’s blog post: Investigating the Role of Monocytes in Inflammaging

Today I’ll point you to an interesting paper in which the authors investigate one of the contributing factors that cause ever greater levels of chronic inflammation to accompany aging, in this case the factor being detrimental changes in the behavior of monocyte immune cells in older individuals. The researchers demonstrate that monocytes are influenced by rising levels of the inflammatory cytokine TNF, and either removing TNF or the problem monocytes improves the impaired immune response in aged mice.

The immune system is enormously complex, one of the many aspects of our biology in which the high level sketch – information that fills books in and of itself – must still be painted in at the detail level. One measure of what is left to learn is the present lack of understand of the root causes of many autoimmune diseases, intricate failure modes in the regulation of immune activities in which immune cells attack healthy tissue. If the research community understood the immune system completely, the scientists involved would also understand autoimmunity well enough to prevent it and reverse it. As it is, there are only hints and connections made in a growing, ceaseless river of data, while cures are yet to be found. The situation for the aging of the immune system is much the same. A variety of theories backed by differing levels of evidence explain why the immune system in aged individuals becomes both progressively less effective and progressively more active at the same time, chasing its tail to no good end. Greater activity means more inflammation, and sustained inflammation is a source of tissue damage and cellular dysfunction, a potent contribution to the pathology of many age-related diseases. Researchers have given the name “inflammaging” to this unfortunate end stage of the immune system and its detrimental effects on health.

Today we are at a point at which the research community can present a convincing story of immune aging based upon processes such as the atrophied thymus reducing the supply of new immune cells, the limited number of immune cells increasingly consisting of those uselessly devoted to a few persistent pathogens rather than capable of dealing with new threats, and so on and so forth. The relevance and importance of these processes can still be argued, however. Given the pace of progress in biotechnology, I believe that the proof of theories on immune aging will be provided by therapies capable of addressing the causes of immune decline, and this will happen long before proof can be provided via a full mapping of the biochemistry and processes of the immune system. Therapies that work will point the way, and the cost of testing any given hypothesis in mice continues to fall year after year.

Studying ‘inflammaging’: Monocytes, cytokines, and susceptibility to pneumonia

Researchers are interested in how the immune system ages. In this study, they focus on monocytes, immune cells that are central to the process of inflammation. Monocytes multiply and mature in the bone marrow and circulate in the blood stream. They are recruited to sites of injury or infection and there turn into macrophages that ingest pathogens, infected cells, or cellular debris. Monocytes are also potent producers of pro-inflammatory cytokines, small molecules that promote an inflammatory immune response.
Comparing younger and older mice, the researchers found that the latter have higher numbers of monocytes both in the bone marrow and in the blood. They also saw higher levels of TNF and IL-6, two pro-inflammatory cytokines, in blood from older mice and blood from older human donors. Studying mouse monocytes in more detail, the researchers found that the increase in TNF levels that occurs with age causes premature release of immature monocytes from the bone marrow into the blood stream. When stimulated with bacterial products, these immature monocytes themselves produce more inflammatory cytokines, thus further increasing levels in the blood.
The researchers then infected younger and older mice with the bacteria Streptococcus pneumoniae, which causes so-called pneumococcal pneumonia. They found that, although the older mice had higher numbers of monocytes in the blood and at the sites of infection, their monocytes were not able to clear the bacteria and successfully fight the infection. However, when the researchers used drugs or mouse mutations that reduced the number of monocytes or removed TNF, they were able to restore antibacterial immunity in aged mice. The researchers conclude that “monocytes both contribute to age-associated inflammation and are impaired by chronic exposure to the inflammatory cytokine TNF, which ultimately impairs their anti-pneumococcal function.” They go on to suggest that “lowering levels of TNF may be an effective strategy in improving host defense against S. pneumoniae in older adults.”

TNF Drives Monocyte Dysfunction with Age and Results in Impaired Anti-pneumococcal Immunity

As we age, levels of inflammatory cytokines in the blood and tissues increase. Although this appears to be an inevitable part of aging, it ultimately contributes to declining health. Epidemiological studies indicate that older adults with higher than age-average levels of inflammatory cytokines are at increased risk of acquiring, becoming hospitalized with and dying of pneumonia but how age-associated inflammation increased susceptibility to was not entirely clear. We demonstrate that the increase in the inflammatory cytokine TNF that occurs with age cause monocytes to leave the bone marrow prematurely and these immature monocytes produce more inflammatory cytokines when stimulated with bacterial products, thus further increasing levels of inflammatory cytokines in the blood. Furthermore, although old mice have higher levels of these inflammatory monocytes arriving at the site of S. pneumoniae, they are not able to clear the bacteria. By pharmacologically or genetically removing the inflammatory cytokine TNF or reducing the number of inflammatory monocytes we were able to restore antibacterial immunity in aged mice.

My Comment:

What drives the rise in TNF Alpha as the mouse ages? Obivously the 7 categories of SENS defined damage, but has anyone mapped a molecular pathway from them to rising systemic TNF?

Michael Rae’s reply to my comment:

@Jim: most directly, we know that TNF-α is released by senescent cells as part of the SASP.

Oxidative stress also activates nuclear factor κB, which in turn promotes the expression of TNF-α and several other inflammatory cytokines, so age-related mitochondrial mutations are an obvious candidate.

Immune cells in the atherosclerotic artery may also produce TNF-α, which may even be locally beneficial in the earliest stages of lesion development even if it has deleterious long-term local and systemic effects. As usual, looking for a solution involving up- or downregulating such production is therefore fraught.

And the rising inflammatory tone with aging can certainly be linked with lifelong dysregulation of the immune system, although probably not directlty linked with the accumulation of anergic T-cells (which, indeed, fail to produce TNF-α upon antigenic stimulus, which is part of why they’re called “anergic” in the first place).

These are all really secondary questions, however. The best way to identify the sources and relative priority of cellular and molecular damage of aging driving increased levels of TNF-α or any other alteration in the systemic environment is to clear them out and see what happens.’s blog post: Scores of Labs Should be Gearing Up to Work on Glucosepane Cross-Link Breakers, But Are They? – Michael Rae’s reply to my comment

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As we age skin and blood vessels lose their elasticity. People care too much about the skin and too little about the blood vessels, but that is always the way of it. Appearance first and substance later, if at all. Yet you can live inside an aged skin; beyond the raised risk of skin cancer its damaged state arguably only makes life less pleasant, and the present state of medical science can ensure that the numerous age-related dermatological dysfunctions can be kept to a state of minor inconvenience. Loss of blood vessel elasticity, on the other hand, will steadily destroy your health and then kill you. Arterial stiffening causes remodeling of the cardiovascular system and hypertension. The biological systems that regulate blood pressure become dysfunctional as blood vessels depart from ideal youthful behavior, creating a downward spiral of increasing blood pressure and reactions to that increase. Small blood vessels fail under the strain in ever larger numbers, damaging surrounding tissue. In the brain this damage contributes to age-related cognitive decline by creating countless tiny, unnoticed strokes. Ultimately this process leads to dementia. More important parts of the cardiovascular system are likely to fail first, however, perhaps causing a stroke, or a heart attack, or the slower decline of congestive heart failure.

From what is known today, it is reasonable to propose that the two main culprits driving loss of tissue elasticity are sugary cross-links generated as a byproduct of the normal operation of cellular metabolism and growing numbers of senescent cells. Elasticity is a property of the extracellular matrix, an intricate structure of collagens and other proteins created by cells. Different arrangements of these molecules produce very different structures, ranging from load-bearing tissues such as bone and cartilage to elastic tissues such as skin and blood vessel walls. Disrupting the arrangement and interaction of molecules in the extracellular matrix also disrupts its properties. Persistent cross-links achieve this by linking proteins together and restricting their normal range of motion. Senescent cells, on the other hand, secrete a range of proteins capable of breaking down or remodeling portions of the surrounding extracellular matrix, and altering the behavior of nearby cells for the worse.

The most important cross-linking compound in humans is glucosepane. Our biochemistry cannot break down glucosepane cross-links, and as a result it accounts for more than 99% of cross-links in our tissues. This isn’t a big secret. Given this you might expect to find researchers working flat out in scores of laboratories to find a viable way to break it down. After all here we have one single target molecule, and any drug candidate capable of clearing even half of existing cross-links would provide a treatment that can both reverse skin aging and vascular aging to a much greater degree than any presently available therapy. The size of the resulting market is every human being, the potential for profit staggering. Yet search on PubMed, and this is all of relevance that you will see published on the topic in the past few years:

– Preferential sites for intramolecular glucosepane cross-link formation in type I collagen: A thermodynamic study.
– Glucosepane and oxidative markers in skin collagen correlate with intima media thickness and arterial stiffness in long-term type 1 diabetes.
– Skin advanced glycation end products glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes.
– Glucosepane: a poorly understood advanced glycation end product of growing importance for diabetes and its complications.
– The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes.

This is a tiny output of work. The research and development world is not beating a path here as it should. The thesis is that this lack of enthusiasm exists because the state of tools and processes needed to work with glucosepane has long been somewhere between underdeveloped and nonexistent. No group will choose to work in an area in which they have to build the tools first when there are so many other choices available. This sort of chicken and egg situation exists in numerous places in every field of science and technology, small fields where a great deal might be achieved, but no-one does anything because the short-term rational choice is to do something else in an area where the tooling already exists. This is why we need advocacy and philanthropy, to fix problems of this nature. In recent years the SENS Research Foundation has been funding development of the tools needed for research groups to work with glucosepane in living tissues, and just this year we have seen the first published results: a simple, cheap, efficient method of creating as much glucosepane as needed for ongoing cell and tissue studies. There is now no roadblock standing in the way of any researcher wanting to run up batches of glucosepane, create small sections of engineered skin and blood vessel tissue, generate cross-links in that tissue, and then carry out assessments of drug candidates for clearing those cross-links.

The tools are a big deal, I think. Glucosepane clearance is a very narrow, very small pharmacological problem with a huge pot of gold on the other side. Pharmaceutical companies and established laboratories should be packed with staff running, not walking, to work on this. It is crazy that anyone has to be out there banging the drum to draw attention.

My Comment:

Um, there still aren’t any validated antibodies to act as markers of glucosepane removal in vivo. Surely that is a missing significant tool?

Jason Hope donated half a million dollars a few years ago to set up a SENS lab at Cambridge headed by Dr William Bains. I don’t know if this money has now run out, or if they are still getting some research done out of it (probably by working largely for free).

I saw mention somewhere (that I can’t remember) that they tested a series of supposed marker antibodies against glucosepane and found that none of them were very specific and useful.

Could the SENS Foundation run another kickstarter campaign on in the new year to raise money for the Cambridge Lab to generate antibodies to glucosepane and then validate them? How much would this cost? Would $45k be enough, or is this a more expensive undertaking?

Michael Rae’s reply to my comment:

@Jim: you’re quite correct that anti-glucosepane antibodies are a critical tool, and you’re remembering rightly that the Cambridge SENS Lab found that none of the commercially- or academically-available putative anti-AGE antibodies were any good at this job. In fact, it’s worse than that: none of the putative anti-AGE antibodies are really any good for detecting any AGE at all, and barely serviceable against related adducts like CML! We shut down the Cambridge lab (indeed, Dr. Bains fell on his sword) largely because without this basic tool, they had no way to carry their research forward.

Happily, the successful and convenient synthesis of glucosepane by our Yale researchers has enabled them to start working on developing this tool. They are now working to incorporate glucosepane into synthetic, chemically-uniform crosslinked peptides, which can then be used as antigens with which to vaccinate rabbits. Once vaccinated with these antigens, the animals are expected to generate antibodies targeting glucosepane-containing peptides. The B-cells that generate the antibodies in such animals can then be isolated and immortalized, generating monoclonal glucosepane-targeting antibodies on an industrial scale.

@Steve H: I appreciate your reasons for wanting to go with IGG. Consider, however, the longer-term advantages to the entire biomedical gerontology community of using the platform: by helping to build up a roster of projects and a track record of success, they can attract more projects and eventually begin digging more aging research studies out of the woodwork, raising the profile of the entire sector and eventually allowing to use their royalties for their advocacy activities for the advancement of anti-aging research.

Fightaging’s post: The Long Road Ahead to Exercise Mimetics – Michael Rae’s Reply to my comment

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Today I’ll point out a couple of recent research publications on the topic of the molecular mechanisms of exercise: how it might work to improve health, how it extends healthy life span but not maximum life span in animal studies, and how the response to exercise might be safely improved or otherwise manipulated. Researchers nowadays tend to comment on future directions for drug discovery based on their investigations of exercise, and in that this slice of the field is becoming much like calorie restriction research ten to fifteen years ago.

Take a moment to think about how much work and funding has gone into investigations of calorie restriction and the search for drug candidates that can mimic even just a fraction of the beneficial metabolic alterations and extension of healthy life spans that occur in response to calorie restriction: probably a few billion dollars and year after year of dedicated investigations by hundreds of scientists in the past decade alone. Yet at the end of all that, and after the collection of enormous amounts of data, there is only a small number of drug candidates, few of which are anything other than marginal in animal studies, none of which can reproduce all of the beneficial changes observed in calorie restriction, and there is still no comprehensive accounting of how calorie restriction works under the hood, just an outline of ever-growing complexity.

It has taken fifteen years to get that far. Processes like the reaction to restricted calorie intake and exercise are enormously complex. They impact near every aspect of metabolism and cellular biology, and the quest to understand them well enough to manipulate them is more or less the same thing as the quest to understand cellular biology completely. This and the past history of calorie restriction mimetic drug research is why I’m not holding my breath waiting on exercise mimetic drugs. Researchers will talk about this as a goal, just as they have talked about calorie restriction mimetic drugs, but the reality is that the inherent complexity involved makes this is a very long-term project, one that tends to produce marginal outcomes at great expense. Exercise mimetics and calorie restriction mimetics that are safe and reliable would be a pleasant thing to have around, to be sure, but it seems to me that at the present time there are better and more cost-effective approaches to the treatment of aging as a medical condition.

Exercise Pills: At the Starting Line

“Excessive caloric intake and limited physical activity contribute to the current explosion of ‘modern’ chronic diseases such as obesity, type 2 diabetes, muscle atrophy, and cardiovascular diseases. By contrast, regular physical exercise maintains glucose homeostasis and induces physiological adaptations that effectively prevent, and often reverse, these diseases. Recognizing the human and economic burdens these diseases cause, and taking into account the health benefits of exercise, have led many exercise scientists to suggest that physical exercise may be the preferred method in the treatment and prevention of these ‘modern’ chronic diseases.
Unfortunately, exercise compliance levels are almost universally low, especially for people using home-based exercise programs. A variety of factors including poor physical condition, weakness, sickness, lack of time, and poor motivation contribute to low exercise compliance. The much publicized poor compliance begs the question: is there an alternative approach that both induces the health benefits of physical exercise and overcomes the problem of low compliance rate? Regular physical exercise activates a number of molecular pathways in whole organ systems and reduces the risk of developing numerous chronic diseases. Although nothing can fully substitute for physical exercise, candidate exercise pills that have emerged in recent years may be an attractive alternative.”

Exercise in a bottle could become a reality

“Researchers exposed a thousand molecular changes that occur in our muscles when we exercise, providing the world’s first comprehensive exercise blueprint. “Exercise is the most powerful therapy for many human diseases, including type 2 diabetes, cardiovascular disease and neurological disorders. However, for many people, exercise isn’t a viable treatment option. This means it is essential we find ways of developing drugs that mimic the benefits of exercise.” The researchers analysed human skeletal muscle biopsies from four untrained, healthy males following 10 minutes of high intensity exercise. Using a technique known as mass spectrometry to study a process called protein phosphorylation, they discovered that short, intensive exercise triggers more than 1000 changes.
“Exercise produces an extremely complex, cascading set of responses within human muscle. It plays an essential role in controlling energy metabolism and insulin sensitivity. While scientists have long suspected that exercise causes a complicated series of changes to human muscle, this is the first time we have been able to map exactly what happens. This is a major breakthrough, as it allows scientists to use this information to design a drug that mimics the true beneficial changes caused by exercise. Most traditional drugs target individual molecules. With this exercise blueprint we have proven that any drug that mimics exercise will need to target multiple molecules and possibly even pathways, which are a combination of molecules working together. We believe this is the key to unlocking the riddle of drug treatments to mimic exercise.”

My Comment

@Ham – Dave Sinclair’s sirtins do have repeatable results in mice. None of the 5 underfunded SENS technologies have this. Senescent cells only have one published paper in a mouse model with a shortened lifespan. The use of enzymes to clear oxidised LDL from the lysozome has only been demonstrated in a dish (although Jason hope has put his money behind this to some unknown degree). Mitosens has only been demonstrated in the dish except for one gene (ND4). And breaking gluscospane has not even been demonstrated yet.

Demonstrate one of the above in a decent mouse model a few times with a health o lifespan benefit and a biotech or pharma may come knocking.

Michael Rae’s reply to my comment:


Posted by: Jim at October 6, 2015 6:56 PM: None of the 5 underfunded SENS technologies have [repeatable results in mice]. Senescent cells only have one published paper in a mouse model with a shortened lifespan. The use of enzymes to clear oxidised LDL from the lysozome has only been demonstrated in a dish (although Jason hope has put his money behind this to some unknown degree). Mitosens has only been demonstrated in the dish except for one gene (ND4). And breaking gluscospane has not even been demonstrated yet.

Hang on … By “None of the 5 underfunded SENS technologies,” I take it that you mean everything except cell therapy and extracellular aggregate clearance. Those two are indeed substantially better-funded than the other planks in the platform, but there is relevant work in rodents for several of the other planks.

First, you’ve yourself already mentioned the proof-of-concept clearance of senescent cells from aging tissues of hypomorphic BubR1 mice. You’re right to call out that this is a quite artificial model, but I’ll remind you that the field was jumpstarted by that work rather than ending with it. I’ll remind you that Julie Anderson from the Buck Institute presented thrilling results using Judith Campisi’s unpublished system (nothing of direct human translatability) in a Parkinson’s disease mouse model at SENS Research Foundation’s Rejuvenation Biotechnology 2014 conference, and the system has now been shown to prevent or reverse a range of diseases of aging modeled in transgenic mice. Additionally, as you know, Kirkland and van Deursen have demonstrated that ablation of senescent cells improves aging phenotypes in wild-type mice.

Alagebrium appears to provide quite multiple in vivo proofs-of-concept for rejuvenating tissues by breaking AGE crosslinks: it reversed age-related increases in myocardial stiffness in dogs, and reduced vascular stiffness and improved left ventricle function in nonhuman primates, and did multiple wonders in diabetic rodents. Its mechanism of action remains unclear, and its direct human translatability is demonstrably zero, but it almost certainly involves glycation and is widely thought to break medically-important crosslinks in these species.

As you parenthetically allude, bit more than 5 years ago, just prior to the formal institutional division, SRF/MF funded research on rendering mitochondrial mutations harmless reversed blindness induced by allotopic mitochondrial DNA mutations in rats. Yes, it’s only one gene, and yes, it’s rescue of an AE-induced harm, so it’s neither as exciting nor as conclusive a demonstration of as we would all like. But it ain’t mechanically-disaggregated hepatocytes 😉 .

As regards intracellular aggregates: while we usually associate vaccine-based therapies with clearance of extracellular aggregates, several vaccines targeting beta-amyloid protein clearly clear intracellular aggregate in the process, and some of the tau-targeting vaccines do the same.

And while it’s a highly incomplete solution (because it’s limited to delivering more of an existing lysosomal enzyme rather than giving the lysosome a novel, engineered enzymatic capacity to degrade intracellular aggregates, we discuss an early proof-of-concept for prevention of atherosclerosis through enhancing the macrophage lysosome in mice in Ending Aging.

The examples start to get less impressive or direct after that, but let’s remember that the “damage-repair” heuristic of SENS has undergone substantial in vivo validation already.

Posted by: Slicer at October 7, 2015 1:35 PMJim – “It works in mice” isn’t a very good qualifier here, because the metabolic differences between humans and mice often involve longevity. Sirtuins could simply be getting these mice up to the human level. Turns out that it’s really, really easy to increase the lifespan of a fruit fly and somewhat easy to increase the lifespan of a mouse.

I don’t think the analogy holds: the main issue with invertebrate models is that they have entirely different body plans and life histories than mammals, and age in a dramatically different way. C. elegans’ mature bodies are composed entirely of cells that don’t divide, so they don’t develop cancer; they don’t have hearts or circulatory systems as they occur in mammals and thus don’t suffer heart disease or atherosclerosis; they don’t live long enough to accumulate mitochondrial DNA deletions, or several other key forms of molecular and cellular damage that contribute to aging in mammals; some investigators believe that they almost always die of starvation due to failure of the muscles in their pharynx; and they have the capacity to enter into the “dauer state,” a kind of deep suspended animation, when challenged with food withdrawal or a range of other stressors, which likely confounds any data on extended fasting periods that (my esteemed mentor to the contrary) is really not analogous to rodent or human CR.

Many, many small molecules extend lifespan in these organisms by activating stress pathways or quenching free radicals; so far, none of these chemicals do so in normal, healthy mice. True, even studies in mice don’t always translate directly to humans — look at all the failed cancer drugs that cure the disease in mice — but they’re a much better start!

Posted by: Slicer at October 7, 2015 1:35 PMThe SENS approach to the obesity epidemic is the same as its approach to the heroin epidemic and the [faster methods of] suicide epidemic. It’s not in the business of stopping people from ending themselves, whether they use guns, needles, or cheeseburgers.

Of course, we aren’t and won’t be in the literal suicide prevention business (and have no intention of attempting to mandate that people accept rejuvenation therapies, but people who become obese aren’t suicidal, nor resigned to premature sickness and death. And while it won’t address the purely aesthetic aspects of obesity, rejuvenation biotechnologies will certainly prevent, arrest, and reverse the diseases and debilities that are caused by the metabolic derangements of obesity, which are (after all) only earlier-onset, selective exacerbation of the byproducts of normal metabolism that drive the disease and debility of aging.

In addition to repair, removal, replacement, and rendering harmless aging damage directly induced or accelerated most directly by excessive visceral adiposity (notably, ablation of excessive visceral adipose tissue macrophages and senescent preadipocytes, to reduce systemic inflammation and restore hepatic insulin sensitivity), the same rejuvenation biotechnologies that will eradicate atherosclerosis, clear out senescent cells, repair damaged joints, replace pancreatic beta-cells destroyed or rendered dysfunctional late in type II diabetes, replace or patch failing kidneys, repopulate failing hearts with functional cardiomyocytes while eliminating the hypertension that drives hypertrophy and dysfunction, etc.

And yes: we’re going to make people’s bodies invulnerable to cancer, whether a woman is on a course toward breast cancer comes from being made obese during her developmental window, or because she worked shift work as a nurse caring for people when aging ravages their bodies, or because she struggled with alcohol, or for no discernible reason other than the normal operation of the machinery of a body always balancing development and tissue renewal against the risk of out-of-control cell growth.

The SENS approach to the obesity epidemic is thus the same as it is for the aging epidemic. The metabolic drivers don’t matter: repairing the damage matters.

Fightaging’s post: A Review of Work on Targeting α-synuclein Aggregates

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Here I’ll point out a recent review of approaches to treat one of the more common synucleinopathies, conditions related to – and thought to be caused by – the abnormal accumulation of α-synuclein in tissues. The pathologies of numerous age-related diseases are linked to various different types of protein aggregate that are observed to build up with age: misfolded or simply overabundant proteins that precipitate to form solid clumps and fibrils. Amyloids are well known for their association with Alzheimer’s disease, but there are many types of amyloid and many corresponding amyloidosis conditions. Similarly tau aggregates are linked to the tauopathies. The list goes on, and of course includes α-synuclein.

Why do these various different aggregates appear in old individuals but not young ones? Most of the evidence to support various theories comes out of Alzheimer’s research, as that field has far more funding and far more scientists working on the problem. Amyloid levels in the brain are dynamic on a fairly short timescale, and the buildup of amyloid has the look of slowly failing clearance mechanisms. These might include general dysfunction in the choroid plexus filtration of cerebrospinal fluid, or in the drainage channels that carry away metabolic waste from the brain, or the mechanisms of the blood-brain barrier intended to shunt unwanted waste out of the brain and into the blood system. These and related forms of dysfunctions could plausibly arise from many of the forms of cell and tissue damage thought to cause aging, or from their consequences such as inflammation, loss of muscle strength, loss of tissue flexibility, and so forth.

The most promising near term approach to protein aggregates is to build treatments than can be periodically applied to clear out the buildup. Immunotherapies are so far the best of ongoing efforts, enlisting the immune system to attack and break down the aggregates, but there is still a way to go towards robust and reliably outcomes. Clinical trials have so far been disappointing, as is often the case in the first round of attempts in any area of medicine. Equally, other classes of rejuvenation therapy will be needed to repair the problems in clearance of aggregates that cause the buildup in the first place: just getting rid of the aggregrates themselves isn’t a full solution, just a much better class of sustaining treatment than is presently available.

Work on clearing α-synuclein runs in parallel to work on amyloid-β, and with the same general pattern of progress, in that immunotherapies look to be the best path forward for now, yet only incremental benefits have been shown to date via this appreach. This review is focused on Lewy body dementia, but the approaches to clearing α-synuclein might be applied to any of the other synucleinopathies, such as Parkinson’s disease.

Disease-modifying therapeutic directions for Lewy-Body dementias

On Persuasion as Activism for Rejuvenation Research

My comment:

To be honest I don’t talk to my friends and family about the prospects for life extension technologies, I don’t know how to do it without sounding like a maniac.

I’m thinking the best way I could get them to contribute would be to try and do a fundraising activity (run a marathon or something) to try and raise $2,000, and tell them the money will go towards mitochondrial research, which may then lead to much longer and healthier human lifespans. Or glucospane cross link breaking enzymes, which may lead to more youthful looking skin “Would you like to have younger looking skin? Then sponsor my attempt to raise $1,000 for research into enzymes that break collagen sugar cross links”.

I can’t afford to join the 300 and pay $1,000 per year for the next 25 years (I am sick and working a simple minimum wage job at the moment). But perhaps I could raise some money from my social network, and at the same time get some of my friends actually thinking about the prospects of aging research.

Only problem with that is that I currently have severe allergic respiratory problems that make me bedridden. So the above plan (if it actually makes sense in real life) is on hold.

First things first 1: I need to get my health back, which hopefully going on a clinical trail by the end of the year (and not winding up in the placebo group) will do.

2: Do a rock climb/run time/weight life goal/visit X towns on the coast goal. Try to raise $1,000.

3: If that works try to do it every year.

4: Set up a site or some tools to enable others to do the same thing (answers to FAQs like “why sponsor this research? Isn’t the government paying for it?”).

On Inevitable Things and Coping Mechanisms – your comment on Ioana Petre’s essay

Ioana’s essayy:

My comment on Ioana’s essay:

“Excellent article. Thanks very much for sharing this. I’ve often thought people’s resistance to even considering whether anti-aging medicine is possible was just due to some innate thing where people always assume things that have never been done before (e.g. powered flight) are naturally considered impossible. But this essay highlights that even considering extended/indefinite life messes with people’s coping mechanism for death. Not thinking about the ‘inevitable’ thing one is trying to cope with is actually an important part of the coping process.

It is a morbid thought, but I’ve got to wonder how many people who contracted HIV in the 1980s, before effective multi drug cocktails, sailed serenely to their deaths rather than raging against the status quo? Ioana makes a good point that HIV viral infection was once an inevitable death sentance that people had to cope with.

I think HIV was different to aging though as other viruses had already been conquered by science (Polio, Smallpox) but the condition of aging has never been conquered. Perhaps it will take an indefinitely living mouse to change most people’s opinions? Until then there will be a funding gap for the basic research needed to create this mouse? There will be no large government funding without a percentage of the population supporting anti-aging research. But there will be no percentage of the population supporting anti-aging research without an indefinitely living mouse. And creating the treatments to create this mouse will go very slowly without large government funding. So anti-aging research is in a bit of a poverty trap.

Is this similar to the period before the industrial revolution where perhaps the entire world was in an economic poverty trap?”

The text of Ioana’s essay:

On Inevitable Things and Coping Mechanisms

On average, coping mechanisms are more good than bad. Imagine going through life without any guardian of your negative thoughts, destructive behavior or haunting problems. Each day would be a pretty messy business, wouldn’t it? But then again, do not think that the opposite is bliss because it really isn’t. Nobody likes overachievers anyways…

Now, as many have already pointed out, the problem with coping mechanisms is that they might gradually lead to a semi-conscious rejection of reality. And at the end of the day, reality denial perpetuates rather than eliminates one’s hardships and frustrations. Thus, don’t be surprised if and when the act of coping, which in its honest self doesn’t commit to deliver more than it promises, fails you. Coping is not problem solving. But, according to some, under certain circumstances, it is the next best thing.

And here is where the issue of inevitability comes into play. By their very definition, inevitable things are bound to happen no matter what. Moreover, most of the time, they are bound to happen in a very specific way, while nothing (or very little, at best) can be done about them. In this context, as problem solving is out of the question, coping is all we’re left with.

There are so many inevitable things around us that people have generally chosen to cope with. Among them, aging and death are my favorite examples, probably because I genuinely and equally dread and despise them. In all likelihood, it is the most rational approach to develop, at the individual level, some defense mechanisms against the disturbing thought of non-existence. But then there is this striking fact that we should not disregard: many times, the inevitability of things comes with an expiration deadline.

Through displays of genius and huge effort, people like you and me have managed to stop the unstoppable over and over again. This is by no means an exaggeration. Just think about those times when viral infections were an irreversible sentence to death or, on a less dramatic note, when one’s inborn sex would forever remain unchanged even if it didn’t correspond to one’s self-image and self-assigned gender. We might take such things for granted nowadays, but this was not always the case. The reason for the accomplishment of such grand projects lies firstly in a change of attitude: from compliance with the given to non-compliance. Only after allowing the ‘what if’ to make its way into our thoughts and speech can we actually proceed to thinking about overcoming the inevitable.

This is what the situation is now with the fight against aging and death. In some ways, embracing religious precepts and the promise of an afterlife transforms non-existence into something that many actually look forward to. Oh, the gardens and the foods and the clouds and the people and the peace… Who would want to give that up and exchange it for nothing, really, except the idea that maybe it doesn’t have to be that way?

Although there are many important scientific breakthroughs related to aging and its associated diseases, the thought of supporting this path gives many people the chills because it forces them to review their life principles and reassess their coping mechanisms. Some will say that living to 200 is not natural, while having absolutely no problem with using antibiotics or birth-control pills. Others will invoke the boredom of a long life. Who knows, non-existence can potentially be more exciting, but it’s also pretty long because it’s infinite. The point of the matter, though, is this: refusing to perceive aging and death as inevitable leaves permanent scars on one’s life views, which will possibly make one’s days a bit more daunting than otherwise. But, on the bright side of it, it prevents the self-sabotaging inertia that kills innovation, progress, and, in this specific case, a whole lot of other people too. Also, if I think about it there are some other reasons for optimism as well: personally, I know more individuals that have conquered death by still being alive than those who didn’t . What about you?

In closing, I would like to highlight the fact that the long and widespread existence of certain things doesn’t make them right, nor acceptable. Inevitability is only as inevitable as one allows it to be.

Comment on Fightaging’s post on the SENS Foundation’s June 2014 newsletter

My Comment:

I had a look at Dr Sudhir Paul’s video on the SENS website. What I found exciting was the idea that catabolic IgM antibodies that break down Alzheimer’s disease amyloids themselves may avoid the inflammation problem caused by more ‘regular’ IgG antibodies which recruit phagocytes to do the job.

I wonder if any Pharmaceutical company or any teams around the world are actively researching this? Or is Dr Paul way ahead of everyone else in the world in the area of catabolic antibodies.

Of course these catabolic IgM antibodies haven’t yet been shown to break down an amyloid in vivo, which seems to be an important milestone before more people start to take notice.

These catabolic antibodies could be a revolutionary new treatment/technology avenue for extra cellular junk. I wonder if they could also be used to break glucospane? Although maybe that is too tangled for them to get near it, or the bonds are too tough for them to break?