Fight Aging! Newsletter, May 7th 2018

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in 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 medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • What Can be Achieved if the Epigenetic Clock is an Accurate Reflection of Aging?
  • How to Plan and Carry Out a Simple Self-Experiment, a Single Person Trial of a Mitochondrially Targeted Antioxidant
  • Gene Therapy to Enhance Proteosomal Activity Slows Retinal Degeneration in Mice
  • Higher Levels of Progerin are Found in Cardiomyopathy Patients
  • Fasting Reverses Age-Related Decline in Regenerative Capacity of Intestinal Stem Cells
  • Leonard Hayflick is not in Favor of Greatly Extending Healthy Human Life Spans
  • Aubrey de Grey in Fine Form on the Ethical Imperative to Defeat Aging
  • An Interview on Mitochondrial Damage and Dysfunction in Aging
  • Reduced Expression of Antimicrobial Peptide Genes Partially Determines the Temperature-Lifespan Relationship in Flies
  • Inflammatory Necroptosis Increases with Aging and is Slowed by Calorie Restriction
  • Promising Long Term Results in Stem Cell Therapy for Peripheral Artery Disease
  • Longevity Industry Landscape Overview Volume II: The Business of Longevity
  • How Many Years of Additional Life Expectancy Does a Healthy Lifestyle Provide?
  • Suggesting that the Gut Microbiome Contributes to Atherosclerosis
  • The Alzheimer's Research Community is Increasingly Supportive of the Leucadia Therapeutics Approach to the Condition

What Can be Achieved if the Epigenetic Clock is an Accurate Reflection of Aging?

The difference between having and not having an accurate, rapid, low-cost measure of biological age is night and day. If such a thing did exist, then it is immediately the case that a good few dozen interventions could be rapidly tested in humans, taking a month or two between before and after measurements. The cost is low enough that volunteer groups and philanthropy could manage it. Look at what Betterhumans is doing in trials of cheap senolytic compounds, for example, and then add a robust assessment to that in order to definitively say whether or not rejuvenation occurred. I expect that only a few of the obvious candidate interventions that people will put forward will in fact turn out to make a difference. This is still important: the absence of results for the rest should go some way towards shutting off useless work on supplements and dietary tinkering that absorbs a great deal of time and funding both within and without scientific community.

Is there such a thing as an accurate, low-cost test that measures biological age, however? The later variants of the epigenetic clock might fit the bill, though it is still impossible to say whether or not they broadly reflect the causes of aging, or are tied to just a few narrow causes of aging. Absent a way to effectively reverse one of those narrow causes on its own, the mystery will likely persist; as of today, only senolytic therapies are capable of that feat, and they are not yet widely tested in humans. That the clock is uncertain in its mechanism of action is actually all the more reason to be running these studies. Both the clock and interventions alleged to slow or reverse or compensate for the progression of degenerative aging can be validated against one another.

The posts noted here cover an outline of one possible direction for evaluation of interventions against the epigenetic clock. They are largely not the sort of thing I believe should be the primary focus of the research community. These approaches are for the most part calorie restriction mimetic and similar compounds that trigger or enhance stress responses. All such methods have been shown to scale down in the extension of healthy life span as species life span increases. Calorie restriction itself produces 40% gains in mouse life span, but is unlikely to change human lifespan by more than five years or so. That said, there is merit, I think, in being able to show, robustly, that these approaches have only small effects, and thus redirect research and development efforts elsewhere, hopefully towards the SENS damage repair approaches that can in principle produce rejuvenation rather than just a slight slowing of aging.

The Mother of All Clinical Trials, Part I

There are a great number of promising interventions that might have anti-aging benefits. There is a testing bottleneck, which means that we don't know what works. By way of contrast, there is a well-documented catalog of life extension interventions in lab worms, but for humans we're mostly in the dark. To complicate things further, lab worms are clonal populations, while every human is different, and there are growing indications that many if not most medications work for some people and not others. Horvath's methylation clock is a disruptive technology that could make human testing of longevity interventions ten times faster and 100 times cheaper than it has been in the past. No one is yet doing this kind of testing, but you and I should be advocating vigorously, and volunteering as subjects to help test whatever it is that we are already doing.

There are a great number of promising interventions that might have anti-aging benefits, singly and in combination. Some are already approved and safe for use in humans, yet we don't know what will be most effective. Because human longevity studies are prohibitively slow and expensive, none have ever been funded or conducted. (We know only accidentally that aspirin and metformin lower mortality rates in humans, because these drugs were prescribed to tens of millions of people beginning in the 1960s for cardiovascular disease and diabetes, respectively, with no premonition that they might extend lifespan.)

Testing of anti-aging interventions in humans has been so expensive and slow that we have been forced to make inferences from animal tests, supplemented by historic (human) data from drugs that happen to have a large user base going back decades. As it turns out, it is much easier to extend lifespan in worms than in mammals, and even the interventions that work in rodents don't always work in humans. Conversely, there are drugs that work in humans that don't work in mice - how are we to find them?

Just this year, a test is available that is accurate enough to measure anti-aging benefits on short time scales, without waiting for subjects to die. DNAm PhenoAge is a simple blood test developed at the lab of Steve Horvath. It determines risk of age-related mortality accurate to about 1 year of biological age. Averaging over just a hundred people pinpoints biological age with accuracy of one month. This implies that an anti-aging benefit can be detected with high reliability using a test population of just a few hundred people, followed for two years, tested at the beginning and end of this period. A study that might have required fifteen years and cost hundreds of millions of dollars can now be completed in two years at a cost of less than 1 million. When this new technology is embraced, we will have the means to separate the most effective treatment combinations from a large field of contenders.

The Mother of All Clinical Trials, Part II

Methylation isn't the only means by which gene expression is controlled - there are many others. But it is far the best-studied and, given present technology, it is the only epigenetic marker that can be routinely measured, for a few hundred dollars in a small sample of blood, urine, or nanogram-scale biopsy of other tissue. The clock was developed by Steve Horvath, and first published in 2013. He scanned the entire genome for sites that changed most with age, and varied least from one tissue type to another. In this way, he identified 353 sites, and optimized a set of 353 multipliers, such that multiplying levels of methylation at each site by each multiplier and adding the products produced a number that could be mapped onto chronological age.

Five years after Horvath's original publication, there are several other clocks based on methylation. Just this spring, Horvath has developed a new clock, not yet published, which, to my knowledge, is the best standard we have. This is the Levine/Horvath clock. It is based on 513 methylation sites and it is calibrated not to chronological age, but to a tighter measure of age-based health, derived from blood lipid profiles, inflammatory markers, insulin resistance, etc, which Horvath calls "phenotypic age". Consequently, it is less well correlated with chronological age than the original, but it is better able to predict mortality than either the classic Horvath clock or chronological age itself.

The original Horvath clock was developed by a statistical process that took into account only chronological age. But Horvath age turns out to be a better predictor than chronological age for risk of all the diseases of old age. This is powerful evidence that methylation is measuring something fundamental about the aging process. If an individual's methylation age is higher or lower than his chronologial age, the difference is a powerful predictor of his disease risk and how long he will live. This can only be true if methylation is associated with a fundamental cause of age-related decline.

How to Plan and Carry Out a Simple Self-Experiment, a Single Person Trial of a Mitochondrially Targeted Antioxidant

This lengthy post walks through the process of setting up and running a self-experiment - a trial of one - with one of the various established mitochondrially targeted antioxidant compounds. Metrics are assessed beforehand and afterwards in order to shed some light on whether or not it worked, in the sense of improving one or more measures of cardiovascular health. The outline here is informed by a recently published small human trial of MitoQ, but cutting down the assessments to those that are cost-effective, easily carried out, and available without the aid of a physician.

The purpose in publishing this outline is not to encourage people to immediately set forth to follow it. This post, like others in this series, is intended to illustrate how to think about self-experimentation in the matter of interventions that might help to improve health or turn back aspects of aging: set your constraints; identify likely approaches; do the research to fill in the necessary details; establish a plan of action; perhaps try out some parts of it in advance, such as the measurement portions, as they never quite work as expected; and most importantly identify whether or not the whole plan is worth actually trying, given all that is known of the risks involved. Ultimately that must be a personal choice.


  • Why Self-Experiment with Mitochondrially Targeted Antioxidants?
  • Caveats
  • Choosing a Mitochondrially Targeted Antioxidant
  • Establishing Dosages
  • Obtaining Mitochondrially Targeted Antioxidants
  • Storage of Mitochondrially Targeted Antioxidants
  • Validating the Purchased Mitochondrially Targeted Antioxidants
  • Ingestion Logistics
  • Establishing Tests and Measures
  • Guesstimated Costs
  • Schedule for the Self-Experiment
  • Where to Publish?

Why Self-Experiment with Mitochondrially Targeted Antioxidants?

Ordinary antioxidant supplements are thought to be, on balance, modestly harmful to long term health. They block signaling that is important to the beneficial response to exercise, for example. Mitochondrially targeted antioxidants, on the other hand, have been shown to slightly slow aging in short-lived species, and improve measures of health along the way. They also appear to be a viable treatment for some localized inflammatory conditions. The theory here is that mitochondria generate oxidative molecules in the normal course of operation that cause damage within the mitochondria themselves, and that in turn leads to dysfunctional cells in which the mitochondria produce a vastly greater amount of oxidative molecules. Delivering a constant supply of mitochondrially targeted antioxidants may either slow down the pace at which mitochondria damage themselves, or dampen the consequences of cells overtaken by damaged mitochondria, or both.

One of those consequences is the bulk export of oxidative molecules into surrounding tissues and the bloodstream, where they react with lipids. Oxidized lipids can cause further harm in all sorts of cellular processes, but of particular interest is the development of atherosclerosis. Oxidized lipids can cause inappropriate inflammatory reactions in blood vessel walls, and some forms can also cause the cells responding to that inflammation to become overwhelmed and die. This is how the fatty plaques of atherosclerosis form, then grow to weaken and narrow major blood vessels. Statin drugs, that reduce blood cholesterol, succeed in slowing atherosclerosis because they reduce the amount of oxidized lipids in the course of reducing the amount of all lipids.

Further, some degree of dysfunction in the vascular smooth muscle responsible for blood vessel contraction and dilation is thought to be caused by rising levels of oxidative stress in aging - too many dysfunctional mitochondria, too many oxidative molecules. This contributes to vascular stiffness and consequent hypertension, cardiovascular disease, and so forth. Suppressing the oxidative consequences of malfunctioning mitochondria may help here as well.

Mitochondrially targeted antioxidants don't solve the roots of these problems. At best, they somewhat compensate or attenuate ongoing mechanisms. They are cheap, however, and if they can produce effects on risk factors for cardiovascular disease that are, say, somewhere in the same order of magnitude as those achieved by statins or drugs that control blood pressure, with minimal side-effects, then they may well be worth using.


While some mitochondrially targeted antioxidants are approved by regulators, widely used, and readily available, or otherwise come with an adequate set of human data to judge risk, one must still think about personal responsibility in any self-experiment. Firstly, read the relevant papers on the mitochondrially targeted antioxidant of choice - its effects, side-effects, and dosages - and make an individual decision on risk and comfort level based on that information. This is true of any supplement, whether or not approved for use. Do not trust other opinions you might read online: go to the primary sources, the scientific papers, and read those. Understand that where the primary data is sparse, it may well be wrong or incomplete in ways that will prove harmful. Also understand that older physiologies can be frail and vulnerable in ways that do not occur in younger people and that are sometimes not well covered by the studies.

Secondly, while work on mitochondrially targeted antioxidants hasn't moved all that rapidly over the past decade, it does move. This post will become outdated in its specifics at some point, as new knowledge and new mitochondrially targeted antioxidants arrive on the scene. Nonetheless, the general outline should still be a useful basis for designing new self-experiments involving later and hopefully better compounds, as well as tests involving more logistical effort.

Lastly, obtaining and using arbitrary compounds not yet approved in your country for human use - such as SkQ1 - in the manner described here is potentially illegal: not yet being a formally registered medical treatment in all jurisdictions, it falls into a nebulous area of regulatory and prosecutorial discretion as to which of the overly broad rules and laws might apply. In effect it is illegal if one of the representatives of the powers that be chooses to say it is illegal in any specific case, and there are few good guidelines as to how those decisions will be made. The clearest of the murky dividing lines is that it is legal to sell such compounds for research use, but illegal to market and sell them for personal use in most circumstances. This is very selectively enforced, however, and reputable sellers simply declare that their products are not for personal use, while knowing full well that this is exactly what their customers are doing in many cases.

Choosing to purchase and use SkQ1 would therefore likely be a matter of civil disobedience, as is the case for anyone obtaining medicines or potential medicines outside the established national system of prescription and regulation. People are rarely prosected for doing so for personal use in the US - consider the legions of those who obtain medicines overseas for reasons of cost, despite the fact that doing so is illegal - but "rarely" is not "never." If you believe that the law is unjust, then by all means stand up against it, but accept that doing so carries the obvious risks of arrest, conviction, loss of livelihood, and all the other ways in which the cogs of modern society crush those who disagree with the powers that be.

Choosing a Mitochondrially Targeted Antioxidant

There are two mitochondrially targeted antioxidants worth considering: MitoQ and SkQ1. These have the greatest human usage and data. A third, SS-31, also has useful data, but must be injected. It may well be that one or another of these compounds is significantly better than the others (and SkQ1 would probably be the one, if so), but there is no compelling reason to pick an injected compound over one that can be taken orally for the purposes of this self-experiment. Injections require a great deal more logistical organization than simply taking a pill.

Establishing Dosages

The only definitive way to establish a dosage for a supplement pharmaceutical in order to achieve a given effect is to run a lot of tests in humans. Testing in mice can only pin down a likely starting point for experiments to determine a human dose, but the way in which you calculate that starting point is fairly well established for most cases. That established algorithm is essentially the same for most ingested and intravenously (or intraperitoneally in small animals) injected medicines, but doesn't necessarily apply to other injection routes. The relationship between different forms of injection, dosage, and effects is actually a complicated and surprisingly poorly mapped topic, and we'll set that to one side here. Some compounds - as always - are exceptions to the rule, and the only way that scientists discover that any specific compound is an exception is through testing at various doses in various species.

Fortunately, some mitochondrially targeted antioxidants do have human data, so guesstimating an initial dose based on a mouse study can be skipped. Just use the amounts from the human studies. If lacking that data, the steps to figure out a suitable starting point for a human test based on data from a mouse study are as follows: firstly read the mouse studies for the compound in question, in order to find out how much was given to the mice and for how long. Doses for most ingested pharmaceuticals of interest will usually be expressed in mg/kg. Secondly apply a standard multiplier to scale this up to human doses, which you can find in the open access paper "A simple practice guide for dose conversion between animals and human". Do not just multiply by the weight of the human in kilograms - that is not how this works. The relative surface area of the two species is the more relevant scaling parameter. Read the paper and its references in order to understand why this is the case. Again, note that the result is only a ballpark guess at a starting point in size of dose. The duration of treatment translates fairly directly, however. For the period of treatment, start with the same number of doses, spacing of doses, and duration as takes place in the animal study.


All the work is already done in this case. The 2018 MitoQ human study used a daily 20mg dose for six weeks, and that seems a good place to start.


SkQ1 is a little more challenging, in that it was initially approved by regulators for the treatment of inflammatory eye disease under the name Visomitin; most of the human data focuses on delivery via eye drop. Dosage there isn't relevant at all to the ingested pill scenario, which is still earlier in the regulatory process. So retreating to one of the mouse life span studies, we find that the daily dose of SkQ1, delivered in drinking water, was in the 0.7-1.0 μmol/kg range. Scaling this up to a 60kg human comes to 3.5-5.0 μmol per day. The study ran for more than 150 days of treatment, as it was assessing life span, but mirroring the six weeks of the MitoQ study above seems reasonable when looking for short term effects.

Visomitin eye drops come in a 5ml container, with 0.155 mcg/ml dilution. To convert between micrograms (mcg or μg) and micromoles (μmol), one needs the molecular weight of SkQ1, which is where resources such as PubChem come in handy. That gives the figure of 617.608 g/mol. Thus a daily dose of 5μmol = 0.000005 x 617.608 = 0.0031g = 3100mcg = 3.1mg. Which suggests that people buying Visomitin to put in their drinking water are wasting their time - it is intended for point administration to a very small area of the body, the eye.

Over 6 weeks of daily administration, the above means a supply of about 130mg is needed.

Verify All of the Above

Assume that anything written anywhere other than the primary materials might be incorrect or misleading. Do not take my word for any of the above information; chase down the primary sources, run the numbers, and make the judgement calls yourself.

Obtaining Mitochondrially Targeted Antioxidants


MitoQ is cheap and readily available from MitoQ Limited via any number of reputable online storefronts. It really isn't worth the effort to find another, cheaper supplier, and then be tasked with verifying the quality of the product batch. Just buy it from a store.


Given a few years, pill forms will be readily available at a useful dosage for oral ingestion. For now, however, it is a matter of finding a manufacturer or supplier in the global marketplace, and then validating the product when it arrives. For individuals without suitable connections, the easiest way to obtain compounds that are not yet mass manufactured is to order them from manufacturers in China or other overseas locations.

As noted at the outset of this post, efforts to obtain, ship, and use a compound yet to be approved for human use in your country, such as SkQ1, may be to some degree illegal - it would be an act of civil disobedience carried out because the laws regarding these matters are unjust, albeit very unevenly enforced. Many people regularly order pharmaceuticals from overseas, with and without prescriptions, for a variety of economic and medical reasons, and all of this is illegal. The usual worst outcome for individual users is intermittent confiscation of goods by customs, though in the US, the FDA is actually responsible for this enforcement rather than the customs authorities. Worse things can and have happened to individuals, however, even though enforcement is usually targeted at bigger fish, those who want to resell sizable amounts of medication on the gray market, or who are trafficking in controlled substances. While the situation with an arbitrary compound such as SkQ1 isn't the same from a regulatory perspective, there is a fair amount written on the broader topic online, and I encourage reading around the subject.

Open a Business Mailbox

A mailbox capable of receiving signature-required packages from internal shipping concerns such as DHL and Fedex will be needed. Having a business name and address is a good idea. Do not use a residential address.

Use Alibaba to Find Manufacturers

Alibaba is the primary means for non-Chinese-language purchasers to connect to Chinese manufacturers. The company has done a lot of work to incorporate automatic translation, to reduce risk, to garden a competitive bazaar, and to make the reputation of companies visible, but it is by now quite a complicated site to use. It is a culture in and of itself, with its own terms and shorthand. There are a lot of guides to Alibaba out there that certainly help, even if primarily aimed at retailers in search of a manufacturer, but many of the specific details become obsolete quickly. The Alibaba international payment systems in particular are a moving target at all times: this year's names, user interfaces, and restrictions will not be the same as next year's names, user interfaces, and restrictions.

Start by searching Alibaba for suppliers of interest. There are scores of resellers and manufacturing biotech companies in China for any even somewhat characterized supplement, pharmaceutical, or candidate pharmaceutical. Filter the list for small companies, as larger companies will tend to (a) ignore individual purchasers in search of small amounts of a compound, for all the obvious economic reasons, and (b) in any case require proof of all of the necessary importation licenses and paperwork. Shop around for prices - they may vary by an order of magnitude, and it isn't necessarily the case that very low prices indicate a scam of some sort. Some items are genuinely very cheap to obtain via some Chinese sources.

Many manufacturers will state that they require a large (often ridiculously large) minimum order; that can be ignored. Only communicate with gold badge, trade assurance suppliers with several years or more of reputation and a decent response rate. Make sure the companies exist outside Alibaba, though for many entirely reliable Chinese businesses there are often sizable differences between storefronts on Alibaba, real world presence, and the names of owners and bank accounts. Use your best judgement; it will become easier with practice.

Arrange Purchase and Shipping via Alibaba

Given the names of a few suppliers, reach out via the Alibaba messaging system and ask for a quote for a given amount of the compound in question. Buy twice what you'll think you need, as some of it will be used to validate the identity and quality of the compound batch, and buy that much from at least two different suppliers present in widely separated regions. Payment will most likely have to be carried out via a wire transfer, which in Alibaba is called telegraphic transfer (TT). Alibaba offers a series of quite slick internal payment options that can be hooked up to a credit card or bank account, but it is hit and miss whether or not those methods will be permitted for any given transaction. Asking the seller for a pro-forma invoice (PI), then heading to the bank to send a wire, and trusting to their honesty is good enough for low cost transactions. It should work just fine when dealing with companies that have a long-standing gold badge.

To enable shipping with tracking via carriers such as DHL, the preferred method of delivery for Chinese suppliers shipping to the US or Europe, you will need to provide a shipping address, email address, and phone number. Those details will find their way into spam databases if you are dealing with more than a few companies, and will be, of course, sold on by Alibaba itself as well. Expect to see an uptick of spam after dealing with suppliers via Alibaba, so consider using throwaway credentials where possible.

Chinese manufacturers active on Alibaba are familiar with international shipping practices, and smaller companies will, on their own initiative, apply whatever description to packages will most likely get it past customs. Since declared pharmaceuticals may well be taken aside and confiscated, the description will therefore not involve pharmaceuticals. This is as much motivated by dealing with customs at the Chinese end as pushing things past the US authorities; it is again a form of widespread civil disobedience that reflects a popular disdain for petty laws and regulators where they act as impediments to useful activity.

Storage of Mitochondrially Targeted Antioxidants

Both MitoQ and SkQ1 have a long shelf life of years if kept in a freezer. For more convenient use over shorter periods of time, say a few weeks to a few months, should be kept in the dark in a refrigerator for shorter periods of time. SkQ1 is less resilient than MitoQ and will degrade after few weeks at room temperature.

Validating the Purchased Mitochondrially Targeted Antioxidants

While it is reasonable to trust MitoQ Limited to deliver what was ordered, that may not be the case for other sources. A compound may have been ordered, but that doesn't mean that what turns up at the door is either the right nondescript powder or free from impurities or otherwise of good quality. Even when not ordering from distant, infrequent suppliers, regular testing of batches is good practice in any industry. How to determine whether a compound is what it says it is? Run the compound through a process of liquid chromatography and mass spectrometry, and compare the results against the standard data for a high purity sample of that compound. Or rather pay a small lab company to do that.

Obtain the Necessary Equipment

Since this process will involve weighing, dividing up, and shipping powders in milligram amounts, a few items will be necessary: spatulas or scoops for small amounts of a substance; a reliable jeweler's scale such as the Gemini-20; sealable vials; small ziplock bags; labels; and shipping and packing materials. All of these are easily purchased online. The recommended shipping protocol is to triple wrap: a labelled vial, secured within a ziplock bag and tape, and then enclosed within a padded envelope.

Use Science Exchange to Find Lab Companies

Science Exchange is a fairly robust way to identify providers of specific lab services, request quotes, and make payments. Here again, pick a small lab company to work with after searching for LC-MS (liquid chromatography and mass spectrometry) services. Large companies will want all of the boilerplate registrations and legalities dotted and crossed, and are generally a pain to deal with in most other ways as well. Companies registered with Science Exchange largely don't provide their rates without some discussion, but a little over 100 per sample is a fair price for LC-MS to check the identity and purity of the compound.

Work with the Company to Arrange the Service

The process of request, bid, acceptance, and payment is managed through the Science Exchange website, with questions and answers posted to a discussion board for the task. Certainly ask if you have questions; most providers are happy to answer questions for someone less familiar with the technologies used. Service providers will typically want a description of the compounds to be tested and their standard data sheets, as a matter of best practice and safety. It is good enough to provide the name for established pharmaceuticals, as the data sheets, mass spectrometry profiles, and other detailed information are freely available online from databases such as DrugBank.

Ship the Samples

Measure out a small amount (1mg is more than enough) from each separate order as a distinct sample, label it carefully, make sure you have a record linking the sample label to the specific supplier, and package it up. More in the sample is better than less, as several attempts might be needed to get a good result out of the machines used, but each attempt really only needs a very tiny amount of the compound. Ship the sample via a carrier service such as DHL, UPS, or FedEx. Some LC-MS service companies may provide shipping instructions or recommendations. These are usually some variety of common sense: add a description and invoice to the package; reference the order ID, sender, and receiver; clearly label sample containers; and package defensively with three layers of packing; and so forth.

Examine the Results

Once the LC-MS process runs, the lab company should provide a short summary regarding whether or not the compound is in fact the correct one and numbers for the estimated purity. Also provided are the mass spectra, which can be compared with the standard spectra for the compound, which can be found at DrugBank or other sources online.

Ingestion Logistics

MitoQ comes prepackaged in a convenient pill form, so there is no need to do any additional work here. Just take the pills in the appropriate amount. If ordered from a source other than MitoQ Limited, it may arrive dissolved in an ethanol solution, or as a solid. Similarly, an order of SkQ1 will arrive as a tiny amount of powder that needs to be dissolved in solution in order to be ingested, however. Neither MitoQ nor SkQ1 is soluable in water. In dry form they should be dissolved in a minimal amount of ethanol or dimethyl sulfoxide (DMSO) - very little is needed, and can be applied gradually with a dropper. Then pour the resulting solution into a glass of water and drink it. This will roughly replicate the delivery mode used in many of the animal studies.

Establishing Tests and Measures

The objective here is a set of tests that (a) match up to the expected outcome based on human trials of mitochondrially targeted antioxidants, and (b) that anyone can run without the need to involve a physician, as that always adds significant time and expense. These tests are focused on the cardiovascular system, particularly measures influenced by vascular stiffness, and some consideration given to parameters relevant to oxidative stress and the development of atherosclerosis.

  • A standard blood test, with inflammatory markers.
  • An oxidized LDL cholesterol assessment.
  • Resting heart rate and blood pressure.
  • Heart rate variability.
  • Pulse wave velocity.
  • Biological age assessment via DNA methylation patterns.

The cardiovascular health measures in that list are those that are impacted by changes in the elasticity or functional capacity of blood vessels, such as would be expected to occur to some degree in a treatment that compensated in some way for the effects of aging on the smooth muscule cells in blood vessel walls - as is thought to be the case for mitochondrially targeted antioxidants. Positive change of the average values in most of these metrics are achievable with significant time and effort spent in physical training, so movement in the numbers in a short period of time as the result of a treatment should be an interesting data point.


There exist online services such as WellnessFX where one can order up a blood test and then head off the next day to have it carried out by one of the widely available clinical service companies. Of the set of test packages offered by WellnessFX, the Baseline is probably all that is needed for present purposes. But shop around; this isn't the only provider.

Oxidized LDL Cholesterol

The more mainstream blood test services such as WellnessFX don't offer as wide a range of testing as some of the specialists. For example, the Life Extension Foundation maintains a blood test service that includes a test for oxidized LDL cholesterol. Again, shop around. There are others.

Resting Heart Rate and Blood Pressure

A simple but reliable tool such as the Omron 10 is all you need to measure heart rate and blood pressure. It is worth noting here a couple of general principles for cardiovascular measures. Firstly, the further away from the center of the body that the measurement is taken, the less reliable it is - the more influenced by any number of circumstances, such as position, mood, stress, time of day, and so forth. Fingertip devices are convenient, but nowhere near as useful as something like the Omron 10 that uses pressure on the upper arm. Secondly, all of the above-mentioned line items also influence every cardiovascular measure, so when you are creating a baseline or measuring changes against that baseline, carry out each measure in the same position, at the same time of day, and make multiple measurements over a week to gain a more accurate view of the state of your physiology. The Omron 10 is solid: it just works, and seems quite reliable.

Heart Rate Variability

Surprisingly few of the numerous consumer tools for measuring heart rate variability actually deliver the underlying values used in research papers rather than some form of aggregate rating derived by the vendor; the former is required for any serious testing, and the latter is useless. Caveat emptor, and read the reviews carefully. As an alternative to consumer products, some of the regulated medical devices are quite easy to manage, but good luck in navigating the system to obtain one. The easiest way is to buy second hand medical devices via one of the major marketplaces open to resellers, but that requires a fair-sized investment in time and effort - which comes back to the rule about keeping things simple at the outset.

After some reading around the subject, I settled on the combination of the Polar H10 device coupled with the SelfLoops HRV Android application. I also gave the EliteHRV application a try. Despite the many recommendations for Polar equipment, I could not convince either setup to produce sensible numbers for heart rate variability data: all I obtained during increasingly careful and controlled testing was a very noisy set of clearly unrealistic results, nowhere near the values reported in papers on the subject. However, plenty of people in the quantified self community claim that these systems work reasonably well, so perhaps others will have better luck than I. Take my experience as a caution, and compare data against that reported in the literature before investing a lot of time in measurement.

Pulse Wave Velocity

For pulse wave velocity, choice in consumer tools is considerably more limited than the sitation for pulse wave velocity. Again, carefully note whether or not a device and matching application will deliver the actual underlying data used in research papers rather than a made-up vendor aggregate rating. I was reduced to trying a fingertip device, the iHeart, picked as being more reliable and easier to use than the line of scales that measure pulse wave velocity. Numerous sources suggest that decently reliable pulse wave velocity data from non-invasive devices is only going to be obtained by measures at the aorta and other core locations, or when using more complicated regulated medical devices that use cuffs and sensors at several places on the body.

Still, less reliable data can be smoothed out to some degree by taking the average of measures over time, and being consistent about position, finger used for a fingertip device, time of day, and so forth when the measurement is taken. It is fairly easy to demonstrate the degree to which these items can vary the output - just use the fingertip device on different fingers in succession and observe the result. All of this is a trade-off. A good approach is to take two measures at one time, using the same finger of left and right hand, as a way to demonstrate consistency. While testing an iHeart device in this way, I did indeed manage to obtain consistent and sensible data, though there is a large variation from day to day even when striving to keep as many of the variables as consistent as possible. That large variation means that only sizable effects could be detected.

DNA Methylation

DNA methylation tests can be ordered from either Osiris Green or Epimorphy / Zymo Research - note that it takes a fair few weeks for delivery in the latter case. From talking to people at the two companis, the normal level of variability for repeat tests from the same sample is something like 1.7 years for the Zymo Research test and 4.8 years for the Osiris Green tests. The level of day to day or intraday variation between different samples from the same individual remains more of a question mark at this point in time, though I am told they are very consistent over measures separated by months. Nonetheless, as for the cardiovascular measures, it is wise to try to make everything as similar as possible when taking the test before and after a treatment: time of day, recency of eating or exercise, recent diet, and so forth.

An Example Set of Daily Measures

An example of one approach to the daily cardiovascular measures is as follows, adding extra measures as a way to demonstrate the level of consistency in the tools:

  • Put on the Polar H10; this is involved enough to increase heart rate a little for a short period of time, so get it out of the way first.
  • Sit down in a comfortable position and relax for a few minutes.
  • Measure blood pressure and pulse on the left arm using the Omron 10.
  • Measure blood pressure and pulse on the right arm using the Omron 10.
  • Measure pulse wave velocity on the left index fingertip over a 30 second period using the iHeart system.
  • Measure pulse wave velocity on the right index fingertip over a 30 second period using the iHeart system.
  • Measure heart rate variability for a ten minute period using the Polar 10 and Selfloops.

Consistency is Very Important

Over the course of an experiment, from first measurement to last measurement, it is important to maintain a consistent weight, diet, and level of exercise. Sizable changes in lifestyle can produce results that may well prevent the detection of any outcome using the simple tests outlined here. Further, when taking any measurement, be consistent in time of day, distance in time from last exercise or meal, and position of the body. Experimentation with measurement devices will quickly demonstrate just how great an impact these line items can have.

Guesstimated Costs

The costs given here are rounded up for the sake of convenience, and in some cases are blurred median values standing in for the range of observed prices in the wild.

  • Business mailbox, such as from UPS: 250 / year
  • Baseline tests from WellnessFX: 220 / test
  • Oxidized LDL test from LEF: 170 / test
  • MyDNAage kits: 310 / kit
  • Osiris Green sample kits: 70 / kit
  • Omron 10 blood pressure monitor: 80
  • Polar H10 heart monitor: 100
  • iHeart monitor: 210
  • American Weigh Gemini-20 microscale: 90
  • Miscellenous equipment: spatulas, labels, vials, pill capsules, etc: 60
  • SkQ1 via Alibaba: 200
  • A bottle of dimethyl sulfoxide (DMSO): 20
  • MitoQ capsules from MitoQ Limited: 190
  • Shipping and LC-MS analysis of samples: 120 / sample

Schedule for the Self-Experiment

One might expect the process of discovery, reading around the topic, ordering materials, and validating the pharmaceuticals to take a couple of months. Once all of the decisions are made and the materials are in hand, pick a start date. The schedule for the self-experiment is as follows:

  • Day 1-10: Once or twice a day, take measures for blood pressure, pulse wave velocity, and heart rate variability.
  • Day 10: Bloodwork and DNA methylation test.
  • Day 11: Start on the six week program of daily doses.
  • Day 53-62: Repeat the blood pressure, pulse wave velocity, and heart rate variability measures.
  • Day 62: Repeat the bloodwork and DNA methylation test.

Where to Publish?

If you run a self-experiment and keep the results to yourself, then you helped only yourself. The true benefit of rational, considered self-experimentation only begins to emerge when many members of community share their data, to an extent that can help to inform formal trials and direction of research and development. There are numerous communities of people whose members self-experiment with various compounds and interventions, with varying degrees of rigor. One can be found at the LongeCity forums, for example, and that is a fair place to post the details and results of a personal trial. Equally if you run your own website or blog, why not there?

When publishing, include all of the measured data, the compounds and doses taken, duration of treatment, and age, weight, and gender. Fuzzing age to a less distinct five year range (e.g. late 40s, early 50s) is fine. If you wish to publish anonymously, it should be fairly safe to do so, as none of that data can be traced back to you without access to the bloodwork provider. None of the usual suspects will be interested in going that far. Negative results are just as important as positive results. For example, given the measures proposed in this post it is entirely plausible that positive changes in a basically healthy late 40s or early 50s individual will be too small to identify - they will be within the same range as random noise and measurement error. Data that confirms this expectation is still important and useful for the community, as it will help to steer future, better efforts.

Gene Therapy to Enhance Proteosomal Activity Slows Retinal Degeneration in Mice

Many of the methods by which aging can be modestly slowed in laboratory species are characterized by increased cellular housekeeping: more repair, more clearance of broken molecular machinery, more removal of metabolic waste. The extended life span produced by calorie restriction appears to depend on this increase: it doesn't happen in mice in which housekeeping processes are disabled. Most of the work on cellular housekeeping in aging is focused on autophagy, responsible for removing protein aggregates and cellular structures. The proteasome is a part of a separate system of housekeeping that deals with broken or otherwise unwanted proteins. (Though it can be debated as to just how separate these two systems actually are in practice - everything inside a cell connects to everything else in some way).

With this in mind, I'll point out a paper that caught my eye today, in which researchers genetically enhance proteasomal activity in a mouse model of retinal degeneration. They show that the mice are better able to resist the loss of retinal cells: the cells are more robust in the face of damaged and harmful proteins that accumulate either with age or because of inherited mutations that disrupt correct cellular function. This is more interesting for the demonstration of the possibility rather than the results in this particular case. Absent side-effects, permanently improved cellular housekeeping would be a desirable enhancement technology, something that might reproduce many of the long-term health benefits of calorie restriction and exercise.

The work in this paper for the proteasome is analogous to the LAMP2A gene therapy used in mice to enhance autophagy in the liver some years ago. That slowed the impact of aging on tissue function by making cells more resilient and capable of carrying out their assigned tasks. Both that and this proteasomal enhancement involve increasing the production of one of the component parts of the housekeeping system, and that is apparently enough to boost overall activity and efficiency. All forms of cellular housekeeping decline with age, an outcome that is caused by fundamental forms of damage, such as the buildup of forms of metabolic waste that our biochemistry cannot effectively break down. Enhancing housekeeping operations without dealing with that damage is essentially compensatory, an approach of limited effectiveness, given that the damage remains to cause all of its other consequences. It may still be cost-effective enough to pursue, provided it isn't pursued to the exclusion of addressing the underlying cell and tissue damage that causes aging and all of its issues.

Strategy prevents blindness in mice with retinal degeneration

More than 2 million people worldwide live with inherited and untreatable retinal conditions, including retinitis pigmentosa, which slowly erodes vision. Developing treatments is challenging for scientists, as these conditions are caused by more than 4,000 different gene mutations. But many of these mutations have something in common - a propensity for creating misfolded proteins that cells in the eye can't process. These proteins build up inside cells, killing them from the inside out.

Now scientists have shown that boosting the cells' ability to process misfolded proteins could keep them from aggregating inside the cell. The researchers devised and tested the strategy in mice, significantly delaying the onset of blindness. Their approach potentially could be used to prevent cell death in other neurodegenerative diseases, such as Huntington's, Parkinson's and Alzheimer's.

The researchers focused on the proteasome: machinery inside all cells that eliminates misfolded proteins. You can compare the barrel-shaped structure to a paper shredder, with the cutting elements hidden inside. Misfolded proteins must pass through a "lid" on the shredder to be processed, but cells in diseased mice do not have enough lids, enabling the buildup of the damaged proteins. Instead of trying to alter the shredders, researchers genetically increased the quantities of lids for the shredders, allowing cells to process more misfolded proteins. In trials, mice with added proteasome lids retained four times the number of functional retinal cells by adulthood than mice with the same form of retinitis pigmentosa, which went blind as adults.

Increased proteasomal activity supports photoreceptor survival in inherited retinal degeneration

Studies of animal models of retinitis pigmentosa (RP) have revealed a number of common pathological conditions: oxidative stress, unfolded protein response, retinoid cytotoxicity, iron toxicity, and aberrant phototransduction. Our recent work demonstrated that another major cellular stress factor prevalent in a broad spectrum of mouse RP models is the insufficient capacity of the ubiquitin-proteasome system to process misfolded or mistargeted proteins in affected cells. We further demonstrated that the severity of photoreceptor retinal degeneration correlates with the degree of misfolded protein production. Conversely, genetic manipulation reducing the proteolytic capacity of proteasomes evoked RP-like pathology in otherwise normal retinas.

The goal of the present study was to determine whether survival of degenerating photoreceptors could be supported by enhancing the proteolytic capacity of their proteasomes. We aimed to increase the proteasome activity in these cells using two independent genetic strategies and found that the strongest effect was achieved by overexpressing the PA28α subunit of the 11S proteasome cap. We also show that the underlying mechanism is based primarily on the stimulation of ubiquitin-independent protein degradation. Breeding PA28α-overexpressing mice with two mouse models of photoreceptor degeneration results in a delay of disease progression.

Higher Levels of Progerin are Found in Cardiomyopathy Patients

Hutchinson-Gilford progeria syndrome (HGPS), or simply progeria, is a rare genetic condition that presents the superficial appearance of greatly accelerated aging. It isn't in fact accelerated aging, but rather one specific form of molecular damage run amok, causing severe and increasing dysfunction in near all cells. Normal aging is a collection of many varied forms of molecular damage that eventually cause severe and increasing dysfunction in near all cells. The consequences of a failure of any given population of cells or an organ to function correctly can appear superficially similar even if the causes are not the same, but as soon as one digs in to the details, the different mechanisms become evidence and significant.

Soon after the turn of the century, the cause of progeria was identified: a mutation in the LMNA gene that gives rise to a broken protein now called progerin. The normal, unbroken form of this protein, lamin A, is a vital part of the internal structure of a cell, and once once that structural support falters, all of the other finely balanced mechanisms begin to fail as well. Soon thereafter, it was discovered that progerin can also be found in small amounts in older genetically normal individuals, and for many years it has been an open question as to whether progerin plays a significant role in the degeneration of normal aging. Given that it exists, it is certainly causing harm, but the size of the effect is key: there are plenty of areas in the biochemistry of aging where it might be argued that observed forms of damage and change do not rise to the level of being significant causes of dysfunction, disease, and mortality. We can worry about them after every other problem is fixed.

The paper here identifies a patient group suffering from an age-related disease in which progerin is elevated in comparison to their healthier peers. This is an intriguing addition to what is known of progerin in normal aging. It is still a long way from being able to assign numbers to the position of progerin in a hierarchy of cell damage, especially given that the research community has yet to achieve this for any of the other root causes of aging, but it is a small step along that road. It also suggests that a more careful survey of age-related disease might turn up other conditions in which progerin may be either a contributing factor, or a consequence of other disease processes.

Upregulation of the aging related LMNA splice variant progerin in dilated cardiomyopathy

Age is a major cardiovascular risk factor including cardiovascular disease. Therefore, elucidating aging-related processes might lead to the identification of novel treatment options for heart failure, which has a prevalence of 1-2% in the adult population in developed countries and is a growing health care problem worldwide. Premature aging-like syndromes like Hutchinson-Gilford progeria syndrome (HGPS) have been investigated to achieve a better understanding of pathophysiological aging processes. HGPS is based on mutations affecting the proper encoding and further processing of lamin A an important protein in the nucleus of eukaryotic cells resulting in misprocessed lamin A (progerin) which also plays an important role in normal ageing.

Lamin A is an intermediate filament protein which is involved in forming a filamentous meshwork between the chromatin and the nuclear membrane. It is very important to keep the nuclear envelope upright regulating important processes like DNA replication, DNA repair, and RNA transcription. In 90% of the cases in HGPS a point mutation in the LMNA A gene results in the production of a truncated prelamin A protein, also called progerin. Consequently, the protein cannot be processed to functional lamin A, causing structural and functional nuclear abnormalities.

With time proceeding progerin accumulates in the nucleus and not only alters the structure of the nuclear lamina but also negatively influences the stiffness and mechanochemical properties of the nucleus. Patients with HGPS develop severe cardiovascular morbidities like atherosclerosis and heart failure and die as teenagers due to stroke or myocardial infarction. Toward the end of life HGPS patients suffer from cardiomegaly and cardiac dilatation. It has been shown that low levels of progerin are expressed in non HGPS-cells and that a positive correlation exists between accumulation of progerin in the nucleus and the process of ageing. However, the role of progerin in human dilated cardiomyopathy (DCM), a major reason of severe heart failure, has never been investigated so far.

Here we provide first experimental evidence that progerin, associated with premature aging in HGPS is upregulated in human DCM. Progerin mRNA expression in the heart was strongly significantly correlated with left ventricular remodeling. Although there was a weak positive correlation between age and progerin mRNA expression, statistical testing revealed no significant differences. These data suggest that not the age of the heart per se but rather the process of "myocardial aging" defined by a progressive deterioration in cellular and organ function with time is associated with increased levels of progerin mRNA.

It is known that prelamin A accumulation plays a key role in aging in several tissues, including the vasculature and is discussed as a marker for vascular aging. However, it is currently unknown whether this is relevant in myocardial aging, too. Since LMNA gene mutations are causally involved in patients with idiopathic dilated cardiomyopathy (3.6%) and familial dilated cardiomyopathy (7.5%), we hypothesized that accumulation of progerin in non-HGPS individuals in the heart may as well be involved in the progression of DCM. To our knowledge we show for the first time that progerin is upregulated in human DCM hearts suggesting that accumulation of progerin (prelamin A) could be involved in the progression of DCM and myocardial aging.

Fasting Reverses Age-Related Decline in Regenerative Capacity of Intestinal Stem Cells

Today I'll point out a demonstration of one of the many ways in which calorie restriction and fasting improve matters in our biology, in this case via improved stem cell function. As always it is worth bearing in mind that while forms of calorie restriction produce useful short term and long term healthy benefits in humans, they don't have anywhere near the same size of effect on life span as occurs in short-lived species such as mice. We didn't evolve to react as strongly to famines, as famines are typically a much shorter fraction of our life span in comparison to that of a mouse.

Stem cell populations, of different types for each variety of tissue in the body, support surrounding tissue by providing a supply of daughter somatic cells. As aging progresses, stem cell populations become ever less active, and this supply diminishes. Tissue function falters and eventually fails as a consequence. The evidence to date suggests that this decline is at least as much an evolved reaction to the state of damage in the body as it is dysfunction in the stem cells themselves. Numerous demonstrations show that, placed into a less damaged environment, old stem cells are just as active as young stem cells. Other lines of research have delivered signal molecules to induce old stem cells into greater activity in situ.

Is this safe? The consensus on why stem cell activity declines with age is that it balances mortality due to cancer versus mortality due to failing tissue function. Stem cells in old individuals do accumulate mutations and other forms of damage, while at the same time rising levels of inflammation and incapacity of the immune system lead to an environment that favors the development of cancer. Thus unrestricted cellular replication should have a higher risk of cancer. Evolutionary pressures have led our species to a long life span among mammals, but at the cost of a slow functional decline in later life.

Conversely, consider what has been discovered and achieved in the field of regenerative medicine: all sorts of methodologies to achieve enhanced stem cell activity. Consider the mice genetically engineered for greater levels of telomerase, in which their enhanced life span is probably mediated by increased levels of stem cell activity and tissue maintenance. The evolutionary balance appears to have a fair degree of wiggle room in which it is possible to build therapies to increase tissue maintenance without also needing to first repair the stem cells involved. The research community should still be aiming to repair and replace stem cell populations, of course - diminished numbers and cell damage become significant and problematic in very late life. This is a part of the SENS rejuvenation research agenda that, despite the high levels of funding and activity in the stem cell research community, hasn't yet made anywhere near enough material progress.

Fasting boosts stem cells' regenerative capacity

As people age, their intestinal stem cells begin to lose their ability to regenerate. These stem cells are the source for all new intestinal cells, so this decline can make it more difficult to recover from gastrointestinal infections or other conditions that affect the intestine. This age-related loss of stem cell function can be reversed by a 24-hour fast, according to a new study. The researchers found that fasting dramatically improves stem cells' ability to regenerate, in both aged and young mice.

Intestinal stem cells are responsible for maintaining the lining of the intestine, which typically renews itself every five days. When an injury or infection occurs, stem cells are key to repairing any damage. As people age, the regenerative abilities of these intestinal stem cells decline, so it takes longer for the intestine to recover. After mice fasted for 24 hours, the researchers removed intestinal stem cells and grew them in a culture dish, allowing them to determine whether the cells can give rise to "mini-intestines" known as organoids. The researchers found that stem cells from the fasting mice doubled their regenerative capacity.

Further studies, including sequencing the messenger RNA of stem cells from the mice that fasted, revealed that fasting induces cells to switch from their usual metabolism, which burns carbohydrates such as sugars, to metabolizing fatty acids. This switch occurs through the activation of transcription factors called PPARs, which turn on many genes that are involved in metabolizing fatty acids. The researchers found that if they turned off this pathway, fasting could no longer boost regeneration. They now plan to study how this metabolic switch provokes stem cells to enhance their regenerative abilities. They also found that they could reproduce the beneficial effects of fasting by treating mice with a molecule that mimics the effects of PPARs.

Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging

Acute fasting regimens have pro-longevity and regenerative effects in diverse species, and they may represent a dietary approach to enhance aged stem cell activity in tissues. Aging in lower organisms and mammals results in the attrition of stem cell numbers, function, or both in a myriad of tissues. Such age-related changes in stem cells are proposed to underlie some of the untoward consequences of organismal aging.

It has long been appreciated that fasting has a profound impact on aging and tissue homeostasis. Our data illustrate that a 24-hr fast augments intestinal stem cell (ISC) function through the activation of fatty acid oxidation (FAO), which subsequently improves ISC activity in young and aged mice. Fasting increases FAO in ISCs by driving both a robust PPAR-mediated FAO program in ISCs and by increasing circulating levels of triglycerides and free fatty acids (FFAs) that can be then used by cells to generate acetyl-CoA for energy. Although FAO is critical for tissues with high-energy needs like skeletal and cardiac muscle, little is known about the role of FAO in ISC biology. An important question is how does increased FAO boost ISC function.

Our data indicate that aged ISCs have a reduced capacity to utilize lipids for FAO. Consistent with this notion, aging has been associated with impaired mitochondrial metabolism and FAO in a number of tissues. Because the addition of palmitic acid (PA) or induction of FAO with PPAR-delta agonists largely restores aged ISC function in our organoid assay, one possibility is that ISCs rely on FAO and a shortage in cellular energy hampers old ISC activity.

Leonard Hayflick is not in Favor of Greatly Extending Healthy Human Life Spans

This is very old news for anyone who participates in the aging research community, but a significant fraction of the leading researchers of recent generations are either not interested in or actively opposed to efforts to extend human life. Leonard Hayflick, for whom the Hayflick limit is named, is in this camp. This is one of the contributing factors in the story of how research and funding institutions spent decades working to suppress any inclination among their members to try to treat aging as a medical condition. It is arguably the case that we could be much further ahead than we are today on the road to human rejuvenation - even given the lesser technological capabilities twenty and thirty years ago, meaningful progress towards, for example, senolytic drugs might have been made in a world in which treating aging was considered seriously by those who steered research strategy.

The potential for undying tyrants or tyrannical bodies is one reason Leonard Hayflick, one of the world's preeminent experts on aging, is against slowing down or eliminating the aging process. He has other reasons, too. "To slow, or even arrest, the aging process in humans is fraught with serious problems in the relationships of humans to each other and to all of our institutions. By allowing antisocial people - tyrants, dictators, mass murderers, and people who cause wars - to have their longevity increased should be undesirable ... I would rather experience the aging process as it occurs, and death when it occurs, in order to avoid allowing the people who I just described to live longer."

Despite his reservations about radical life extension, Hayflick is a big proponent of studying aging at a more fundamental level. "Most studies are either descriptive, studies on longevity determinants, or studies on age-associated diseases. None of this research will reveal information about the fundamental biology of aging. Less than 3 percent of the budget of the National Institute on Aging in the past decade or more has been spent on research on the fundamental biology of aging." He's a bit annoyed, for instance, that about a half of the National Institute on Aging's budget goes toward researching Alzheimer's disease. "The resolution of Alzheimer's disease as a cause of death will add about 19 days onto human life expectancy. I have suggested that the name of the institute be changed to the National Institute on Alzheimer's Disease. Not that I support ending research on Alzheimer's disease, I do not, but the study of Alzheimer's Disease and even its resolution will tell us nothing about the fundamental biology of aging."

Hayflick also has some advice on what we should teach scientists and the public about aging. "That education must include an understanding that the massive amount of research funds spent on studying the leading causes of death will not advance our understanding of the basic biology of aging. It also must include an understanding that the study of longevity determinants (anabolic processes) will not reveal information about the basic biology of aging (catabolic processes). Finally, we need to educate scientists and the public, to support research on the differences between young cells and old cells that make the latter more vulnerable to age-associated diseases."

Aubrey de Grey in Fine Form on the Ethical Imperative to Defeat Aging

Aubrey de Grey, cofounder of the Methuselah Foundation and SENS Research Foundation, has little patience for those people who persist in clinging to the idea that it is in any way acceptable to let the death and suffering caused by aging continue. If we lived in a world in which there was nothing we could do, then perhaps accepting aging would be the sensible thing to do. But we do not. We live in a world in which the first rejuvenation therapies capable of reversing a root cause of aging, the accumulation of senescent cells, are entering human trials. Numerous other classes of potential rejuvenation therapy are well described, well understood, and only lacking sufficient financial support to move forward at the same pace. Aging and all of its consequences can be brought under medical control: all that is needed is the will and the funding to move ahead and get the job done.

Having publicly declared that the first person to live for more than a millennium is likely alive today, de Grey has dedicated large amounts of energy and time to the pursuit of medical technology which may one day allow humans to live indefinitely. Having graduated with a degree in computer science in 1985, de Grey switched fields in his late twenties upon discovering "the horrifying fact that most people, and indeed most biologists, viewed ageing as not very important or interesting." He appears both astonished and disgusted that the world pays so little attention to ageing, the one malady which affects us all.

De Grey defines ageing as "the collection of types of damage that the body does to itself throughout life as consequences of its normal operation." His major breakthrough came through the realisation that rather than attempting to delay the damage inflicted by ageing, as was the established practice, gerontologists could do better by repairing this damage after it has occurred. This idea, though "counterintuitive" to many of his colleagues, has now become "totally mainstream" in the field, and forms the basis of the Strategies for Engineered Negligible Senescence (SENS) Research Foundation which de Grey co-founded in 2009.

Speaking of the work taking place at SENS, and around the world, de Grey proudly declares that there have been "huge advances" in implementing his theory of damage repair. "Among the most high-profile is the ability to remove senescent cells using certain drugs, but there's a lot more that is more esoteric, such as making backup copies of the mitochondrial DNA in the nucleus and introducing bacterial enzymes to eliminate otherwise indigestible waste products." Asked about the biggest barriers currently facing progress, de Grey replies: "Money, money and money." He blames the field's financial struggles on "the desperation that almost all people have to put ageing out of their minds and pretend that it is some kind of blessing in disguise, so that they can get on with their miserably short lives without being preoccupied by the terrible thing that awaits them." According to de Grey, this attitude is "psychologically understandable but morally inexcusable".

De Grey rejects criticism of his field as "unnatural", citing this challenge as another "great example of the desperation of so many people to switch off their brains when confronted with the need to discuss the defeat of ageing." Towards those who make the "unnatural" claim, de Grey is both indignant and dismissive: "It takes about ten IQ points and ten milliseconds to notice that the whole of technology is 'unnatural' - including, of course, the whole of medicine - endeavours that those who voice this objection do not tend to oppose."

Morally, de Grey does not have any doubts about the quest to extend life: "For something to be an ethical issue it has to be a meaningful dilemma and in order to make that case one must make the case either that people who were born a long time ago have less entitlement to health, as a human right, than younger people, or that health itself is a lesser human right than other things that might end up being mutually exclusive with it, like parenthood. Once one focuses on the fact that this is just medicine, that any longevity effects would be just side-effects of health, the 'ethics' of the matter rather rapidly vaporises."

An Interview on Mitochondrial Damage and Dysfunction in Aging

In this interesting interview, the topic is mitochondria and their role in aging. Mitochondria are the power plants of the cell, descendants of ancient symbiotic bacteria that still contain a small genome left over from that origin. Small it might be, but it is significant: stochastic damage to mitochondrial DNA (mtDNA) is one of the root causes of aging. Through a complex chain of events, this results a small but significant fraction of cells overtaken by mutant mitochondria and made to export harmful levels of oxidative molecules into surrounding tissues. This, to pick one example, produces oxidized lipids in the bloodstream that irritate blood vessel walls to start the inflammatory cascade that results in atherosclerosis. Quite aside from this process, however, mitochondria also undergo a general decline with advancing age, changing in many ways, and failing to keep up with their primary task of energy store production. This may be a reaction to other forms of damage in the tissue environment, and is particularly problematic in energy-hungry tissues like the brain and muscles.

Mitochondria, first and foremost, are these double membrane bound organelles that are in, essentially, all cells in your body. What makes them particularly interesting is that there are hundreds to thousands of them in each cell. The mitochondria produce the bulk of the ATP that you use every day, ATP is the energy currency of the cell. The other critical thing about mitochondria, is they have their own genome. You have your nuclear genome, where you got one copy from your mother, one from your father, but with respect to mitochondrial genomes, you have hundreds to thousands of them. Those are distributed among these organelles floating in the cytoplasm.

A final feature of mitochondria that turns out to be very important, they're not just static structures that sit in the cytoplasm like parked cars. They actually fuse with each other and then share contents and then they can also break apart, undergo fission. The sharing of components allows cells to, often times, maximize the amount of ATP that they want to produce. This turns out to have important consequences because it also does something else that's not so good, that defeats the ability to identify mitochondria containing mitochondrial DNA that is in some way mutant.

The way to think about this is the idea of quality control. The question is, mitochondria are always being generated, they have to work very hard, they create a lot of free radicals, a lot of damaging small molecules, and eventually they get turned over. So, even in non-dividing cells like muscle and neurons in your brain, the mitochondria are always being generated and then always being destroyed. That's important, because if you didn't get rid of these damaged mitochondria they would accumulate, and your cells wouldn't survive that, because they would lose the ability to generate energy.

The key issue with respect to quality control and mtDNA, and the fact that there are many mitochondria, or many mitochondrial genomes per cell, is that quality control may take a backseat, often times, to meeting more immediate cellular needs, like maximizing ATP production. Which is fine when you're young, but as you get older, and as that damage starts to accumulate, then you would really like it if quality control could kick in and do a bit of housecleaning.

We should think of mitochondrial DNA in a way, perhaps, still having its own selfish interests, left over from symbiosis. Because there is constant turnover, the mitochondria in you today aren't necessarily the ones that make you the most fit as an individual. They're the ones that survive this intracellular competition with other mitochondria and other mitochondrial genomes, the ones that have found a way to increase in frequency. The reason this relates to aging is that it turns out, as we age, we accumulate mutant mitochondrial DNA, such that, at some point, cells have so much mutant mtDNA that they either die or become otherwise dysfunctional. That leads to loss of function in critical tissues like heart, muscle, and the nervous system.

A very interesting question that we don't know the answer to is to figure out how it is that mutant genomes, in particular, deleterious genomes, seem to preferentially get amplified. There seems to be something a little bit haywire in cells, often, such that the quality control machinery, while it may exist, it doesn't get rid of the bad mitochondria with their mutant genomes. Those genomes have instead, found some way to increase in frequency and that then leads to a problem with aging.

Reduced Expression of Antimicrobial Peptide Genes Partially Determines the Temperature-Lifespan Relationship in Flies

Short-lived species have a much greater plasticity of life span in response to environmental circumstances than is the case for long-lived species such as our own. Among the most important factors are calorie intake and temperature of the surrounding environment. Both produce sweeping changes in metabolism, and are thus challenging to investigate. Nonetheless, researchers here appear to have identified one of the drivers of the relationship between temperature and lifespan in flies, centered around a portion of the innate immune system that may have multiple roles in the regulation of metabolism.

Fruit flies, which are ectothermic animals, can live more than twice as long at 18°C than at 25°C. Even though it has been thought that this enhanced longevity at a lower temperature (18°C) is caused by a change of metabolic rate, the mechanisms that regulate longevity by ambient temperature are poorly understood. Previously, we found that development at 18°C significantly enhances stress resistance of adult flies with more accumulation of nutrients (especially fat) in the body than development at 25°C. This enhanced resistance to stress was similarly observed in both sexes and sustained up to 30 days after hatching of the adult flies indicating that development at a lower temperature, 18°C, significantly enhances the mechanism(s) of stress resistance.

Higher stress resistance and/or fat accumulation are frequently found in long-lived flies such as mutants of the IGF (insulin/insulin-like growth factor) signaling pathway. From tests of representative stress-related genes, we showed that the development at a lower temperature (18°C) downregulates antimicrobial peptide genes, AttA and DptB, of the Immune deficiency (Imd) pathway. The Imd pathway is known to regulate innate immune responses in Drosophila, and the Imd protein activates two downstream branches which are subsequently responsible for the upregulation of stress tolerance and antimicrobial peptide genes.

The roles of the Imd pathway have been well studied in a humoral response against intruders, which is characterized by the secretion of antimicrobial peptides (AMPs) into the hemolymph. However, whether the Imd pathway is involved in a longevity mechanism has not been reported. Using hypomorphic imd and AttC mutant flies, here, we show that the mild downregulation of the Imd pathway has a beneficial effect for stress resistance with higher fat content in the body even when developed at 25°C. The Imd pathway functions for the immune response in the fat body which is involved in the metabolism and storage of fat in adult flies. Surprisingly, our data show that the fat-body-specific downregulation of Imd AMP genes significantly enhances heat resistance and extends lifespan.

In summary, our data indicate that mild downregulation of the Imd pathway increases stress resistance, lifespan, and fat content in adult flies, which mimics the enhanced stress resistance caused by a lower developmental temperature.

Inflammatory Necroptosis Increases with Aging and is Slowed by Calorie Restriction

Calorie restriction modestly slows near every measure of aging, so it isn't surprising to see it in action here. Putting that to one side, the interesting part of this paper is the new data on necroptosis, a form of programmed cell death recently enough discovered to receive little attention in comparison to other, similar cell fates. Necroptosis is inflammatory, and rising levels of chronic inflammation occur with aging, driving progression of many of the common age-related diseases. To what degree is this caused by necroptosis versus malfunction in the immune system versus senescent cells versus other causes? Time will tell. Based on research from past years, I'd guess that necroptosis will turn out to be significant as one of the mediating mechanisms linking excess fat tissue with chronic inflammation - there is evidence for cellular debris from dead fat cells to produce that outcome.

Aging is characterized by the progressive increase in chronic, low-grade inflammation termed "inflammaging," which is believed to play an important role in the mechanism underlying aging. Necroptosis is a newly identified form of cell death that initiates an inflammatory process when the dying cells release cell debris and self-molecules, that is, damage-associated molecular patterns, DAMPs or alarmins. DAMPs are a major activator of NLRP3 inflammasome that triggers maturation of interleukin-1β (IL-1β), and NLRP3 inflammasome activation is one of the mechanisms that induces low-grade chronic inflammation with age. Several studies show that blocking necroptosis either genetically or pharmacologically dramatically reduces inflammation in a variety of mouse models. In addition, blocking/reducing necroptosis appears to have an impact on the aging of the male reproductive system and increases the lifespan of ApoE knockout mice and G93A transgenic mouse model of ALS. Necroptosis also appears to play a role in neuron loss in Alzheimer's disease.

To determine whether necroptosis might be a factor in inflammaging, we determined whether necroptosis increases with age and whether it was attenuated by dietary restriction (DR), which retards aging and reduces the increase in chronic inflammation. We measured necroptosis in epididymal white adipose tissue (eWAT), which is a visceral fat depot that is associated with the greatest inflammatory cytokine production, compared to other fat depots, and inguinal WAT (iWAT), which is a subcutaneous fat depot less inflammatory in nature. The level of P-MLKL, a well-accepted marker of necroptosis, was 2.7-fold greater in eWAT of old mice (25-29 months) compared to adult mice (9 months), and DR (started at 4 months of age) reduced P-MLKL to a level similar to adult mice.

We next determined whether the increase in necroptosis in eWAT was associated with increased inflammation. DAMPs produced by necroptosis are reported to increase the release of pro-inflammatory cytokines from innate immune cells through the activation of NF-κB. Therefore, we measured activation of NF-κB in eWAT by the phosphorylation of NF-κB. The level of phospho-NF-κB normalized to NF-κB was 1.4-fold greater in eWAT of old mice compared to adult mice, and DR reduced phospho-NF-κB to a level similar to adult mice.

In summary, our study is the first to demonstrate that biomarkers of necroptosis increase with age. The observation that the changes in necroptosis in eWAT with age and DR are paralleled by changes in the expression of pro-inflammatory cytokines support the possibility that necroptosis may play a role in the age-related increase in chronic inflammation in visceral fat, and possibly inflammaging in the whole animal. Using genetic and pharmacological manipulations which block necroptosis, it will be possible to determine whether the age-related increase in necroptosis causes the increased inflammation observed with age.

Promising Long Term Results in Stem Cell Therapy for Peripheral Artery Disease

Five years ago, a small group of patients who had exhausted other treatment options for their peripheral artery disease were treated with stem cells. Researchers have followed the patients since then, and here report on the long term results - they are promising. This is also the case for a range of other comparatively simple stem cell transplant therapies, now that the research and medical communities have had years to practice and refine the methodologies involved.

A long-term study of patients who received stem cells to treat angiitis-induced critical limb ischemia (AICLI) shows the cells to be both safe and effective. The study could lead to an option for those who suffer from this serious form of peripheral arterial disease (PAD). AICLI is caused by an inflammation of the blood vessels that leads to a severe blockage in the arteries of the lower or upper extremities. It causes severe pain and impaired mobility, and can even lead to amputation and death. While endovascular and surgical reconstruction are the mainstream treatments for critical limb ischemia (CLI), these classical treatments are unfeasible in approximately 15 to 20 percent of patients.

Stem cell therapy is a promising option for these otherwise no-option CLI patients. As one of the promising stem cell therapies, purified CD34+ cell transplantation (PuCeT) has shown favorable short-term results, but prior to this new study no one had looked at its long-term outcome. Researchers tracked 27 AICLI patients for five years after each had received an intramuscular injection of PuCeT to treat their disease. The primary endpoint - major-amputation-free survival rate - as well as secondary endpoints such as peak pain-free walking time and the scale of the patient's pain, were routinely evaluated during the five-year follow-up period.

The results showed that the major-amputation-free survival rate of these patients was 88.89%, the pain free walking time increased nearly 6-fold and the level of pain they experienced was reduced by more than half. Notably, in 17 patients (65.38 percent) not only were their limbs saved, but they also fully recovered their labor competence and returned to their original jobs by week 260.

Longevity Industry Landscape Overview Volume II: The Business of Longevity

The second volume has been published in the Longevity Industry Landscape Overview compendium. The various authors and funding organizations aim to survey all of the participants in the present scientific and business communities focused on the treatment of aging as a medical condition. The focus is on breadth of coverage rather than depth, so this is another sizable document. Once past the introductory sections, most of it is useful for reference rather than reading. But you should still take a look at those opening chapters.

"The majority of politicians and the general public are unaware of the tremendous potential benefits of regenerative medicine. They fail to grasp the profound implications that extended longevity could have on the global economy, on their respective nation's economic survival, and on their own lifespan and health." When did geroscience become a science? When did longevity become an industry? When did it become a 'business'? For almost all of recorded history, it has been a fantasy. During the first half of the 20th century, healthy life extension meant either devising specialised techniques for treating specific diseases or nursing and elderly care. This remained the case throughout both the scientific and industrial revolutions, until the 1940s, when the metabolic processes of aging became an area of modest scientific interest.

Thus began what would eventually become modern geroscience. It retained something of a fringe reputation even into the 21st century. Driven by academic curiosity and the vague hope of modest biomedical intervention, the science plodded along, gaining occasional insights for half a century under the title of 'biomedical gerontology'. As biomedical gerontology advanced, parallel technologies such as regenerative medicine and gene therapy, which dealt with the constituent phenomena of aging but using the language of engineering, had been been coming of age. In the mid-2000s technologists began to notice that the science was ahead of the technology and that the identification of the problem was nearly complete. The solution lay in the technology, which was then, as now, woefully underdeveloped.

This was the period when the concept of 'rejuvenation biotechnology' emerged - not an industry unto itself but an arm of regenerative medicine. Propped up by various non-profits, rejuvenation biotechnology staggered forward into the second decade of the century. In 2013 Google launched the healthcare venture Calico (the 'California Life Company', whose stated remit is healthy human life extension by technological means), an act which dramatically raised the profile of healthy life extension as a legitimate, technological pursuit, thereby bringing the notion of a longevity industry from the fringe to the cutting edge of biomedicine. If 2013 raised the science of longevity out of obscurity, 2017 did the same for the industry, marking the end of a long winter of non-investment in longevity technologies.

The net benefit of all these developments has been that those initially highly skeptical of the formation of a veritable, scientifically validated and profitable longevity industry began to sit up and take notice. The 2015 investment boom was followed by another boom in 2017 in longevity biomedicine. This was the period in which investors finally began to equate rejuvenation with repair. That is, with regenerative medicine. After a long period of dismissal, an increasing number of prominent scientists have come to work for and publicly endorse efforts to enable and accelerate progress in this area, changing the face of medicine and improving the prospects for human lifespan - and healthspan. This, however, has not yet become a fully fledged commercial industry.

How Many Years of Additional Life Expectancy Does a Healthy Lifestyle Provide?

What does a healthy lifestyle achieve for life expectancy? It is surprisingly hard to answer that question for humans. Researchers can't construct carefully cultivated lifestyle choice groups and follow them from birth to death. Instead, messy and imperfect vaults of epidemiological data must be fed into complicated statistical machinery, using strategies that are, at the end of the day, guided by a healthy dose of intuition and common sense. Different groups can and do produce widely different answers to questions regarding additional years added by diet, exercise, or other factors. One has to survey the field in aggregate, averaging over dozens of studies to try to get an idea of what might or might not be the reality. So take this one study in that context - the number produced at the end is large in comparison to other studies I've seen in past years, but the authors are trying to consider all of the major effects rather than just one.

Maintaining a healthy lifestyle, including eating a healthy diet, regular exercise, and not smoking, could prolong life expectancy at age 50 by 14 years for women and just over 12 years for men, according to new research. Heart disease and stroke are major contributors to premature death in this country, with 2,300 Americans dying of cardiovascular disease each day, or one death every 38 seconds. Researchers point out that the U.S. healthcare system focuses heavily on drug discovery and disease management; however, a greater emphasis on prevention could change this life expectancy trend.

To quantify the effects of prevention, researchers analyzed data from two major ongoing cohort studies that includes dietary, lifestyle and medical information on thousands of adults in the Nurses' Health Study and the Health Professionals Follow-up Study. These data were combined with National Health and Nutrition Examination Survey (NHANES) data, as well as mortality data from the Centers for Disease Control and Prevention (CDC), to estimate the impact of lifestyle factors on life expectancy in the U.S. population. Specifically, they looked at how the following five behaviors affected a person's longevity: not smoking, eating a healthy diet (diet score in the top 40 percent of each cohort), regularly exercising (30+ minutes a day of moderate to vigorous activity), keeping a healthy body weight (18.5-24.9 kg/m), and moderate alcohol consumption (5-15 g/day for women, 5-30 g/day for men).

Over the course of nearly 34 and 27 years of follow-up of women and men, respectively, a total of 42,167 deaths were recorded, of which 13,953 were due to cancer and another 10,689 were due to cardiovascular disease. Following all five lifestyle behaviors significantly improved longevity for both men and women. Compared with people who didn't follow any of the five lifestyle habits, those who followed all five were 74 percent less likely to die during the follow-up period; 82 percent less likely to die from cardiovascular disease and 65 percent less likely to die from cancer. There was a direct association between each individual behavior and a reduced risk of premature death, with the combination of following all five lifestyle behaviors showing the most protection.

Between 1940 and 2014, Americans' life expectancy at birth rose from around 63 years to nearly 79 years. However, researchers believe the improvement of life expectancy would be even larger without the widespread prevalence of obesity - a known risk factor for heart disease, stroke, and premature death. "It is critical to put prevention first. Prevention, through diet and lifestyle modifications, has enormous benefits in terms of reducing occurrence of chronic diseases, improving life expectancy as shown in this study, and reducing healthcare costs."

Suggesting that the Gut Microbiome Contributes to Atherosclerosis

Researchers here report a correlation that suggests age-related changes in gut bacterial populations may contribute to the development of atherosclerosis. This is a condition in which damaged lipids in the bloodstream produce an inflammatory overreaction in blood vessel walls. The macrophages that arrive to help clear up damage are overcome and die, producing more inflammation and cellular debris. Over years this grows into fatty plaques that narrow and weaken blood vessels, eventually resulting in catastrophic structural failure or blockage. How might bacteria in the gut contribute to this process? The most plausible mechanisms involve secretion of compounds that encourage chronic inflammation or oxidative stress, changing cell behavior in ways that drives the creation of more of the damaged lipids that spur atherosclerosis. While a range of evidence supports such a role for the compounds mentioned below, this is an area of research in which much remains to be conclusively proven.

Researchers have shown a novel relationship between the intestinal microbiome and atherosclerosis, one of the major causes of heart attack and stroke. This was measured as the burden of plaque in the carotid arteries. In order to understand the role that bacteria in the gut may play in atherosclerosis, the researchers examined blood levels of metabolic products of the intestinal microbiome. They studied a total of 316 people from three distinct groups of patients - those with about as much plaque as predicted by traditional risk factors, those who seem to be protected from atherosclerosis because they have high levels of traditional risk factors but normal arteries, and those with unexplained atherosclerosis who don't have any traditional risk factors but still have high levels of plaque burden.

"What we found was that patients with unexplained atherosclerosis had significantly higher blood levels of these toxic metabolites that are produced by the intestinal bacteria." The researchers looked specifically at the metabolites TMAO, p-cresyl sulfate, p-cresyl glucuronide, and phenylacetylglutamine, and measured the build-up of plaque in the arteries using carotid ultrasound. The study noted that these differences could not be explained by diet or kidney function, pointing to a difference in the make-up of their intestinal bacteria. "There is growing consensus in the microbiome field that function trumps taxonomy. In other words, bacterial communities are not defined so much by who is there, as by what they are doing and what products they are making."

The Alzheimer's Research Community is Increasingly Supportive of the Leucadia Therapeutics Approach to the Condition

The Leucadia Therapeutics team are developing a means to restore the pace at which cerebrospinal fluid drains from the brain. Atrophy of systems of drainage with age causes metabolic wastes such as amyloid and tau to accumulate, leading to Alzheimer's disease. In the past few years, a growing number of papers have emerged in support of this class of approach to the treatment of Alzheimer's. This one is a more general example, suggesting that any means of reducing protein aggregates in cerebrospinal fluid would help - though since a simple fluid flow mechanism already exists in the body, it seems like a good idea to get that working again in older individuals rather than trying something more complex and biochemical, such as immunotherapy.

Amyloid-β (Aβ) is cleared from the brain by several independent mechanisms, including drainage to the vascular and glymphatic systems, and in situ degradation by glial cells. Astrocytes and microglia can produce Aβ degrading proteases like neprilysin, as well as chaperones involved in the clearance of Aβ. There is also a receptor mediated endocytosis, where receptors located in the surface of glial cells are involved in the uptake and clearance of Aβ. In transcytosis, Aβ is removed from interstitial fluid (ISF) across the blood brain barrier (BBB) into the systemic blood.

A perivascular pathway facilitates cerebrospinal fluid (CSF) flow through the brain parenchyma and the clearance of interstitial solutes, including Aβ. It was thought that changes in arterial pulsatility may contribute to accumulation and deposition of toxic solutes, including Aβ, in the aging brain. However, mathematical simulation showed that arterial pulsations are not strong enough to produce drainage velocities comparable to experimental observations and that a valve mechanism such as directional permeability of the intramural periarterial drainage pathway is necessary to achieve a net reverse flow.

The pathophysiology of Alzheimer's disease (AD) is characterized by the accumulation of Aβ and phosphorylated tau protein in the form of neuritic plaques and neurofibrillary tangles, respectively. Amyloid-β accumulation has been hypothesized to result from an imbalance between Aβ production and clearance. An overproduction is probably the main cause of the disease in the familial AD where a mutation in the APP, PSEN1, or PSEN2 genes is present while altered clearance is probably the main cause of the disease in sporadic AD. A good amount of studies reporting altered clearance of Aβ in AD have been published in recent years, becoming one of the hot topics in AD research today.

The different clearance systems probably contribute to varying extents on Aβ homeostasis. Any alteration to their function may trigger the progressive accumulation of Aβ, which is the fundamental step in the hypothesis of the amyloid cascade. There is a relationship between the decrease in the rate of turnover of amyloid peptides and the probability of aggregation due to incorrect protein misfolding resulting in its accumulation. As soluble molecules can move in constant equilibrium between the ISF and the CSF, Aβ monomers and oligomers can be detected in the CSF. Indeed, measuring the levels of Aβ in the CSF is one of the main proposed biomarkers already accepted in the diagnostic criteria of AD.

Different approaches have been investigated with the aim of removing brain Aβ. Among all strategies to enhance the clearance of Aβ, immunotherapy is the most explored approach so far, but has failed to show conclusive results to date. There is an urgent need to find alternative methods to achieve a depletion of Aβ in the brain. A number of studies showed that blood dialysis and plasmapheresis reduces Aβ levels in plasma and CSF in humans and attenuates AD symptoms and pathology in AD mouse models, suggesting that removing Aβ from the plasma seems to be an effective - albeit indirect - way of removing Aβ. However, there might be a much more direct way of removing Aβ from the ISF than clearing it from the plasma: clearing it from the CSF.

The "CSF-sink" therapeutic strategy consists on sequestering Aβ from the CSF. Today, we can conceive several ways of accessing the CSF with implantable devices. These devices can be endowed with different technologies able to capture target molecules, such as Aβ, from the CSF. Thus, these interventions would work as a central sink of Aβ, reducing the levels of CSF Aβ, and by means of the CSF-ISF equilibrium would promote the efflux of Aβ from the ISF to the CSF. The "CSF-sink" therapeutic strategy is expected to provide an intense and sustained depletion of Aβ in the CSF and, in turn, a steady decrease Aβ in the ISF, preventing the formation of new aggregates and deposits in the short term and potentially reversing the already existing deposits in the medium and long terms.


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