Fight Aging! Newsletter, September 8th 2014

September 8th 2014

The Fight Aging! Newsletter is a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: both the road to future rejuvenation and the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the longevity science community, advocacy and fundraising initiatives to help advance rejuvenation biotechnology, links to online resources, and much more.

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  • Recent Updates on Naked Mole Rat Research
  • An Optimistic View on What Hydra Can Do For Us
  • Rejuvenation Biotechnology Update for September 2014
  • Antigen-Specific Immunotherapy to Treat Autoimmune Disease
  • Promote Longevity Research on October 1st, the International Day of Older Persons
  • Latest Headlines from Fight Aging!
    • An Interview with Aubrey de Grey
    • HSV-1 and Alzheimer's Disease
    • On Proteostasis and the Endoplasmic Reticulum
    • Arguing for Cellular Senescence as a Contribution to Chronic Obstructive Pulmonary Disease
    • Moderate Exercise Correlates with Lower Risk of Heart Failure
    • Jason Hope's Contribution to SENS Research
    • Calico Partnering with AbbVie
    • Working Towards In Situ Muscle Tissue Engineering
    • Proposing Synthetic Mitochondria as a Treatment for Aging
    • Intervening to Prevent Consequences of Cellular Senesence


Comparative study of the biology of aging in species with widely divergent life spans is undertaken by a number of groups in the broader research community. The idea here is that, especially in the case of similar species that nonetheless have very different life spans, chasing down the root causes of these differences will help identify the most important aspects of the biology of aging in our species. This is a very different approach to the problem of aging to the strategy I favor, which is to skip over much of this investigation of the details in favor of focusing on ways to repair known differences between old tissue and young tissue, as exemplified by the SENS research programs.

In any case, it turns out that a great deal of the interaction between metabolism and aging is very similar in many species, and the specific mechanisms present today are inherited from a common but distant evolutionary past, such as the response to calorie restriction that increases health and longevity. Given this, a better understanding of differences in aging between various types of mammal should in turn help to inform research aimed at understanding or treating human aging. In the most optimistic viewpoint the study of aging in diverse species may yield treatments based on importing or mimicking beneficial aspects of non-human biochemistry. Whether or not that turns out to be an effective path forward is up for debate. It depends greatly on the details of any specific attempt and it is really far too early in this process to do more than speculate on that front.

Naked mole rats are one of the better studied species with respect to the comparative biology of aging. From a taxonomic point of view they are not so very distant from mice of a similar size and yet live up to nine times longer. Why? Further, and of perhaps greater interest to today's medical research community, where funding is very biased towards treatment of specific named diseases and there is comparatively little money for aging research, naked mole rats appear to be essentially immune to cancer. Thus there is a growing interest in this species in many quarters. The research group run by João Pedro de Magalhães, who you might recall published a call to action on life extension research earlier this year, recently released an open online database for the naked mole rat genome:

The Naked Mole Rat Genome Resource: facilitating analyses of cancer and longevity-related adaptations.

The naked mole rat (Heterocephalus glaber) is an exceptionally long-lived and cancer-resistant rodent native to East Africa. Although its genome was previously sequenced, here we report a new assembly sequenced by us. We analyzed the annotation of this new improved assembly and identified candidate genomic adaptations which may have contributed to the evolution of the naked mole rat's extraordinary traits, including in regions of p53, and the hyaluronan receptors CD44 and HMMR (RHAMM).

Furthermore, we developed a freely-available web portal, the Naked Mole Rat Genome Resource, featuring the data and results of our analysis, in order to assist researchers interested in the genome and genes of the naked mole rat, and also to facilitate further studies on this fascinating species. This resource is open source and the source code is available at:

Meanwhile, other researchers are looking for mechanisms to explain how it is that naked mole rats maintain relative levels of undamaged proteins, or proteostasis, far more efficiently throughout their life spans than other rodent species. Aging is characterized by the accumulation of damage and change in cell structures and relative levels of circulating proteins, and slower or more negligible aging is associated with more effective maintenance of proteostasis over time. This doesn't say too much about cause and effect when stated at the high level in this way: it is just what can be observed.

In the research quoted below scientists are on the trail of a noteworthy difference in naked mole rat damage control mechanisms, structures called proteasomes within the cell responsible for breaking down damaged or otherwise unwanted proteins. In naked mole rats the proteasome is more effective at its job as well as being more resilient to interference and damage, and these researchers have found that they can cause proteasomes from other mammalian species to perform just as well by importing a grab bag of proteins and structures from naked mole rat cells. At this point it remains to be seen as to what the crucial factors are, but I can't imagine it'll take long to pin that down:

Factor in naked mole rat's cells enhances protein integrity

A factor in the cells of naked mole rats protects and alters the activity of the proteasome, a garbage disposer for damaged and obsolete proteins. The factor also protects proteasome function in human, mouse and yeast cells when challenged with various proteasome poisons, studies showed. These proteasomes usually rapidly stop functioning, leading to the accumulation of damaged proteins that further impair cell function, contributing to the vicious cycle that leads to cell death. "I think this factor is part of an overall process or mechanism by which naked mole rats maintain their protein quality."

Generally, as an organism ages, not only are there more damaged proteins in need of disposal, but the proteasome itself becomes damaged and less efficient in clearing out the damaged proteins. As a result, protein quality declines and this contributes to the functional declines seen during aging. Enhancement of protein quality, meanwhile, leads to longer life in yeast, worms, fruit flies and naked mole rats.

A cytosolic protein factor from the naked mole-rat activates proteasomes of other species and protects these from inhibition

The naked mole-rat maintains robust proteostasis and high levels of proteasome-mediated proteolysis for most of its exceptional (~ 31 years) life span. Here, we report that the highly active proteasome from the naked mole-rat liver resists attenuation by a diverse suite of proteasome-specific small molecule inhibitors. Moreover, mouse, human, and yeast proteasomes exposed to the proteasome-depleted, naked mole-rat cytosolic fractions, recapitulate the observed inhibition resistance, and mammalian proteasomes also show increased activity.

Gel filtration coupled with mass spectrometry and atomic force microscopy indicates that these traits are supported by a protein factor that resides in the cytosol. This factor interacts with the proteasome and modulates its activity. Although HSP72 and HSP40 (Hdj1) are among the constituents of this factor, the observed phenomenon, such as increasing peptidase activity and protecting against inhibition cannot be reconciled with any known chaperone functions. This novel function may contribute to the exceptional protein homeostasis in the naked mole-rat and allow it to successfully defy aging.


As I noted in a recent post on naked mole rats, there are at least two good reasons to study the comparative biology of aging, which is to say how and why aging differs between species. Why are some species long lived, some short lived, and some very few exhibit negligible senescence, a near absence of age-related changes across their life spans? Why do whales live longer than humans, humans longer than other primates, primates longer than horses, and naked mole rats nine times as long as standard issue rats? Firstly, isolating small but important differences between similar species with different life spans may help to conclude debates over which of the possible causes of aging are more important. (Though to my eyes less time spent debating and more time spent trying to repair all known forms of cellular damage associated with aging is the better, faster way to figure out what is and isn't important). Secondly, some researchers see the potential to generate therapies or enhancements for humans from the biological differences present in other species. There are several lines of research here funded to varying degrees, including identification of the basis for exceptional regeneration in salamanders, or the roots of longevity and cancer resistance in naked mole rats, to pick two examples from the crowd.

It is hard to say whether or not the quest for ways to alter human biochemistry to produce effects seen in other species is going to lead to meaningful results in the near term. On the one hand, it is clear that there is a lot of shared biology between even comparatively distant species such as humans and lizards. On the other hand there is no reason to expect that even a fully understood mechanism would be easy or even possible to bring to humans as enhancement or therapy: the devil is in the details, and the answer will probably vary widely mechanism by mechanism. So it is too early to say what will come of all of this. That said, I think the odds of beneficial outcomes in the near term shrink the further away from our species you go. When investigating the biology of tiny possibly ageless organisms such as the highly regenerative hydra, I suspect that the end result will be knowledge and little more. Hydra are just too different, and their regenerative prowess is based on constant aggressive reconstruction that is simply impractical in a higher organism that must keep the fine structure of its central nervous system basically intact. Nonetheless some researchers are optimistic that hydra studies will teach us some things that we can use to produce regenerative treatments in humans:

In Swiss Lakes, Scientists Search For The Source Of Immortality

"Since the mid-20th century, scientists have been interested in the longevity of this animal," Galliot explains. "When it's maintained in satisfactory conditions, hydrae reproduce asexually. They bud. We could observe them for years, and we wouldn't see any decline. They stay in shape." One day, Belgian researcher Paul Brien decided to plunge one of his group of hydrae into 10° C. "In that species, cold is a natural stimulus that tells them 'Oh, life is going to become harder,' because they don't survive very low temperatures." The result was incredible. Although they lived until then without partners, hydrae suddenly started looking for other hydrae to mate. They developed oocytes or testicles. "The animal started a sexual cycle. It reproduced. Then parents died and only their offspring survived in a small gangue that allowed them to survive the winter at the bottom of the water."

In 2000, a Japanese team renewed the experiment and confirmed the result. Then Brigitte Galliot came along, but something wasn't quite right. "The first year, the poor student who was checking on the hydrae was going nowhere. We were working with the same species, the very common Hydra oligactis, but the animals remained super happy. We maintained them for over a year at 10°. They were fine, they were still budding. So we thought ... drat!" The solution to this mystery was simple and ideal for the scientists. "There are, in the same species, different strains. One can resist, the other can't, and it ages. So by comparing the molecular and cellular processes of these two strains, we can understand what induces aging and what enables hydrae to resist it."

In practical terms, there could be two ways to take advantage of these findings to stop our own aging. "One of the approaches consists in telling ourselves that with evolution, these species developed all sorts of small molecules, some peptides and lipids that could be used as a source for new pharmacological agents," she says. The other approach, on which Galliot and her team are currently focusing, centers on autophagy, "a process through which cells digest their own content." A temporary survival strategy when faced with a lack of food but also a self-cleaning method to evacuate toxic waste, autophagy is controlled by very similar molecular tracks in animals that could not be more different, hydrae and mice.

Therefore, if this cellular process survived through millennia of evolution, it might still be triggered. The stakes are immense. "It's about understanding how to promote an efficient autophagy, which would enable our cells to digest the increasing number of aggregates we produce as we age, and which are at the root of Alzheimer's disease, as well as other neurological pathologies," Galliot explains. To achieve this, the comparison between "immortal" hydrae and those that age is illuminating. "The two strains seem to have different efficiencies in the way they get rid of these toxic aggregates." Galliot, however, remains cautious. "I'm not saying that we'll have a ready-to-use molecule in five years. What we're doing is very basic, but the implications can be very relevant. We do have, at the moment, a molecular candidate that is most interesting."

If you are going to try to slow down aging, which isn't the best approach to the problem at all, then it has long seemed to me that artificially upregulating the cellular housekeeping mechanisms of autophagy is a more promising approach than trying to more blindly mimic other aspects of the calorie restriction response that enhances health and longevity. Upregulated autophagy is present in many slow-aging animal models, and there are very good reasons to believe it is a cause rather than an effect of this outcome. Despite a fair number of researchers including this sort of work in their portfolio not much has come of it in the past decade, however. I don't see much going on today to convince me that we are closer to a generation of practical, effective autophagy-inducing treatments than we were at the turn of the century. Want more autophagy? Either practicing calorie restriction or regular moderate exercise will get you further in terms of upregulated autophagy than what was has emerged from the labs to date - and neither of those options will do much for your longevity in the grand scheme of things. Thus it isn't surprising to see that these hydra researchers are still at a fairly early stage in their studies:

Hydra, a powerful model for aging studies

H. oligactis is a model that has numerous features that complement the drawbacks of existing invertebrate model systems used for aging research, namely hundreds of human orthologs that were lost in nematode and fruit fly ancestors. To identify the putative aging genes present in Hydra but missing in C. elegans and D. melanogaster, we analysed the hydra-human orthologs associated with aging. Among 259 human aging genes retrieved from The Human Ageing Genomic Resources, we found that 207 (80%) were conserved in Hydra. Interestingly, some of these genes are missing or poorly conserved in D. melanogaster and C. elegans, such as the p53 regulator MDM2 or the TGFβ inhibitor noggin. The aging-induced regulation of these genes is currently under investigation.

As an alternative approach to aging studies, several studies aimed at dissecting the mechanisms that underlie the lack of senescence in Hydra focused on FoxO, an evolutionarily conserved transcription factor. In bilaterian organisms, FoxO regulates the response to stress, the proliferation of stem cells, and modulates lifespan. In nematodes and fruit flies, the knockdown of FoxO significantly shortens lifespan. In Hydra, FoxO is expressed in stem cells, and appears to respond to stress. Reduction in FoxO levels in the H. vulgaris AEP strain negatively affected the proliferation of stem cells, the speed of the budding process, the growth of Hydra population, and the production of immune peptides. However, no mortality was observed in FoxO deficient polyps, suggesting that other factors contribute to negligible senescence in H. vulgaris.


The Methuselah Foundation is presently partnering with the SENS Research Foundation to put out a quarterly update on ongoing research for members of the 300. This focuses on work relevant to the end goal of bringing aging under medical control, preventing and curing age-related frailty and disease. Members of the 300 are largely long-standing donors who have pledged to give at least $1000 each year for the next 25 years to fund the work of the Methuselah Foundation. Many of the 300 were early backers and signed up when SENS research was coordinated by the Methuselah Foundation, prior to the SENS Research Foundation spinning off as an independent organization. Their donations still go towards SENS programs even today. Members of the 300 will see their names inscribed on a lasting monument to be raised in the US Virgin Islands, and perhaps more pertinently have access to perks such as glossy updates on SENS research and other insider news from ongoing Methuselah Foundation initiatives.

There are still a very small number of positions left in the 300 - give it some thought. Given just how important funding and public support are for longevity science at this juncture, and the scale of what will be possible with rejuvenation treatments in the future, I'd argue that the 300 is probably the most influential organization that I belong to. The growth in membership was the spur to Methuselah Foundation success a decade ago, and thus the existence of the SENS Research Foundation, as well as a web of other influences on the aging and longevity research community over recent years. This in turn paves the road to a welcome future in which aging no longer causes suffering and death, bringing that era closer than would otherwise be the case. We all make a difference, and every last action counts.

Rejuvenation Biotechnology Update

The Methuselah Foundation is thrilled to partner with SENS Research Foundation in order to bring out the most recent advancements in tissue engineering, regeneration, and rejuvenation research for members of The 300. Because it doesn't take a scientist to understand the vital importance of investing in healthy life extension, these news-letters attempt to frame three significant studies from the past 3-6 months as accessibly and approachably as possible, describing how each one fits into the broader landscape of longevity research.

Regeneration of the aged thymus by a single transcription factor

In this study, the researchers used a genetic switch to induce FOXN1 expression in the thymic epithelial cells of mice, and compared them with mice that did not have FOXN1 induced. They observed that with FOXN1 induction, the thymus was regenerated from progenitor thymic epithelial cells that were still present in the aged thymus. They found that when FOXN1 was induced, the size of the thymus was larger, the expression of genes associated with a young, active thymus was increased, and the production of native T cells was boosted.

Thymic involution is one of the main contributors to declining immune system function with age. In the SENS paradigm, it could be categorized in the class of damage known as "cell loss and tissue atrophy." SENS Research Foundation is currently collaborating with the Wake Forest Institute of Regenerative Medicine on thymic regeneration research. The fact that induced expression of a single transcription factor could have such profound effects on thymic function and T-cell output in aged mice makes this study very interesting. Wouldn't it be nice if we could find a single transcription factor for each organ that, when upregulated, would restore the organ to a "youthful" state?

However, there are some caveats to consider, as one always should with scientific research. One is that, although the researchers did measure T-cell output from the regenerated thymuses of aged mice, they did not test their overall immune function. The quantity of T-cells produced by the regenerated thymuses was increased, but did these T-cells function similarly to young, normal T-cells? It is also prudent to be cautious about the idea of "robust thymus regeneration." In some autoimmune diseases, such as myasthenia gravis, thymic hypertrophy is observed. This kind of autoimmunity might also happen with an approach similar to FOXN1, because the thymus itself, being old, may have other dysfunction besides its reduction in size. Contrast this approach with genuine tissue engineering, where one would receive a new, youthful thymus. More research about thymic regeneration will be needed to determine whether FOXN1 overexpression will contribute to immune hyperreactivity and autoimmunity.

Physiological IgM class catalytic antibodies selective for transthyretin amyloid

TTR amyloidosis is a canonical example of "extracellular junk" - one of the fundamental types of aging related damage that SENS Research Foundation (SRF) attempts to treat. This work was partially funded by SRF, with the goal of finding a reliable way to break down misfolded TTR.

In Alzheimer's disease research, similar strategies of "vaccination" or treatment with antibodies against amyloid plaques have been tried. These treatments yielded some promising results but also some dangerous side effects in a few patients (inflammation of the protective membrane covering the brain). However, there are a few important distinctions between the catabody strategy and the immunization strategy. Perhaps the most notable difference is that catabodies actually break down the target protein (in this case, amyloid aggregates of TTR) themselves, without the requirement for other immune or blood components. Conversely, in previous studies on Alzheimer's disease, the antibodies did not break down ß-amyloid themselves but merely encouraged its clearance through the recruitment of other immune proteins and cells, which also initiates tissue-damaging inflammatory processes. Catabodies may prove to be less inflammatory, since they do not require other immune components to work. Additionally, the dose required for therapeutic effects may be smaller, and potentially less costly to produce.


Autoimmunity as a term covers a broad range of ways in which the immune system can run awry to attack healthy tissues. It bears some semblance to cancer in that an autoimmune disorder can occur at any age, there are many, many different types, and the details of the biochemistry involved are enormously complex and comparatively poorly understood. There is no good consensus on why some of the most common autoimmune diseases such as rheumatoid arthritis occur, for example, and the most successful of presently available treatments focus on suppressing the activities of the malfunctioning immune system in as targeted a way as possible rather than addressing the root causes of that malfunction - as the root causes are not yet well enough categorized to identify a point of action. A number of named autoimmune disorders are diagnoses of exclusion: you have the condition because you show some of a grab bag of unpleasant symptoms yet all of the tests for other named autoimmune conditions come back negative. There tend to be no reliable treatments in those cases.

Some autoimmune diseases are not age-related at all, but others are, beyond the assurance of "live long enough and something will go wrong," that is. Certainly the immune system as a whole deteriorates and malfunctions in other characteristic ways with advancing age, becoming increasingly ineffective yet constantly active to generating increased and harmful levels of chronic inflammation. Some researchers have made inroads in a fairly drastic approach to treating autoimmunity: wipe out the entire immune system with chemotherapy and repopulate it with immune cells derived from the patient's own stem cells. This has proven effective in a number of trials for more serious, life-threatening autoimmune conditions, and was even tried for rheumatoid arthritis some years ago before the advent of TNF inhibitors and other immune suppression treatments. The medical community embraced the less drastic approach of partially effective medical control over the more drastic approach of a sometimes cure, however. I suspect the chemotherapy would have to be replaced with a kinder, gentler, and less risky process of stripping the immune system for that approach to gather more funding and attention, or even be considered as a way to reset an age-damaged immune system.

Here is recent news from researchers working on an interesting alternative approach to treating autoimmunity. This has been under investigation for some time, and involves a process of steadily desensitizing key immune cells, training them not to react to certain proteins known to be involved in the autoimmune response. While full details of causation remain to be determined for many autoimmune disorders, researchers do have lists of protein targets to work with in this way in some cases. Note that the paper is open access if you want to delve further:

Scientists discover how to 'switch off' autoimmune diseases

Rather than the body's immune system destroying its own tissue by mistake, researchers have discovered how cells convert from being aggressive to actually protecting against disease. It's hoped this latest insight will lead to the widespread use of antigen-specific immunotherapy as a treatment for many autoimmune disorders, including multiple sclerosis (MS), type 1 diabetes, Graves' disease and systemic lupus erythematosus (SLE).

Scientists were able to selectively target the cells that cause autoimmune disease by dampening down their aggression against the body's own tissues while converting them into cells capable of protecting against disease. This type of conversion has been previously applied to allergies, known as 'allergic desensitisation', but its application to autoimmune diseases has only been appreciated recently. The group has now revealed how the administration of fragments of the proteins that are normally the target for attack leads to correction of the autoimmune response. Most importantly, their work reveals that effective treatment is achieved by gradually increasing the dose of antigenic fragment injected.

Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy

While progress has been made in developing disease-modifying therapies for the treatment of autoimmunity, it is increasingly clear that successful therapy will need to reinstate long-lasting immunological tolerance to the targeted self-antigens, thereby preventing pathogenic ​CD4+ T-cell responses. This must be achieved without perturbation of normal immune function, leaving anti-microbial and tumour immunosurveillance responses intact. Antigen-specific immunotherapy aims to fulfil these requirements: administration of disease-associated ​CD4+ T-cell epitopes in a tolerogenic form has been shown to restore immune homeostasis and prevent immunopathology in experimental models, as well as in clinical trials of both autoimmune diseases and allergies.

We have developed a dose escalation strategy for efficient self-antigen-specific tolerance induction and characterized sequential modulation of ​CD4+ T-cell phenotype at each consecutive stage of escalating dose immunotherapy (EDI). We show that self-antigen-specific tolerance can be effectively induced via the subcutaneous (s.c.) route. We demonstrate that antigen dose plays a critical role in determining the efficacy of immunotherapy, and that a dose escalation protocol is imperative to allow safe s.c. administration of the high antigenic doses required for efficient tolerance induction. We reveal that EDI minimizes ​CD4+ T-cell activation and proliferation during the early stages of immunotherapy, preventing excessive systemic cytokine release.


A few weeks from now, on October 1st, advocates for longevity research around the world will hold local events and show their support for the cause. We'd all like to see faster progress towards the control of degenerative aging and elimination of age-related frailty, disease, and aging. Coordinated events are one way to gain greater attention for the staggering cost of degenerative aging and the potential for near future medicine to treat and ultimately reverse the causes of aging. The yearly October 1st events are grassroots efforts encouraged and coordinated by groups such as the International Longevity Alliance and Longecity. A strong grassroots is an essential part of growing the community, generating an environment in which more new ventures launch, more advocates undertake new work, and more seed funding can be raised for early stage research. Big donors only arrive much later in the process, and even then only because a strong grassroots advocacy community has spent years successfully generating growth and public support.

The first step to getting anything done in this world is to make a contribution yourself, and then persuade a few friends to join you in that effort. Enormous, world-changing movements grow from such small roots and successes:

Promoting Longevity Research on October 1 - The International Day of Older Persons

Dear friends,

There are now efforts by longevity activists around the world to organize events (meetings, lectures and publications) dedicated to promotion of longevity research on or around October 1 - the International Day of Older Persons. This symbolic day can be a great opportunity to raise the topic of longevity research in the mainstream (including the media, officials and wide public).

Just about 1 month is left until October 1 - a good time to prepare small events, create publications and distribute materials. Last year, events for that day - ranging from small meetings of friends to seminars and rather large conferences, alongside publications, distributions of outreach materials (petitions and flyers) and media appearances - were held in over 30 countries. Longecity will support these efforts. It will offer small reimbursements for the best events organized by longevity activists around the world toward that day.

The criteria for choosing the event to be supported include (but not restricted to):

1) Maximum outreach,
2) Building up the local pro-longevity community,
3) Educational value,
4) A special preference will be given to events organized in countries where little or no longevity activism existed so far.

If you would like to organize an event, please contact us and send us a description. You are welcome to give additional support to these and further local events by longevity activists around the world by donations. This initiative is a part of the general effort to promote Regional Longevity Outreach and Activism around the world, by forming and developing local activist groups.

Coincidentally, October 1st is also the launch of the Fight Aging! 2014 matching fundraiser in support of SENS Research Foundation programs. The Foundation funds ongoing scientific research focused on repairing the cellular and molecular damage that causes aging. All of that funding is provided by charitable donations from people like you and I who feel strongly that this work should move forward rapidly. To help meet that goal have assembled a matching fund: every $1 donated will draw down $2 from the fund. Do you want to triple the effect of your charitable donations this year? Then look no further!

If you are considering organizing an event for October 1st, take a look at the full size posters assembled for the fundraiser:

  • Fight Aging! 2014 Fundraiser Poster #1
  • Fight Aging! 2014 Fundraiser Poster #2

Print them out, and show them off to your circle. Your help in reaching this fundraising goal in support of SENS research would be greatly appreciated: it makes a real difference to the pace of progress.


Monday, September 1, 2014

Aubrey de Grey is cofounder of the SENS Research Foundation, one of the few groups presently coordinating and funding serious scientific work on ways to repair the root causes of aging:

Marty Nemko: You claim that the public is indifferent to, even resistant to, efforts to extend lifespan. Isn't there strong evidence to the contrary, for example, people's commitment to exercise and the massive dietary supplement industry?

Aubrey de Grey: The public is terminally conflicted about life extension. Yes, they desperately try to stave off the ill-health of old age by already available means but are scared by the idea that we might some day have anti-aging medicine that actually delivers. This irrationality arises from fear: fear of the unknown and of getting one's hopes up prematurely. So they put the issue out of their mind.

MN: What about people who oppose extending longevity because they believe overpopulation is bad for the environment?

AD: That fear is based on a misconception: that the defeat of aging would occur without other progress. We are already addressing issues such as overpopulation by developing renewable energy, nuclear fusion etc. Birth rates are falling and maternal age at birth is rising as women become more educated and emancipated worldwide.

MN: You and those at your foundation and allied scientists believe there's a 50 percent chance that your proposed strategies for repairing age-related cell damage will come to fruition within 20 to 25 years. What's your evidence for that?

AD: It's the same kind of evidence that any pioneering technologist has: We have a concrete idea of what real anti-aging medication would consist of plus detailed knowledge of what technology already exists that constitutes the starting-points for developing that medication. So we have a reasonable sense of how hard it is to get from here to there and thus how long it will probably take.

Monday, September 1, 2014

There is a range of evidence to suggest infection by various fungi, bacteria, and viruses might contribute to the development of Alzheimer's disease (AD), all of this being somewhat unrelated to evidence suggesting that Alzheimer's is a lifestyle disease created by many of the same root causes as type 2 diabetes, such as obesity and lack of exercise. It may yet turn out to be the case that Alzheimer's is better considered as a collection of discrete conditions that happen to have the same end point. In this open access paper researchers look over what is known of the relationship between the ubiquitous persistent herpes simplex virus 1 (HSV-1) and Alzheimer's:

Among the multiple factors concurring to Alzheimer's disease (AD) pathogenesis, greater attention should be devoted to the role played by infectious agents. Growing epidemiological and experimental evidence suggests that recurrent herpes simplex virus type-1 (HSV-1) infection is a risk factor for AD although the underlying molecular and functional mechanisms have not been fully elucidated yet.

Herpes simplex type 1 virus primarily infects epithelial cells of oral and nasal mucosa. The newly produced viral particles may enter sensory neurons and, by axonal transport, reach the trigeminal ganglion where usually establishes a latent infection. The virus undergoes periodic reactivation cycles in which the newly formed viral particles are transported back to the site of primary infection through the sensory neurons, causing the well-known cold sores and blisters. However, the bipolar trigeminal ganglion neurons also project to the trigeminal nuclei located in the brainstem. From here, neurons project to the thalamus to finally reach the sensory cortex. This is the path through which the reactivated virus may reach the central nervous system (CNS), where it may cause acute neurological disorders like encephalitis or a mild, clinically asymptomatic, infection, or establish life-long latent infection. The weakening of immune system occurring during aging may favor this process. In addition to the neuronal route, HSV-1 may enter the CNS through the blood stream. Experimental evidence suggest that accumulation of intracellular damage caused by repeated cycles of viral reactivation may concur to neurodegeneration.

Some reports suggest that during infection herpes virus interacts with several human proteins that it uses to enter the cell and to move from plasma membrane to the nucleus and back. HSV-1 also uses the host's transcriptional machinery to replicate and binds to proteins that control immune surveillance or apoptosis. Noteworthy, in the attempt to eliminate the virus, host may even cause cell damage via immune and inflammatory responses targeting the virus-containing cells. If this happens in the CNS, HSV-1-induced inflammatory response may result in cell death and neurodegeneration.

Epidemiological, immunological and molecular evidence link HSV-1 infections to AD pathogenesis. HSV-1 is a ubiquitous virus that affects more than 80% of people over 65 worldwide. The first evidence suggesting the involvement of HSV-1 in AD dates back to 1982 and is based on the observation that people surviving HSV-1 related encephalitis showed clinical signs reminiscent of AD (i.e., memory loss and cognitive impairment), and that brain regions primarily affected were the same regions compromised in AD. During the last 30 years several research groups have conducted many studies providing solid support to the involvement of HSV-1 infection in AD pathogenesis. Here we will briefly summarize the main results of these researches.

Tuesday, September 2, 2014

Proteostasis is a shorthand term used to mean that the balance of proteins in cells remains steady and correct over time: proteins are produced and destroyed at more or less the same pace, relative levels of different proteins in different places in cells remain the same, levels of damaged proteins are low and consistent, and so forth. There are always ongoing variations in the amounts of some proteins in some places, as this is how the machinery of metabolism works, but overall you'd expect to see much the same thing tomorrow as you do today. Aging disrupts proteostasis, however. It changes the picture of what is going on inside cells through both an increased level of damaged proteins and altered rates of production of many proteins: cellular machinery reacts to local damage directly and remote damage through signaling networks and altered levels of circulating proteins outside cells.

By way of following on from yesterday's post on proteostasis in naked mole rats, a species that shows only comparatively small changes in the machinery of metabolism over much of the course of its life span, here is a paper on the role of the endoplasmic reticulum in proteostasis. Much of it is in the context of genetic conditions unrelated to aging, and their effects on proteostasis, but it is still relevant and interesting material:

The endoplasmic reticulum (ER) is an intracellular compartment dedicated to the synthesis and maturation of secretory and membrane proteins, totalling about 30% of the total eukaryotic cells proteome. The capacity to produce correctly folded polypeptides and to transport them to their correct intra- or extracellular destinations relies on proteostasis networks that regulate and balance the activity of protein folding, quality control, transport and degradation machineries. Nutrient and environmental changes, pathogen infection, aging, and, more relevant for the topics discussed in this review, mutations that impair attainment of the correct 3D structure of nascent polypeptide chains may compromise the activity of the proteostasis networks with devastating consequences on cells, organs and organisms' homeostasis.

Production and maintenance of a functional proteome is crucial for cells, tissues and organisms viability. Highly efficient folding, quality control and transport machineries located in specific intracellular compartments such as the ER convert the genetic information stored into the cell nuclei into functional proteins and protein complexes that fulfil the wide array of functions required for life. Paradoxically, mutations that do not affect the function of a given polypeptide may result in debilitating and life threatening diseases if they introduce small structural defects. In fact, the quality control devices that prevent exit of aberrant polypeptides from the biosynthetic compartment and insure their clearance from cells are alerted by non native features such as exposure at the polypeptide surface of hydrophobic patches, unpaired cysteine residues or otherwise unstructured determinants, independent of the capacity of the mutant polypeptide to fulfil its biological activity.

This "quality control paradox" highlights the importance of basic research in cell biology aiming at understanding the molecular basis of retention- and degradation-based mechanisms operating in our cells. Characterisation of these processes at the molecular level is required to develop therapeutic interventions that promote selective export of functional mutant proteins inappropriately segregated for architectural biases or to sustain "unfolded protein responses" that must intervene when misfolded polypeptides start to accumulate in or outside cells. This becomes even more important for aging-related diseases such as many neurodegenerative disorders, which result from gradual impairment of the proteostasis network, as the increased life expectancy is a fact in our society, and the number of patients will ineluctably raise.

Tuesday, September 2, 2014

Senescent cells rise in number with aging, in an evolved adaptation of developmental machinery that at least initially reduces cancer risk by removing potentially damaged cells from the cycle of division and replication. Many senescent cells are destroyed by the immune system, at least until the immune system begins its own age-related decline in earnest. More than enough senescent cells remain to cause issues, however: they export proteins that degrade surrounding tissues and promote chronic inflammation in a process known as the senescence-associated secretory phenotype (SASP). When many senescent cells are present in tissue SASP becomes a serious issue, causing enough harm and inflammation to promote the development of cancer and many other serious age-related conditions. This is more readily apparent and measured where external factors such as smoking are at work to provide the sort of toxicity that strongly promotes cellular senescence:

Chronic obstructive pulmonary disease (COPD) is a major disease of the lungs. It primarily occurs after a prolonged period of cigarette smoking. Chronic inflammation of airways and the alveolar space as well as lung tissue destruction are the hallmarks of COPD. Recently it has been shown that cellular senescence might play a role in the pathogenesis of COPD.

Cellular senescence comprises signal transduction program, leading to irreversible cell cycle arrest. The growth arrest in senescence can be triggered by many different mechanisms, including DNA damage and its recognition by cellular sensors, leading to the activation of cell cycle checkpoint responses and activation of DNA repair machinery.

Senescence can be induced by several genotoxic factors apart from telomere attrition. When senescence induction is based on DNA damage, senescent cells display a unique phenotype, which has been termed "senescence-associated secretory phenotype" (SASP). SASP may be an important driver of chronic inflammation and therefore may be part of a vicious cycle of inflammation, DNA damage, and senescence. This research perspective aims to showcase cellular senescence with relevance to COPD and the striking similarities between the mediators and secretory phenotype in COPD and SASP.

Wednesday, September 3, 2014

The expected result emerges from the study results noted below, joining the mountain of evidence linking exercise and long term health. In human studies it is challenging to prove causation, but the evidence for regular moderate exercise to cause enhanced healthy longevity in animal studies is extensive, although unlike the practice of calorie restriction it apparently doesn't extend maximum life spans.

Why care about exercise when we are a few steps away from radical advances in medical science? Because we are still a few steps away. In terms of interaction with medicine your life to date is likely little different from that of your parents, and you will continue to age and decline like them until new medical technologies of rejuvenation arrive. That could be decades from now, even in this present age of revolutionary progress in biotechnology, so why shorten your odds of living long enough to benefit?

Researchers say more than an hour of moderate or half an hour of vigorous exercise per day may lower your risk of heart failure by 46 percent. Heart failure is a common, disabling disease that accounts for about 2 percent of total healthcare costs in industrialized countries. Risk of death within five years of diagnosis is 30 percent to 50 percent. Swedish researchers studied 39,805 people 20-90 years old who didn't have heart failure when the study began in 1997. Researchers assessed their total and leisure time activity at the beginning of the study and followed them to see how this was related to their subsequent risk of developing heart failure. They found that the more active a person, the lower their risk for heart failure.

The group with the highest leisure time activity (more than one hour of moderate or half an hour of vigorous physical activity a day) had a 46 percent lower risk of developing heart failure. Physical activity was equally beneficial for men and women. Those who developed heart failure were older, male, had lower levels of education, a higher body mass index and waist-hip ratio, and a history of heart attack, diabetes, high blood pressure and high cholesterol. "You do not need to run a marathon to gain the benefits of physical activity - even quite low levels of activity can give you positive effects. Physical activity lowers many heart disease risk factors, which in turn lowers the risk of developing heart failure as well as other heart diseases."

Wednesday, September 3, 2014

Most very early stage medical research is funded by philanthropy, even in labs that largely depend on grants from established institutional sources of funding. Obtaining public and other private funding is usually impossible until a researcher can provide a proof of concept, which is only the case after most of the high risk early stage work is accomplished. In larger labs this results in a juggling of funds from government and industry, trying to squeeze out enough time and money from existing projects to actually work on new things, and patching over the gap with philanthropic donations from supporters. Any group that is entirely focused on early stage work must rely almost entirely upon philanthropy, and thus have patrons with deep pockets. This is the case for the establishment of the Glenn Consortium laboratories, for example, and for the ongoing work of the SENS Research Foundation.

Philanthropist Jason Hope is a patron for SENS rejuvenation research aimed at repairing the cellular and molecular damage that is the root cause of aging. He funds ongoing work organized by the SENS Research Foundation and does more than most patrons to help publicize and explain the science involved:

When it comes to age-related illness, the direction of modern medicine seems more reactive than proactive. In other words, what type of research is being done to prevent conditions like Alzheimer's disease and diabetes from happening in the first place? Enter people like Jason Hope, an Arizona-based Internet entrepreneur who's using his money and influence to advance anti-aging initiatives. Much of Hope's philanthropy efforts are concentrated on the SENS Research Foundation, a non-profit formed in 2009 to tackle age-related disease head on. Since its inception, SENS has been a driving force in what's known as rejuvenation biotechnology. This line of research focuses specifically on addressing age-related disease.

Hope's involvement with SENS began in 2010, when he donated half a million dollars to the organization. Because of these funds, the group was able to establish its Cambridge SENS laboratory and implement new research initiatives. Since then, he's gone on to contribute over $1 million of his own money to the cause. "I'm invested in the SENS Research Foundation for a number of reasons. In simplest terms, I believe in their work and understand how essential it is in terms of advancing human medicine. It has the power to completely redefine the healthcare, pharmaceutical and biotech industries."

In addition to lending his financial support to SENS, Hope also plays an active role in the group's outreach efforts. According to Hope, rejuvenation biotechnologies represent the future of human health. This approach to anti-aging is geared less toward treating diseases, and more toward understanding prevention as a way to create a longer, better quality of life. Over time, normal metabolism gradually damages the body. This, in turn, leads to the ravaging diseases associated with old age. To combat this, the SENS approach specifically works to repair this kind of damage before the body develops deadly pathologies.

Thursday, September 4, 2014

This news from Calico is not unexpected; deals of this nature were a given at some point in the process of building out the company. It does reinforce current views on the direction that will be taken in their research and development, however. It is my hope that Calico turns out to be something other than a hybrid of the Ellison Medical Foundation and a continuation of the past ten years wasted on sirtuins, rapamycin, and other exceedingly expensive investigations aimed at slowing aging, efforts that can do no more than produce marginal benefits even if completely successful, and which despite years and billions spent have not even advanced to the point at which a realistic timeframe or cost for that success can be proposed. Metabolism is too complex and too little is known of its detailed relationship with aging to have a firm plan of action at this point.

We shall see, but I suspect that the only way to make Calico effective by diverting it from the current mainstream is for groups like the SENS researchers, people working on much more promising means of treating aging by repairing the damage that causes degeneration, where there is enough existing knowledge to have a plan and a projected cost and timeline for success, to demonstrate that they can produce better results at far less cost than the mainstream of longevity science. That in turn requires funding: the chicken and the egg issue for making significant progress towards the treatment of aging these days.

Calico, a Google-backed biotech company run by the former Genentech chief executive Arthur D. Levinson, said it would build a new Bay Area-based facility that will research diseases that afflict the elderly, such as neurodegeneration and cancer. The facility, which doesn't have a precise location just yet, is being built in partnership with AbbVie, a Chicago-area pharmaceutical company that has a research facility in Redwood City, Calif., just a few miles from Google's Mountain View headquarters. The companies will put up equal money - $500 million at first, and up to $1.5 billion if things go well - and split any profits down the middle.

The partnership is a standard biotech deal in which, more or less, one company deals with the early phases of drug development while the other takes responsibility for testing and making whatever gets discovered. You could say that Calico will look for drugs in test tubes and, if they're successful, AbbVie will test them out and make them in factories. "Calico will set up a world-class research and development facility in the San Francisco Bay Area, where we will explore the basic biology of aging and develop new medicines for patients with aging-related diseases," said Mr. Levinson, Calico's chief executive. "AbbVie will use its deep pharmaceutical expertise to provide scientific and clinical development support and its commercial expertise to ensure these therapies are widely available."

The AbbVie partnership seemingly makes it clear that Calico will be a drug discovery and development company, which is what many observers expected based on Mr. Levinson's background in drug development.

Thursday, September 4, 2014

The end goal for tissue engineering is not the generation of organs and tissues outside the body for transplantation, but rather to direct the rebuilding of complex tissue structures in situ inside the body:

What if repairing large segments of damaged muscle tissue was as simple as mobilizing the body's stem cells to the site of the injury? [Researchers have] demonstrated the ability to recruit stem cells that can form muscle tissue to a small piece of biomaterial, or scaffold that had been implanted in the animals' leg muscle. The secret to success was using proteins involved in cell communication and muscle formation to mobilize the cells. "This is a proof-of-concept study that we hope can one day be applied to human patients."

The current treatment for restoring function when large segments of muscle are injured or removed during tumor surgery is to surgically move a segment of muscle from one part of the body to another. Of course, this reduces function at the donor site. Several scientific teams are currently working to engineer replacement muscle in the lab by taking small biopsies of muscle tissue, expanding the cells in the lab, and placing them on scaffolds for later implantation. This approach requires a biopsy and the challenge of standardizing the cells. "Our aim was to bypass the challenges of both of these techniques and to demonstrate the mobilization of muscle cells to a target-specific site for muscle regeneration."

Most tissues in the body contain tissue-specific stem cells that are believed to be the "regenerative machinery" responsible for tissue maintenance. It was these cells, known as satellite or progenitor cells, that the scientists wanted to mobilize. The scientists tested the effects of several proteins known to be involved in muscle formation by designing the scaffolds to release these proteins. The protein with the greatest effect on cell recruitment was insulin-like growth factor 1 (IGF-1). After several weeks of implantation, lab testing showed that the scaffolds with IGF-1 had up to four times the number of cells than the plain scaffolds and also had increased formation of muscle fibers. Next, the scientists will evaluate whether the regenerated muscle is able to restore function and will test clinical feasibility in a large animal model.

Friday, September 5, 2014

Mitochondria are the power plants of the cell, generating chemical energy stores used in many cellular processes. A herd of them exists in every cell, dividing like bacteria to keep up their numbers. Mitochondrial damage occurs as a side-effect of the normal operation of metabolism and is an important contribution to degenerative aging, but fortunately there are a wide range of fairly well understood methods by which this issue could be prevented or treated. All that is needed is more funding for research and development.

One possibility is the delivery of replacement mitochondria, and if doing this why not deliver better, more effective mitochondria? Some of the existing mitochondrial haplogroups are objectively better than others, but we could also in theory greatly improve upon what exists based on present knowledge. At the end of this road lies the replacement of mitochondria with optimal synthetic versions, resistant to damage, which influence surrounding cellular mechanisms in beneficial ways, and which minimize the mitochondrial contribution to aging. That isn't a near term prospect, but in the decades ahead it will become very plausible to start replacing more discrete cellular components with designed molecular machinery that is more efficient and less vulnerable, and thus helps to extend healthy life span:

We hypothesize herein that synthetic mitochondria, engineered or reprogrammed to be more energetically efficient and to have mildly elevated levels of reactive oxygen species (ROS) production, would be an effective form of therapeutics against systemic aging. The free radical and mitochondria theories of aging hold that mitochondria-generated ROS underlies chronic organelle, cell and tissues damages that contribute to systemic aging. More recent findings, however, collectively suggest that while acute and massive ROS generation during events such as tissue injury is indeed detrimental, subacute stresses and chronic elevation in ROS production may instead induce a state of mitochondrial hormesis (or "mitohormesis") that could extend lifespan.

Mitohormesis appears to be a convergent mechanism for several known anti-aging signaling pathways. Importantly, mitohormetic signaling could also occur in a non-cell autonomous manner, with its induction in neurons affecting gut cells, for example. Technologies are outlined that could lead towards testing of the hypothesis, which include genetic and epigenetic engineering of the mitochondria, as well as intercellular transfer of mitochondria from transplanted helper cells to target tissues.

Friday, September 5, 2014

Senescent cells are those that have removed themselves from the cell cycle in response to damage or a tissue signaling environment that reflects nearby damage. This is an adaptation that serves to reduce cancer risk, at least in the early stages of aging, but it also causes harm as senescent cells accumulate in larger numbers. These cells emit signal molecules that degrade surrounding tissue structures, harm tissue function, and increase the odds of nearby cells also becoming senescent. Thus the accumulation of senescent cells over the years is one of the contributing causes of degenerative aging.

The ideal and simplest approach to removing this issue is to adapt targeted cell killing technologies under development in the cancer research community to periodically clear out senescent cells in the body. Other more complicated paths may be an option, however, such as reprogramming cells to reverse senescence, or as in this case blocking some of the signal molecules released by senescent cells, making them much less harmful to surrounding tissues:

Many age-related diseases are associated with an impaired fibrinolytic system. Elevated plasminogen activator inhibitor-1 (PAI-1) levels are reported in age-associated clinical conditions including cardiovascular diseases, type 2 diabetes, obesity and inflammation. PAI-1 levels are also elevated in animal models of aging.

While the association of PAI-1 with physiological aging is well documented, it is only recently that its critical role in the regulation of aging and senescence has become evident. PAI-1 is synthesized and secreted in senescent cells and contributes directly to the development of senescence by acting downstream of p53 and upstream of insulin-like growth factor binding protein-3. Pharmacologic inhibition or genetic deficiency of PAI-1 was shown to be protective against senescence and the aging-like phenotypes in [mice]. Further investigation into PAI-1's role in senescence and aging will likely contribute to the prevention and treatment of aging-related pathologies.


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