Fight Aging! Newsletter, February 10th 2014

February 10th 2014

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

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  • Genetic Damage or Epigenetic Change as a More Important Cause of Cancer?
  • Chronic Inflammation is Important in the Progression of Aging
  • Aging and Those Little Protein Clumps Called Amyloids
  • SENS: Defeating Aging and the Avenues Ahead
  • Theorizing That Some Change in the Aging Brain is Optimization, Not Degeneration
  • Latest Headlines from Fight Aging!
    • Considering Cellular Senescence in Aging
    • The Road to a Cure for Aging Lies Straight Ahead
    • The Importance of the Immune System in Suppressing Cancer
    • Activism For Rejuvenation Research Should Follow the Model of High-Profile Activism for AIDS and Cancer Research
    • More Investigations of the Harm Done By Cytomegalovirus
    • Towards an Understanding of How Cellular Senescence Spreads
    • More Evidence for Antioxidant Supplements to Cause Harm
    • Arguing for More Work on Lengthening Telomeres
    • The JenAge Ageing Factor Database
    • Modeling the Effects of Predation on the Evolution of Aging


Cancer is an age-related disease. It can happen at any age, but the odds are very low until you start into later life. There are many possible reasons as to why this is the case: the progressive decline in effectiveness of the immune system, which detects and destroys cancerous and potentially cancerous cells; rising levels of stochastic damage to nuclear DNA; greater inflammation and disarray in metabolism resulting from other forms of cellular and molecular damage associated with aging.

How about epigenetic changes, however? The number, type, and position of molecules attached to nuclear DNA continually alter in response to environment, health, and age. Much of this is presumably a response to the above noted damage and dysfunction, a reaction to circumstances. These decorating molecules act to alter gene expression, the rate at which proteins are produced from each blueprint gene, and thus alter the behavior of cells. Epigenetic patterns are different in every cell and tissue and between individuals, but characteristic differences between old people and young people can be discerned given enough data and computing power.

NIH Study Offers Insight into Why Cancer Incidence Increases with Age

Scientists have known for years that age is a leading risk factor for the development of many types of cancer, but why aging increases cancer risk remains unclear. Researchers suspect that DNA methylation, or the binding of chemical tags, called methyl groups, onto DNA, may be involved. Methyl groups activate or silence genes, by affecting interactions between DNA and the cell's protein-making machinery.

[Researchers] identified DNA methylation sites across the human genome that changed with age. They demonstrated that a subset of those sites - the ones that become increasingly methylated with advancing age - are also disproportionately methylated in a variety of human cancers. "You can think of methylation as dust settling on an unused switch, which then prevents the cell from turning on certain genes. If a cell can no longer turn on critical developmental programs, it might be easier for it to become a cancer cell."

You might recall that in recent years researchers have started to make inroads in using DNA methylation patterns as a measure of chronological and biological age. If that works - and it appears to - it shouldn't be surprising to also find associations with cancer.


A biological mechanism might be important in aging if it is comparatively easy to produce good correlations between measures of the progression of that mechanism and mortality rates. The effects of minor contributions to aging can be swamped when looking at human data, since you can't carefully construct your study populations and follow them for their entire lives - it is hard to pick out small effects using statistical analysis of general study data. But if every study group consistently shows strong associations for the measure at hand, then that is a sign that there is something worth looking into there.

It is well known that chronic inflammation is a bad sign when it comes to long-term health. On the one hand higher levels of constant inflammation are produced by conditions that are harmful in and of themselves, such as the functional decline of the immune system and an excess of visceral fat tissue and the lifestyle choices needed to produce it, and so on. On the other hand chronic inflammation is also harmful in and of itself, a dysfunction in the normal operation of metabolism and destructive to tissues, a process that contributes to the progression of numerous age-related conditions.

Here is an example that demonstrates how straightforward it is now to find good correlations between measure of inflammation and human mortality, and that these correlations are very consistent across study populations:

Simple Biologically Informed Inflammatory Index of Two Serum Cytokines Predicts 10 Year All-Cause Mortality in Older Adults

In total, 15 nuclear factor-kappa B-mediated pathway markers of inflammation were first measured in baseline serum samples of 1,155 older participants in the InCHIANTI population. Of these, C-reactive protein, interleukin-1-receptor antagonist, interleukin-6, interleukin-18, and soluble tumor necrosis factor-α receptor-1 were independent predictors of 5-year mortality. These five inflammatory markers were measured in baseline serum samples of 5,600 Cardiovascular Health Study participants. A weighted summary score, the first principal component summary score, and an inflammation index score were developed from these five log-transformed inflammatory markers, and their prediction of 10-year all-cause mortality was evaluated in Cardiovascular Health Study and then validated in InCHIANTI.

The inflammation index score that included interleukin-6 and soluble tumor necrosis factor-α receptor-1 was the best predictor of 10-year all-cause mortality in Cardiovascular Health Study, after adjusting for age, sex, education, race, smoking, and body mass index compared with all other single and combined measures. The inflammation index score was also the best predictor of mortality in the InCHIANTI validation study. Stratification by sex and [cardiovascular disease] status further strengthened the association of inflammation index score with mortality.

[Thus] a simple additive index of serum interleukin-6 and soluble tumor necrosis factor-α receptor-1 best captures the effect of chronic inflammation on mortality in older adults among the 15 biomarkers measured.

A great deal of chronic inflammation is self-inflicted in this age of low-cost and widely available calories. Eat to excess and become fat, and you pile an additional burden on yourself that will wear you down into age-related disease far earlier than your peers, all other things being equal. Even small amounts of excess visceral fat tissue held for years have a large impact on health in later life. Calorie restriction and regular exercise seem to be the optimal way to go when it comes to making the most of an imperfect biology.

As to the rest of it, the chronic inflammation that you cannot avoid because it stems from low-level biological damage to your immune system and tissues that happens to everyone, no matter how good your health, the best you can do today is to support the research that will lead to rejuvenation treatments tomorrow. Reverse the damage, restore the immune system, and that will remove the causes of chronic inflammation. That can't be done today, but it will be possible in the near future. Just how near depends on fundraising and advocacy here and now: new medicine doesn't just emerge from nothing.


One of the fundamental ways in which old tissue is different from young tissue is the presence of deposits of misfolded proteins between cells. In their normal form these proteins should remain dissolved in tissue fluids, but with age ever more precipitate to form the strands and fibrils known as amyloid. There are a number of different types of amyloid, each corresponding to a particular protein that is prone to this outcome. For many of these types the research community cannot yet explain exactly why and how the amyloid contributes to the age-related conditions it is associated with, or indeed why and how this is an age-related phenomenon. Is it a failure in clearance mechanisms caused by other forms of damage, perhaps? For some forms of amyloid a great deal is known, however: take Alzheimer's disease, for example. If the average fellow in the street has heard of amyloid at all, it is probably in connection with Alzheimer's research and the present focus of treatment.

There is another arguably equally important condition and form of amyloid, one that appears to act as a limiting factor on human life span, and receives far less attention and funding than does Alzheimer's disease. The results of autopsies performed on supercentenarians, people who lived to be 110 years of age or older, suggest that those of us who survive or evade every other potential fatal age-related condition are eventually felled by the buildup of transthyretin amyloid, leading to a condition known as TTR amyloidosis, or senile systemic amyloidosis when referring to the age-related condition rather than the genetic disease that can cause similar early-life buildup of amyloid.

Since there is all too little work taking place on senile system amyloidosis, this is one of the areas in which the SENS Research Foundation has stepped into accelerate matters in the past couple of years. One of the key insights that led to the existence of the Foundation is that we don't in fact have to have a complete understanding of the mechanisms involved in any particular cause of aging to effectively treat it. What we do need is a comprehensive list of differences between old tissue and young tissue, a good identification of which of those differences are fundamental - primary causes versus secondary effects - and a plan to reverse those differences.

In the case of amyloids we have all of these items: it doesn't matter that researchers cannot yet explain how and why some forms of amyloid cause harm if the development community can build the means to remove these amyloids. We should just remove them, as they are not a feature of young tissue. Much of the work of the Alzheimer's research community, for example, will hopefully be broadly applicable to forms of amyloid other than that associated with the condition. Progress by Alzheimer's researchers towards immune therapies that can attack and break down amyloid is watched with interest in a number of other fields.

Here is a piece by Jason Hope, a philanthropist who has contributed meaningfully to some of the SENS Research Foundation programs:

Fight Aging  -  Extracellular Aggregates

Aggregation of one specific protein causes problems in many parts of body but inflicts special harm to the heart in particular. Transthyretin, or TTR, is a transporter protein that carries thyroid hormones to the various parts of the body that need it. By the time they reach the age of 70 years, 10 percent of people suffer significant accumulations of TTR amyloids. The condition becomes nearly universal as people reach the century mark. TTR amyloid may prevent a body from reaching its destiny as a "supercentenarian" who lives more than 110 years.

To date, there is no approved treatment for amyloids aside from organ transplant to replace organs damaged by amyloids. The SENS Research Foundation-funded TTR Extracellular Aggregates collaboration is working to develop antibodies that identify and safely remove TTR amyloid deposits from body tissues. The antibodies do this by binding to TTR. Physicians could someday use these antibodies to diagnose and treat both age-induced and genetic forms of TTR.

To create these antibodies, Dr. Brian O'Nuallain and his collaborators immunized three strains of mice with three different TTR-containing substances intended to provoke an immune response. Exposure to these substances triggered an immune response in the mice  -  each group of mice created unique antibodies that would target different types of aggregating TTR. This means the scientists created antibodies already armed to fight only clumping TTR, ignoring any TTR remaining in a form that can remain dissolved in body fluids. Seven of these antibodies show diagnostic and therapeutic potential. All seven bind strongly to clumped TTR and ignore soluble TTR well. O'Nuallain is collaborating with Dr. Sudhir Paul to learn if these antibodies can facilitate the breakdown of TTR amyloids.

Dr. Paul works on developing catalytic antibodies, known as catabodies for short, which break down TTR amyloids. Catabodies do not just bind to TTR amyloids and carry them away  -  catabodies destroy TTR amyloids. In earlier research, Dr. Paul identified naturally occurring catabodies that break down TTR amyloids found in the brains of patients with Alzheimer's disease. Today, with funding from SENS Research Foundation, he has identified catabodies that completely dissolve TTR amyloids in a test tube without damaging TTR proteins that are functioning correctly.

This is important work on the foundations of human rejuvenation, and I look forward to hearing of further advances towards clinical application. Given the present structure of medical regulation that will probably involve development of a treatment of the genetic version of TTR amyloidosis however - it remains the case that regulators at the FDA do not recognize aging as a condition to be treated, and there is thus no path to approval for treatments for aging. This roadblock echoes all the way back down the research and development pipeline, which goes some way towards explaining why there is still comparatively little funding for work on amyloidosis and other necessary portions of a rejuvenation toolkit.

That said, it is good to see progress in the laboratory towards targeted and focused methods of designing treatments: attack the problem molecule and only the problem molecule. We live in an age of biotechnology, and ongoing work should absolutely be far above and beyond the old school drug development programs in which compounds from the natural world are thrown at the problem until something is found that causes more good than harm. Sadly there is still all too much of that going on today.


Earlier this week I pointed out the first part of a three part series by Eric Schulke of the Movement for Indefinite Life Extension. Taken as a whole it's a point by point examination and defense of SENS, the Strategies for Engineered Negligible Senescence, as the best path forward towards extending human life. Moreover it is a defense of getting up and actually doing something about degenerative aging - and these days that has more need of defense than the viability of rejuvenation research after the SENS model.

We live in a bizarre mirror world in which the populace sleepwalk towards decrepitude and death, and in which the vast majority of the public have no interest in supporting efforts to extend healthy life spans. Instead they lavish their attention and dollars on fake "anti-aging" products, ways to create a pretense of youth, while talking heads tell us how terrible it would be if we actually lived longer. Yet at the same time the possibility of actually treating and reversing degenerative aging is right there in front of us, a realistic near-term goal for the research community. Further, we already live longer, on average, than our ancestors, and life expectancy for adults has slowly risen for more than a century - something taken for granted and then forgotten. It's a madhouse.

I like to see enthusiasm for longevity science of the sort exhibited in the articles quoted below: people have to speak out to illustrate the madness of the common culture and the importance of work on human rejuvenation therapies. It is helpful and encouraging that sentiments of this nature continue to emerge from the community. This is what is needed to move the needle, to continue the progress in research and advocacy that in the past decade or two has brought us from nothing to the point at which we can talk at all about SENS and tangible progress towards rejuvenation of the old.

Defeating aging, and the avenues ahead of us: Part 1

"[...] the most promising ways to postpone aging are by disrupting the pathways underlying it, just as we do for specific diseases." That line sums up an important element of strategies for engineering negligible senescence (SENS) in Aubrey de Grey's book Ending Aging, published in 2007. The book outlines the straightforward sense in disrupting the pathways that cause us to age: by engineering the damage of aging out of our biology after the body has experienced the damage, but before the damage accumulates to deadly levels.

Defeating aging, and the avenues ahead of us: Part 2

There seem to be only those seven forms of damage that age us to death by accumulating in and around our cells. These forms of damage have been discovered by science over the years, the last one being found in the 1980s. It's not "seven plus all the ones we can't get a grip on or figure out yet." It's not "seven just because these are Aubrey's or some group's favorite seven", and it's not "seven but we have absolutely no idea how we could even begin to think about tackling any of them." This isn't a widely disputed list of items. It has accumulated and been independently peer-reviewed through all of science over time.

As written in Ending Aging, "You could stop thinking of aging as a hopelessly complex theoretical problem to solve, and get on with attacking it head-on, as an engineering challenge that needed to be overcome." You can, and you must. At the very least, this engineering approach is one of the main avenues that needs full support of as many people from around the world as possible, and as soon as possible.

Defeating aging, and the avenues ahead of us: Part 3

Act like you've seen the growing graveyards in your area, and face the reality that you, too, will be dead soon if the world, which includes you, doesn't rise to the challenge and do something about it.

Almost everything you do can and should involve this cause. Going on vacation? Bring some books or literature about this to give away. Socializing? Talk to them about it a bit and hang out with the ones that are amicable to this cause when you can. Going on the Internet? Be sure to share or comment on a related topic or three when you can. Looking for a career to get into or ways to spend your free time? Get involved with this cause. I and the people I know do these things and more.

Pick up the proverbial shovel and help with SENS. Help spread awareness, bring more people into the related conferences, write books, work with the media, talk to politicians, etc. Go into research if you have the aptitude for it. You can pick any lead that you find to be viable. Research existing methods to combat the damage, create your own methods, or do an exhaustive study to try to make the case for forms of damage in addition to the seven generally accepted types. Get in where you fit in.

If you need help with it, then ask in just about any of the communities involved in this. Help us get these mountains moved. Through exhausting more and more avenues and pathways, the picture will continue getting clearer. Answers to achieving negligible senescence and extending our happy, healthy life spans, will materialize. There is no "well, it can't work", "they aren't sure if we should yet", "it's too speculative", etc. It's not. We are dying, we have options, we get moving.


The nature of neural networks is perhaps better understood by more people nowadays than used to the be the case. Forms of neural network are used for a range of computational purposes, where they have proved useful as a way to economically discover solutions to difficult problems in pattern recognition, optimization, and other fields. How a particular solution works isn't always clear, especially when using larger networks, but if it can be proven to work well then why worry?

We ourselves are neural networks: the complex adaptive phenomena that we choose to call the self arises from comparatively simple exchanges between many, many neurons. The machine is the connections and the state of its neurons, constantly altering itself in response to circumstances and its own operation.

The brain, like all tissues, suffers due to the accumulation of cellular and molecular damage that drives aging. But which of the characteristic differences between a young brain and an old brain are aging, and which are the expected operation of the neural network as it processes and reprocesses the data gathered throughout life? In some cases the classification is obvious: broken blood vessels and white matter hyperintensities are damage, as is the amyloid that accumulates in Alzheimer's disease. We would be better off without them, and they harm us by destroying physical structures needed for operation of the brain. Once researchers start looking at the structure of neural connections, or activity in response to stimulus, or gene expression maps in various portions of the brain things become a little less clear, however:

The Brain Ages Optimally to Model Its Environment: Evidence from Sensory Learning over the Adult Lifespan

The aging brain shows a progressive loss of neuropil, which is accompanied by subtle changes in neuronal plasticity, sensory learning and memory. Neurophysiologically, aging attenuates evoked responses - including the mismatch negativity (MMN). This is accompanied by a shift in cortical responsivity from sensory (posterior) regions to executive (anterior) regions, which has been interpreted as a compensatory response for cognitive decline.

Theoretical neurobiology offers a simpler explanation for all of these effects - from a Bayesian perspective, as the brain is progressively optimized to model its world, its complexity will decrease. A corollary of this complexity reduction is an attenuation of Bayesian updating or sensory learning.

Here we confirmed this hypothesis using magnetoencephalographic recordings of the mismatch negativity elicited in a large cohort of human subjects, in their third to ninth decade. Employing dynamic causal modeling to assay the synaptic mechanisms underlying these non-invasive recordings, we found a selective age-related attenuation of synaptic connectivity changes that underpin rapid sensory learning. In contrast, baseline synaptic connectivity strengths were consistently strong over the decades. Our findings suggest that the lifetime accrual of sensory experience optimizes functional brain architectures to enable efficient and generalizable predictions of the world.

My suspicion is that it would be faster to implement rejuvenation biotechnologies and then assess what happens to an aging brain that remains physiologically young than to fully pick apart and understand present contributions to changes over time in the brain.

This line of research is of interest because of a potential threat to extreme longevity, past the present limits of human life span, once we have build the necessary medical technologies. The threat is this: it is possible that the brain is like the immune system, in that it is poorly structured for long term use, and will fail for reasons inherent to that structure, even in the absence of damage. We have no reason to suspect that this is the case, but equally there is no good reason to rule this out - the scientific community simply doesn't understand enough about the detailed operation of the brain to say either way with confidence.

On the plus side, this is a comparatively remote potential threat, something that lies decades past all the other fatal forms of damage and age-related disease that we have to deal with. Old people with little physical damage to their brains are sharp and on the ball, to the degree allowed by their failing bodies and decades of increasing caution required in their interaction with the world. Further, by the time we are at the point of worrying about this, biotechnology will be far more advanced. So it is, I think, worth considering, but not worth panicking over.


Monday, February 3, 2014

A mini-review on the topic of cellular senescence, one of the contributing causes of degenerative aging:

Replicative cellular senescence was first described in cell culture as an irreversible growth arrest triggered by the accumulation of cell divisions in human fibroblasts. It has since been demonstrated in virtually all vertebrate species and cell types that have been examined. Telomere shortening due to replicative exhaustion was the first cause of senescence to be well understood. In the last decade, however, it has become evident that cellular senescence can be triggered by many intrinsic and extrinsic stimuli, including the activation of oncogenes, ionizing and ultraviolet irradiation, reactive oxygen species, pharmacological agents that modify DNA or chromatin, and even nutrient imbalances and ill-described cell culture stresses.

Recent data have implicated cellular senescence as an important in vivo tumor suppression mechanism. However, solid connections between cellular senescence and organismal aging have been slower to emerge. An important impediment has been the lack of reliable assays to distinguish senescent cells from the majority of healthy but quiescent cells found in normal tissues. While a few years ago it was questioned whether senescent cells existed in vivo in appreciable numbers, today it is increasingly evident that they accumulate with age as well as at sites of age-associated pathologies.

Implication of cellular senescence in stem cell aging has added renewed credence for its importance in species with considerable renewable tissues. Studies in mouse models lacking p16Ink4a-positive senescent cells, as a result of p16Ink4a gene inactivation or drug-induced cell clearance, have implied a causal link between senescence and age-related functional decline of tissues and organs. This together with the discovery that some of the major aging-related diseases are characterized by accumulation of senescent cells has raised the possibility that therapeutic removal of senescent cells may improve healthy lifespan.

Monday, February 3, 2014

I am far from the only person out there who sees the Strategies for Engineered Negligible Senescence (SENS) research programs as the best and most clear path to lengthening healthy human life spans - including our own, by reversing the course of aging should these new medical technologies be developed rapidly enough.

A great deal has changed over the past twenty years when it comes to the prospects for longevity-enhancing therapies. The topic wasn't even discussed openly in the mainstream research community back then, and to talk about extending life was a usually a quick ticket to losing your funding for the study of aging. Those days are gone, thankfully, due to a combination of activism and demonstrations of extended lifespans in a range of laboratory species.

Still, time is ticking, and it remains the case that there is no massive program underway to treat, prevent, and reverse human aging. SENS offers the possibility of rejuvenation biotechnologies arriving twenty years from the point at which it becomes that massive program, but as of today it is only funded with a few million dollars in philanthropic donations each year. That is more than zero, which is where we were ten years ago, but it is a long way from what is needed for best possible speed.

When I was in high school in the 1990s, as I recall, a segment of one of our classes focused on aging and lasted for a few weeks. Our teacher left us with the impression that aging was impossibly mysterious and probably always would be. He seemed to take a somber tone when talking about it. I wish I would have kept thinking about it then. I wish my science teacher, and science teachers around the world, had possessed more scientific and critical-thinking courage to instill more of a drive in us students to take the challenge on, daunting though they were convinced it was in those days.

[Over the past two decades] the reality of what humanity knows about aging and its surrounding issues has been changed through a multitude of scientific insights, from a variety of researchers and organizations around the world. The clearest of the ways forward, leading the charge, is the concept of eradicating the damage that is building up in our bodies and killing us, as outlined and taken on by SENS.

Regardless of which paths we take, one way or another we have to go through, around, over, under, or some other way to obviate the effects of this damage. And yes, we do have to do it. Life is far too mysterious and incredible to coddle the grave and yawn at the future. If there were semi-understandable reasons to excuse away potential paths and hypotheses to defeating aging in the 1990s and before, the first decade of the 21st century has been the herald of a new age in understanding of aging. It has been over a decade now since there was an excuse for teachers to discourage students from thinking about cures for aging. We can't accept procrastination as an answer.

Tuesday, February 4, 2014

One of the reasons that cancer is overwhelmingly a condition of the old is that the immune system is responsible for eliminating potentially cancerous cells, but declines in effectiveness with age due to a combination of damage and structural issues. The immune system supports a limited number of cells and continually devotes some of those cells to remembering threats - by late in a normal human life space it begins to experience resource issues, overburdened by memory cells and lacking enough naive cells to effectively tackle new threats.

Methods of even partially rejuvenating the immune system, such as implementing portions of the SENS program, or selectively destroying the burden of immune cells uselessly specialized to fight CMV so as to free up space for new and more useful immune cells to emerge, should reduce incidence of cancer in the old.

The research noted here illustrates this point, demonstrating just how important the immune system is to suppression of one particular type of cancer:

Immune cells undergo 'spontaneous' changes on a daily basis that could lead to cancers if not for the diligent surveillance of our immune system. This immune surveillance accounts for [the] 'surprising rarity' of B-cell lymphomas in the population, given how often these spontaneous changes occur.

The discovery provided an answer to why B-cell lymphomas occur in the population less frequently than expected. "Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function. It is then somewhat of a paradox that B cell lymphoma is not more common in the population. "Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle, and proves that immune surveillance is essential to preventing the development of this blood cancer."

The research team made the discovery while investigating how B cells change when lymphoma develops. "As part of the research, we 'disabled' the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years. It seems that our immune system is better equipped than we imagined to identify and eliminate cancerous B cells, a process that is driven by the immune T cells in our body."

Tuesday, February 4, 2014

A point is made here by Maria Konovalenko of the Science for Life Extension Foundation, who has been involved in the past couple of years of work on starting single issue longevity science political parties in Europe and Russia:

If a given idea has 20 million followers, it doesn't need a state to win. It has already won. It can form an alternative system of decision making on the Internet, i.e. create the crowd-power.

Radical life extension is the strongest idea in the history of mankind. The Pirate party and the Green party may serve as an example of how the international life extension party will be created. First of all, there has to be a circle of people who share the same value, and separate flamboyant actions that highlight this value. Just like Greenpeace performed this action when they sailed to the island where the nuclear testing was about to take place.

However we are aware that radical life extension idea still hasn't got enough followers, and public actions are needed to attract new supporters, because actionism is also quite fascinating. Maybe we should float 400 coffins into the Hudson River so that people will see with their own eyes how many people die in New York every day.

Another way of using the power of the crowd is crowdfunding of scientific experiments. And it's important to say that there are such experiments that possess the power of political acts, meaning they extend the limits of what's possible and set the direction of further movement.

Wednesday, February 5, 2014

One contributing cause of age-related immune system dysfunction is exposure to cytomegalovirus (CMV). Near everyone has it by the time they reach old age, and this persistent herpesvirus coerces ever more of the immune system's limited resources to uselessly battling it - the body cannot effectively clear CMV, but it continues to try, year after year. Immune cells that should be undertaking other, far more vital work are sidelined into the dedicated watch for CMV.

The best short term approach to this problem may be to adapt targeted cell-killing technologies developed for use against cancer and adapt them to destroy CMV-specific immune cells, based on targeting the distinctive surface chemistry of these cells. That would free up immune system capacity for more useful cells to emerge.

This study identified a novel, striking link between CMV-specific cellular immunity and vascular changes in older life. The vast majority of CMV-infected people had CMV-specific CD4+ T cells in their peripheral blood that displayed the hallmarks of iTregs and whose frequency was significantly associated with both mean arterial blood pressure and diastolic blood pressure in a linear regression model. The frequencies of CMV-specific CD8+ effector T cells were highly correlated with these regulatory-type CD4+ T cells and, likewise, significantly associated with mean arterial blood pressure and diastolic blood pressure. These observations point to a direct link between quantitative measurements of CMV-specific immunity and functional vascular parameters. These findings were not explained by confounders such as age, inflammation (ie, CRP level), BMI, smoking history, or use of antihypertensive medication.

In conclusion, our study provides new and compelling evidence of a quantitative link between CMV-specific cellular immunity and blood pressure or, indirectly, vascular stiffness in older age. Together, these findings may indicate that CMV has an important role in driving vascular changes in older life that ultimately affect survival. The level of cellular immunity to CMV might become an important target for intervention in the future, because it is doubtful that the huge CMV-specific T-cell expansions observed in some CMV-infected people are actually required to control infection.

Wednesday, February 5, 2014

In its role as an adaptation to suppress cancer, it makes sense that cellular senescence can to some degree spread through a cell population, as well as alter the behavior of surrounding cells in other ways. After all if one cell in a tissue is at risk of cancer, then it is likely others will also be under threat. So the more senescent cells there are, there more likely it is that nearby cells will also become senescent. This is driven by what is called senescence-associated secretory phenotype (SASP) - the particular combination of signaling and other proteins emitted by senescent cells.

This would all be fine and well, but the presence of senescent cells harms tissue integrity and causes other forms of dysfunction that contribute to the advance of degenerative aging. The immune system does work to destroy these cells, but falls down badly on that job in later life: senescent cells accumulate and cause great harm. Ideally we'd want to destroy them all and management of cancer suppression and treatment through medical technology, thus having the best of both worlds. This approach lies near in the future: almost all of the necessary pieces already exist, and it is just a matter of marrying some form of targeted cell destruction technology of the sort developed for use as a cancer therapy with some way of reliably detecting senescent cells based on their distinctive biochemistry.

Here researchers are looking at SASP in more detail, to see how it impacts the ability of one stem cell population to do its job of tissue maintenance:

Cellular senescence is the permanent arrest of cell cycle, physiologically related to aging and aging-associated diseases. Senescence is also recognized as a mechanism for limiting the regenerative potential of stem cells and to protect cells from cancer development. The senescence program is realized through autocrine/paracrine pathways based on the activation of a peculiar senescence-associated secretory phenotype (SASP).

We show here that conditioned media (CM) of senescent mesenchymal stem cells (MSCs) contain a set of secreted factors that are able to induce a full senescence response in young cells. To delineate a hallmark of stem cells SASP, we have characterized the factors secreted by senescent MSC identifying insulin-like growth factor binding proteins 4 and 7 (IGFBP4 and IGFBP7) as key components needed for triggering senescence in young MSC.

These results suggest the occurrence of novel-secreted factors regulating MSC cellular senescence of potential importance for regenerative medicine and cancer therapy. [We] believe that our results pave the way to further investigations aiming to modify, in the near future, the current in vitro MSC expansion protocols for therapeutic purposes, thereby preventing or reducing the occurrence of negative senescence-related effects, and to better understand the complex process of senescence and aging in stem cells.

Thursday, February 6, 2014

A number of studies show that general antioxidant supplementation interferes with beneficial processes, and is thus harmful to long term health. This post references some of the more recent research on this topic:

You may remember a study that suggested that antioxidant supplement actually negated the effects of exercise in muscle tissue. (The reactive oxygen species generated are apparently being used by the cells as a signaling mechanism, one that you don't necessarily want to turn off). That was followed by another paper that showed that cells that should be undergoing apoptosis (programmed cell death) could be kept alive by antioxidant treatment. Some might read that and not realize what a bad idea that is - having cells that ignore apoptosis signals is believed to be a common feature in carcinogenesis, and it's not something that you want to promote lightly.

Here are two recent publications that back up these conclusions. The BBC reports on this paper from the Journal of Physiology. It looks like a well-run trial demonstrating that antioxidant therapy (Vitamin C and Vitamin E) does indeed keep muscles from showing adaptation to endurance training. The vitamin-supplemented group reached the same performance levels as the placebo group over the 11-week program, but on a cellular level, they did not show the (beneficial) changes in mitochondria, etc.

Then there's this report in The Scientist, covering this paper in Science Translational Medicine. The title says it all: "Antioxidants Accelerate Lung Cancer Progression in Mice". In this case, it looks like reactive oxygen species should normally be activating p53, but taking antioxidants disrupts this signaling and allows early-stage tumor cells (before their p53 mutates) to grow much more quickly.

This is all rather frustrating when you consider the nonstop advertising for antioxidant supplements and foods, especially for any role in preventing cancer. It looks more and more as if high levels of extra antioxidants [at] the very least help along any cancerous cells that might arise on their own. Evidence for this has been piling up for years now from multiple sources, but if you wander through a grocery or drug store, you'd never have the faintest idea that there could be anything wrong with scarfing up all the antioxidants you possibly can.

Thursday, February 6, 2014

From my perspective the balance of evidence suggests that the progressive shortening of average telomere length with advancing age is a marker of damage and dysfunction, not a primary form of damage in and of itself. That telomerase gene therapy has lengthened life span in mice means that reseachers should focus on how this might be happening rather than assuming it is because of telomere lengthening: for one thing telomerase has many functions, not all of which are at all well understood, and for another mouse telomere dynamics are quite different from those of humans.

Nonetheless, there are plenty of folk who think that we should focus on telomere lengthening, such as this advocate who holds to the programmed view of aging:

You would think that the 2009 Nobel Prize might have done more to raise the profile of research in telomere biology, but the field remains a specialized backwater of medical research, and few biologists (fewer doctors) take it seriously as a panacea for the diseases of old age. If the National Institutes of Health have money to put into heart disease and cancer and Alzheimer's and Parkinson's diseases, there is no better place to invest than in telomere biology. Research on these diseases commands multi-billion dollar budgets, because they are considered "medicine", funded by NIH, while telomere biology is considered "science" and is funded by NSF. The total NSF budget for all cell biology is only $123 million, and the portion devoted to telomere biology is a few million. The private sector is doing a little better - there are several companies selling herbs that stimulate our own bodies to liberate telomerase. But this is short-sighted venture capital, and what we need is focused research with a ten-year vision.

There is good reason to think that telomere length is a primary aging clock in the human body. The body knows perfectly well how to lengthen telomeres, but chooses not to. All we have to do is to signal the body to activate the telomerase genes that are already present in every cell. Of course, there is no guarantee that this will work, but compared to the sluggish rate of progress on individual diseases, it's a pretty good bet, and the target is rather simple. IMHO, it's worth a crash research effort.

Friday, February 7, 2014

AgeFactDB is an abstraction layer built on top of other published databases relevant to aging. One of the benefits of open access science is that people can far more easily work on better ways to present and analyze research results: it enables a faster process of evolution towards ever more useful tools. In this the scientific community is catching up but still years behind the open source software world, held back by a culture of restricted access to information that has only comparatively recently started to give way to the much more sensible ideal of open access.

The JenAge Ageing Factor Database AgeFactDB is aimed at the collection and integration of ageing-related data. In a first step it combines data from existing databases with age-related information, such as the Lifespan Observations Database and the GenAge Database. Information from further data sources will be included step by step. Value will be added to these data in several ways. One example is the consistent usage of synonyms for gene and protein names. In addition, new ageing-related information will be included both by manual and automatic information extraction from the scientific literature.

Ageing factors include genes, chemical compounds and other factors such as dietary restriction or overfeeding, heat shock, low temperature and so on whose action results in a changed lifespan or another ageing phenotype. Information related to the effect of ageing factors on life span and/or ageing phenotype is called an observation and is presented in the database on observation pages. To provide an easy and compact access to the complete information for a particular gene or a specific compound or for one of the other factors the corresponding observations are also summarised on ageing factor pages.

Based on a comprehensive homology analysis, AgeFactDB provides, in addition to known ageing-related genes, a compilation of genes that are homologous to these known genes. These homologs can be considered as candidate or putative ageing-related genes.

Friday, February 7, 2014

Species that experience greater levels of predation should not tend to evolve greater longevity, or so the established theory goes. There is debate on this topic, however, as in all areas where researchers must rely as much on models and inference as on data. Here is an example of the sort of modeling work that takes place in this field:

The evolutionary theories of aging are useful for gaining insights into the complex mechanisms underlying senescence. Classical theories argue that high levels of extrinsic mortality should select for the evolution of shorter lifespans and earlier peak fertility. Non-classical theories, in contrast, posit that an increase in extrinsic mortality could select for the evolution of longer lifespans. Although numerous studies support the classical paradigm, recent data challenge classical predictions, finding that high extrinsic mortality can select for the evolution of longer lifespans.

To further elucidate the role of extrinsic mortality in the evolution of aging, we implemented a stochastic, agent-based, computational model. We used a simulated annealing optimization approach to predict which model parameters predispose populations to evolve longer or shorter lifespans in response to increased levels of predation. We report that longer lifespans evolved in the presence of rising predation if the cost of mating is relatively high and if energy is available in excess. Conversely, we found that dramatically shorter lifespans evolved when mating costs were relatively low and food was relatively scarce.

We also analyzed the effects of increased predation on various parameters related to density dependence and energy allocation. Longer and shorter lifespans were accompanied by increased and decreased investments of energy into somatic maintenance, respectively. Similarly, earlier and later maturation ages were accompanied by increased and decreased energetic investments into early fecundity, respectively. Higher predation significantly decreased the total population size, enlarged the shared resource pool, and redistributed energy reserves for mature individuals. These results both corroborate and refine classical predictions, demonstrating a population-level trade-off between longevity and fecundity and identifying conditions that produce both classical and non-classical lifespan effects.


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