problem, and only requires the ability to reliably identify and target the cells to be destroyed. Given better understanding of cells and their signals in any given tissue type or system in the body, it should also be possible to change cell behaviors for the better, however. This more complex strategy may be particularly applicable to the immune system, given that so much of its age-related dysfunction is a matter of misconfiguration rather than damage. So in this research, you might see the seeds of more complex and comprehensive reprogramming efforts in the future:

Immunosenescence is characterised by decline in both adaptive and innate immune functions. Innate immune responses are activated, mainly, by stimulation of Toll-like receptors (TLRs), the expression and function of which declines with age. Dendritic cells (DCs) from both young and aged individuals exhibit comparable activation in response to most TLR ligands, and are equally capable of direct and cross-presentation of antigens to T cells in vitro, underscoring the likely importance of TLR-induced DC activation in promoting adaptive immunity. TLR stimulation is therefore a promising strategy to enhance vaccine efficacy in the elderly. Combinations of TLR agonists may be especially effective, as demonstrated in animal models and clinical trials.

We previously showed that triggering of multiple TLRs, using a combined adjuvant for synergistic activation of cellular immunity (CASAC), incorporating polyI:C, interferon (IFN)-γ and MHC-class I and II peptides, results in potent cytotoxic T cell-mediated immunity in young mice. Optimization of the adjuvant formulation and investigation of mechanism of action were also performed. We now report the ability of CASAC to improve vaccination-induced responses in aged mice by promoting induction of antigen-specific cellular immunity to both foreign and self tumour-associated peptide antigens.

We have demonstrated that our combined molecular adjuvant CASAC effectively promotes functional antigen-specific CD8+ T cell responses to vaccination with peptides in aged mice, despite their immunosenescent phenotype. CASAC improved responses in aged mice not only to a highly immunogenic foreign antigen, but also to the tumour-associated self-antigen TRP-2 whose immunogenicity is being evaluated in clinical trials. Restoration of response to vaccination in immunosenescent aged mice by CASAC likely reflects the benefits of multiple TLR triggering on DC function and provision of IFN-γ could substitute for lack of IFN-γ from CD8+ memory cells during the early phase of immune response. Since CASAC comprises a combination of agents that individually are approved for human use, our findings suggest that a CASAC-based vaccination strategy may be amenable to rapid clinical translation, particularly against chronically experienced antigens such as persistent infections or tumour-associated antigens in older people.

Link: http://dx.doi.org/10.1186/s12979-015-0033-0

Are Mitochondrial Mutations Really All That Important?
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Prompted by attention given to a recent study claiming to cast doubt on the primary role of damaged mitochondria in aging, here is a lengthy and detailed article from the SENS Research Foundation on what is known of mitochondrial DNA damage and aging. It is worth bearing in mind when reading the scientific literature that any single study, especially if claiming to overthrow the consensus, should always be weighed against the rest of the recent literature in a given field:

The study was of fibroblasts, which are a kind of skin cell. It is interesting and contributes to a long-standing debate in this field about the frequency of specific mitochondrial DNA mutations with age and tissue type, and whether they contribute to specific diseases. It is clear at this point that mitochondrial dysfunction occurs with age and that damage in the form of mutations to mitochondria contributes to the diseases and disabilities of aging. We don't believe that this particular study is actually a challenge to scientists' existing understanding about how changes in mitochondria with age both drive and are driven by cellular and molecular damage, and the diseases and disabilities of aging.

What is actually known about the frequency and impact of specifically age-related mitochondrial mutations? First, in line with the ability of dividing cells to dilute out structural damage, multiple studies in aging rodents and humans report that the mutations in mitochondria that persist in cells and thus accumulate with age are confined almost entirely to cell types that don't divide during adulthood (e.g., brain neurons, heart muscle cells, and skeletal muscle). Second, those mutations are quite surprisingly rare: even in tissues that are actually affected by mitochondrial mutations with age, fewer than 1% - and perhaps as few as 0.1% - of cells are found to be affected.

Still, the evidence suggesting that this damage drives degenerative aging is powerful. The level of oxidative damage to mitochondrial DNA, the rate of accumulation of mitochondrial DNA mutations with age, and the structural vulnerability to such mutations are collectively robustly correlated with species maximum lifespan (the strongest integrative measure of the overall rate of aging in a species). Remarkably, this has recently been demonstrated even in rockfish, whose senescence is nearly negligible: lifespan in rockfish species was found to correlate negatively with the rate of mutation of their mitochondrial, but not nuclear, genomes - a relationship that the investigators' analysis suggested was not likely to be an artifact of tradeoffs with fecundity or the rate of germline DNA replication.

Calorie restriction (the most robust intervention that slows the rate of aging in mammals) lowers the rate of accumulation of mitochondrial deletion mutations with age. And when mice are given a transgene that directs a form of the antioxidant catalase directly to their mitochondria - an enzyme that complements the existing antioxidant machinery in the mitochondria in a way that reduces total mitochondrial DNA oxidative damage, including but not limited to deletion mutations - it extends their mean and maximal lifespan and ameliorates multiple pathologies of aging. Yet no such effects are observed when the same enzyme is directed to sites outside of the mitochondria, or when other antioxidant enzymes are expressed elsewhere in the cell, or even when non-complementary enzymes are sent to the mitochondria.

The apparent paradox in all of this is the strong link between mitochondrial DNA deletions and the rate of degenerative aging in the face of the rarity of such mutations. There are two broad kinds of resolution to this paradox. The first is the tissue-specific one. Although cells overtaken by mitochondria bearing DNA deletions are rare, they can have powerful effects on health in tissues where they are unusually enriched in critical cell types, particularly if relatively few of those cells exist in the first place. Such is the case for the key dopamine-producing neurons in an area of the brain known as the substantia nigra pars compacta (SNc). SNc dopaminergic neurons are much more vulnerable to being overtaken by mitochondria bearing large deletions in their DNA than are other cell types in the brain, and such mutations clearly drive dysfunction, including being tightly liked to Parkinson's disease. The same high regional vulnerability to mitochondrial DNA deletions occurs in people suffering with non-Parkinson movement disorders and even in "normal" aging brains, albeit at a lower rate and yet the finding has no parallel in the smaller and less harmful point mutations.

The other kind of tissue-specific effect relates more to the unique properties of the affected cell type itself, with the cardinal case in this category being skeletal muscle. Unlike most cell types, skeletal muscle "cells" are not isolated from all of their neighbors by a membrane. Instead, the long stretches of skeletal muscle fibers are comprised of multiple segments, each of which contains its own nucleus, which is in turn supported by a local population of mitochondria, with additional mitochondria in the membrane-bound space outside the fiber itself. Mitochondrial DNA deletions not only accumulate with age at a faster pace in skeletal muscle than in many other aging tissues, but because of that structure their effects are much more catastrophic. When a local nucleus' mitochondrial population is overtaken by deletion mutations, the segment first atrophies at that point, and then fails, leading the fiber to split or break locally and ultimately causing the loss of the entire fiber. These processes - loss of energy production and the splitting and loss of fibers - are a key driver of sarcopenia, the age-related loss of skeletal muscle mass and function that occurs even in lifelong master athletes.

Because deletion mutations in mitochondrial DNA are core molecular lesions driving these diseases, repair of these mutations will be central to their prevention, arrest, and reversal. But you can't tell that from a study of skin cells.

Link: http://sens.org/research/research-blog/question-month-11-are-mitochondrial-mutations-really-all-important

Changing the View of Aging: Are We Winning Yet?
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Peter Thiel, who has invested millions into the SENS rejuvenation research programs over the past decade, has of late been talking much more in public on the topic of treating aging. Having wealth gives you a soapbox, and it is good that he is now using it to help the cause of treating aging as a medical condition. One of Thiel's recent public appearances was a discussion on death and religion in this context.

In the struggle to produce meaningful progress in rejuvenation research, the tipping point can come from either a very large amount of money, hundreds of millions of dollars at least, dedicated to something very similar to the SENS research programs, or from a widespread shift in the commonplace view of aging. At the large scale and over the long term medical research priorities reflect the common wisdom, and it is my view that public support is needed to bring in very large contributions to research. The wealthiest philanthropists and largest institutional funding bodies follow the crowd as a rule, they only rarely lead it. They presently give to cancer and stem cell research precisely because the average fellow in the street thinks that both of these are a good idea.

So it is very important that we reach a point at which research into treating degenerative aging is regarded as a sensible course of action, not something to be ridiculed and rejected. Over the past decade or two a great deal of work has gone into this goal on the part of a small community advocates and researchers. It is paying off; the culture of science and the media's output on aging research is a far cry from what it was ten years ago. When ever more authorities and talking heads are soberly discussing the prospects of extended healthy life and research into the medical control of aging, it is to be hoped that the public will follow. Inevitably religion is drawn in as a topic in these discussions once you start moving beyond the scientific community:

The Venn diagram showing the overlap of people who are familiar with both Peter Thiel and N.T. Wright is probably quite small. And I think it is indicative of a broader gap between those doing technology and those doing theology. It is a surprise that a large concert hall in San Francisco would be packed with techies eager to hear a priest and an investor talk about death and Christian faith, even if that investor is Peter Thiel.

Thiel has spoken elsewhere about the source of his optimism about stopping and even reversing aging. The idea is to do what we are doing in every other area of life: apply powerful computers and big data to unlock insights to which, before this era, we've never had access. Almost everyone I talk with about these ideas has the same reaction. First there is skepticism  - that can't really happen, right? Second, there is consideration  - well those Silicon Valley guys are weird, but if anyone has the brains and the money to do it, it's probably them. Finally comes reflection, which often has two parts - 1. I would like to live longer. 2. But I still feel a little uneasy about the whole idea.

The concept of indefinite life extension feels uncomfortable to people, thinks Thiel, because we have become acculturated to the idea that death, like taxes, is inevitable. But, he says, "it's not like one day you'll wake up and be offered a pill that makes you immortal." What will happen instead is a gradual and increasingly fast march of scientific discovery and progress. Scientists will discover a cure for Alzheimer's and will say, "Do you want that?" Of course our answer will be "Yes!" They will find a cure for cancer and say, "Do you want that?" And again, of course, our answer will be "Yes!" What seems foreign and frightening in the abstract will likely seem obvious and wonderful in the specific. "It seems," Thiel said, "that in every particular instance the only moral answer is to be in favor of it."

One of Wright's objections was to articulate a skepticism about whether the project of life extension really is all that good, either for the individual or for the world. "If [I] say, okay I'll live to be 150. I'll still be a sinner. I'll still be conflicted. I'll still have wrong emotions. Do I really want to go on having all that stuff that much longer? Will that be helpful to the world if I do?" This roused Thiel. "I really have to disagree with that last formulation...it strikes me as very Epicurean in a way." For Peter Thiel, Epicureanism is akin to deep pessimism. It means basically giving up. One gets the sense he finds the philosophy not just disagreeable but offensive to his deepest entrepreneurial instincts and life experience. "We are setting our sights low," he argued, "if we say everyone is condemned to a life of death and suffering."

Link: http://www.forbes.com/sites/valleyvoices/2015/06/24/peter-thiel-n-t-wright-on-technology-hope-and-the-end-of-death/

Trametinib Modestly Extends Healthy Life Spans in Flies
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Researchers have found that the MEK inhibitor trametinib, used as a cancer treatment, modestly extends life in flies. This is of interest for researchers involved in mapping the relationships between metabolism and natural variations in longevity, but otherwise not all that significant in the grand scheme of things. The plasticity of life span in response to drug treatments that alter the operation of metabolism is much greater in short-lived creatures, and it should be expected that a small extension of life such as this one would map to next to nothing in humans, even assuming that the underlying mechanism of action is in fact shared. I believe that efforts to develop drug treatments to slow aging in humans based on this sort of result are doomed to lengthy and expensive failure, or at best result in very marginal therapies that will do no more than add a couple of years to life expectancy - something that can already be achieved through exercise or calorie restriction.

Adult fruit flies given a cancer drug live 12% longer than average, according to a study researching healthy ageing. Trametinib is used to treat skin cancer and was chosen for its ability to inhibit Ras signalling as part of the Ras-Erk-ETS cell pathway. The role of Ras has been well characterised in cancer but it is also known to affect the ageing process. Previously, the DNA of yeast was changed to reduce Ras activity, which extended lifespan, so the team wanted to explore inhibitors of this pathway in an animal. "Our aim is to understand the mechanisms of ageing and alter the processes that lead to loss of function and to disease. We studied this molecular pathway in flies because they are reasonably complex and yet age more quickly than mammals. We were able to extend their lifespan both genetically and by using a cancer drug to target the Ras pathway, which provides us with the first evidence for the anti-ageing potential of drugs developed to dampen this pathway."

Female fruit flies were given trametinib as an additive in their food. A small dose of 1.56 µM, which is approximately equivalent to a daily dose of the drug in a human cancer patients, increased the fruit flies' average life expectancy by 8%. With a higher dose of 15.6 µM, the flies lived 12% longer on average. To test the anti-ageing properties of the drug in later life, fruit flies over 30 days old that had almost all stopped laying eggs were given the same moderate dose of 15.6 µM, and still had an increased life expectancy of 4%. Flies exposed continuously to the drug from an earlier stage in life lived longer than those who began dosing later in life, possibly indicating a cumulative effect of the drug. "Identifying the importance of the Ras-Erk-ETS pathway in animal ageing is a significant step on the way to developing treatments that delay the onset of ageing. The pathway is the same in humans as it is in flies and, because the Ras protein plays a key role in cancer, many small molecule drugs already exist, some of which have been approved for clinical use. With support from pharma, we can refine these molecules over the next 10-20 years to develop anti-ageing treatments which don't have the adverse effects of cancer drugs."

Link: https://www.ucl.ac.uk/news/news-articles/0615/250615-fruit-flies-live-longer/