Fight Aging! Newsletter, February 26th 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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Contents

  • Recent Genetic Studies Claiming a Slowing of Aging may be Largely Incorrect
  • An Energetic Exploration of the Biochemistry of Cellular Senescence is Underway
  • How Would One Go About Building a Company to Bring Cheap Senolytics to the World?
  • TET2 Overexpression Enhances Neurogenesis and Cognitive Function in Old Mice
  • Quantifying Nuclear DNA Mutation Rates in Stem Cells Doesn't Tell Us the Degree to which those Mutations Contribute to Aging
  • Towards Lasting Therapeutic Manufactories that Operate Inside the Body
  • How Does Age Affect Induced Pluripotency for Regenerative Medicine?
  • Astrocytes Become Inflammatory in the Aging Brain
  • Assembling Cells and Scaffolds into a Suitable Trachea Replacement
  • Arguing for Tau to be More Important than Amyloid-β in Alzheimer's Disease
  • A Measure of Cerebrospinal Fluid Flow Suggests that Brain Aging Commences Early
  • Present Medical Practice is Not Configured to Manage a Future of Ever-Improving Rejuvenation Therapies
  • DAMPs May Link Age-Related Mitochondrial Dysfunction and Chronic Inflammation
  • Calorie Restriction Boosts Intestinal Stem Cell Numbers and Improves Regeneration
  • The Latest Rejuvenation Research Commentary on Relevant Papers

Recent Genetic Studies Claiming a Slowing of Aging may be Largely Incorrect
https://www.fightaging.org/archives/2018/02/recent-genetic-studies-claiming-a-slowing-of-aging-may-be-largely-incorrect/

It is fair to ignore most studies showing extension of life span in laboratory species conducted much prior to the turn of the century. A majority failed to control for calorie restriction, and thus the (usually small) effects evaporate when more rigorously tested. The way this works is that an intervention makes mice nauseous or otherwise uncomfortable, they eat less as a consequence, and thus live longer solely due to lowered calorie intake. This is on top of the usual estimate that most of all published research results are flawed in some way. That includes animal studies that use too few animals, and thus tend to be prone to statistical happenstance, for example. Small studies with few animals are distressingly common in the study of aging, where funding is typically very restricted. Matters did improve once it was no longer possible to be ignorant of the size of the calorie restriction effect on longevity in short-lived species, as that research gained increasing popularity and interest after the 1990s. But as the open access paper I'll point out here suggests, not improved enough.

I think that part of the problem is that too many people were - and still are - trying to evaluate marginal effects on aging. It is hard to accurately detect and quantify small effects in animal studies. A 10% life span extension observed in a group of twenty mice, as compared to a control group of twenty mice, tells us just about nothing other than perhaps it would be good to seek corroboration in a group five times that size - and this example is around the size of effect for most reported interventions based on adjusting the operation of metabolism to slow aging.

One thing I wish was better understood and discussed in our community of advocates, supporters, and researchers is that size of effect and reliability of effect matter enormously. They are the point of the exercise, and the future of our health depends upon them. Everything shown to result in either small or only intermittently apparent outcomes should be rapidly dropped in favor of the continuing search for truly useful approaches to aging. Senescent cell clearance is a shining example of reliability: it always works; it works on many different aspects of aging; it works to treat many different age-related diseases; in fact it puts just about everything else tried to date to shame. The only item from the camp of metabolic manipulation that is as reliable in animal studies is the use of mTOR inhibitors such as rapamycin - and they are notably less effective when it comes to impact on specific age-related diseases. All in all, far too much time and effort is wasted on hoping that unreliable approaches with small effects are magically hiding something useful.

A Reassessment of Genes Modulating Aging in Mice Using Demographic Measurements of the Rate of Aging

The discovery that single gene manipulations can significantly modulate longevity is arguably the major breakthrough in biogerontology thus far. Genetic manipulations of aging in mice are crucial to gather insights into the underlying mechanisms of aging, to discover pathways modulating longevity and to identify candidate genes for drug discovery. Moreover, the manipulation of the aging process in mammalian models (particularly mice) via genetic manipulation (gene knockouts, overexpression, etc.) is crucial to test mechanistic hypotheses of aging. However, determining if such genetic interventions actually affect the aging process and not some others factor of health is not always straightforward.

For example, should a genetic intervention reduce an organism's resistance to disease, this could conceivably reduce the lifespan of the organism, although the rate of aging would not have been affected. Differentiating between genetic interventions that affect the lifespan of an organism through altered health as opposed to changes in the rate of aging is therefore essential to gain insights on aging, and determine interventions with wide ranging effects.

There are two fundamental methods to determine if a life-extending genetic intervention has altered the rate of aging rather than general health. One can track the onset and progression of age-related ailments and physiological degeneration to determine if there is a shift in the onset and on progression of the ailment. In addition, efforts have been made to quantify aging rates with mathematical models such as the Gompertz law of mortality. From the Gompertz parameters, the mortality rate doubling time (MRDT) can be calculated. The MRDT is the amount of time it takes for the mortality rate to double for a given cohort.

A change in MRDT indicates a change in the demographic rate of aging, which is not a perfect reflection of biological aging but a metric that correlates with physiological deterioration and health. Although some studies have investigated MRDT, many authors still often assume that changes in the lifespan of mice following a genetic intervention directly equates to changes in the rate of aging, leading to the misrepresentation of certain genes as having a causal role in aging, when in reality they do not.

Many studies have reported altered median and/or maximum lifespan as a result of an intervention but lifespan alterations may have a number of causes, including altered age at onset of senescence and age-independent mortality. To address this lack of distinction, we previously used linear regression to fit the Gompertz model to longevity data from published mouse studies, and statistically compared the rates of aging in these cohorts. For example, we showed that caloric restriction increases the MRDT and thus retards the demographic rate of aging. Here, the same methodology was employed to reassess mouse longevity data published since 2005 and to identify which genes are more important in determining the demographic rate of aging.

Overall, only 7 of 54 genes were found to have a statistically significant effect on the demographic rate of aging as expected from longevity manipulations. These results suggest that only a relatively small proportion of interventions reported to affect longevity in mice do so through directly influencing the demographic rate of aging. Surprisingly, 20 of 54 genes had a statistically significant impact on the demographic rate of aging in the opposite direction than would be expected for the published longevity effects. One possible explanation is that many mutations impacted on various parameters affecting longevity in non-linear ways, and indeed we observed that increases in aging independent mortality correlated with a slower demographic aging rate. For instance, Sirt1 deficiency extended lifespan but increased the demographic rate of aging; its effect appeared to be exerted instead by delaying the age of onset of mortality rate escalation. This highlights the complex relationship between lifespan and the demographic rate of aging.

Another caveat of our approach concerns the number of mice used in some of the original studies, which ranged from 10 to 146 animals per cohort. Whilst research reported here has attempted to compensate for this by using the Gompertz equation which allows for small sample sizes, one cannot escape the low statistical power that accompanies such small sample sizes. Interestingly, caloric restriction has been shown to significantly retard the demographic rate of aging, but this was a large study with over 200 animals in total. Therefore, caution must be taken when interpreting some of the results detailed here from studies with small sample sizes. Indeed, we observed that in smaller experimental cohorts subjective decisions in estimating Gompertz parameters can significantly affect the results.

Our main conclusions are: 1) most genetic manipulations of longevity in mice do so by modulating aging-independent mortality; 2) there is substantial variation in the lifespan of controls of the same strain across experiments; 3) studies in which the lifespan of the controls is short have a greater lifespan increase, emphasizing the importance of having adequate control groups; 4) mouse lifespan studies employing small cohorts can yield unreliable results; 5) lifespan-reducing experiments tend to be noisier and more difficult to analyze for demographic parameters than life-extending experiments; 6) a greater aging-independent mortality is usually accompanied by a slower demographic aging rate.

An Energetic Exploration of the Biochemistry of Cellular Senescence is Underway
https://www.fightaging.org/archives/2018/02/an-energetic-exploration-of-the-biochemistry-of-cellular-senescence-is-underway/

In 2011 a research group published the results from an animal study that demonstrated, in a way that couldn't be ignored, that the accumulation of senescent cells is a significant cause of aging and age-related disease. In fact, the evidence for this to be the case had been compelling for a very long time - this demonstration came nearly a decade after Aubrey de Grey, on the basis of the existing evidence at the time, included cellular senescence as one of the causes of aging in the first published version of his SENS research proposals. Yet nothing had been done to move ahead and achieve something with this knowledge. That did not change until researchers obtained sufficient philanthropic funding to run the 2011 animal study, using a sophisticated genetic mechanism that eliminated senescent cells as they formed.

From that point on, a slow-moving avalanche of interest and funding fell into this part of the field of aging research. All of the groups with an existing interest in cellular senescence, and that had previously struggled to raise sufficient resources to make progress, could now move rapidly. With the aim of selectively destroying senescent cells to reverse aspects of aging, small molecule senolytic pharmaceuticals and then other methods such as gene therapies and immunotherapies were discovered or constructed. Today there are at least a dozen such small molecule drugs, published and in the works, and a handful of increasingly well-funded startup biotech companies bringing these therapies to human trials and the clinic.

That is the practical side that will lead to rejuvenation treatments in the near future. But the pure scientific impulse isn't to build new technology, it is to learn how our biochemistry works. Much of the funding for further work on cellular senescence goes towards mapping and understanding its details. Now that it is inarguable that this phenomenon is important in the progression of degenerative aging, scores of research groups are picking apart the biochemistry of senescent cells. They are categorizing, trying to understand whether all senescence is essentially the same, or whether there are significant differences in different cell types. They are attempting to better grasp all of the relevant mechanisms that operate inside cells as senescence occurs, and how the triggering change works - or, indeed, whether or not it is a single trigger. They are exploring the details of the senescence-associated secretory phenotype (SASP), the means by which these cells cause harm to tissues.

The four open access papers noted here are recent examples of this sort of thing. There is a great deal to learn, and while the work is largely irrelevant to the senolytic therapies currently in development, there will no doubt be discoveries that steer and inform development of the second generation of more subtle and sophisticated therapies. Those will likely commence development five to ten years from now, and be mature and in widespread use by the early 2030s.

TNFα-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion

Cellular senescence is a cell fate program that entails essentially irreversible proliferative arrest in response to damage signals. Tumor necrosis factor-alpha (TNFα), an important pro-inflammatory cytokine secreted by some types of senescent cells, can induce senescence in mouse and human cells. However, downstream signaling pathways linking TNFα-related inflammation to senescence are not fully characterized. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that TNFα induces permanent growth arrest and increases p21CIP1, p16INK4A, and SA-β-gal, accompanied by persistent DNA damage and ROS production. By gene expression profiling, we identified the crucial involvement of inflammatory and JAK/STAT pathways in TNFα-mediated senescence. We found that TNFα activates a STAT-dependent autocrine loop that sustains cytokine secretion and an interferon signature to lock cells into senescence.

3′ UTR lengthening as a novel mechanism in regulating cellular senescence

Cellular senescence has been viewed as a tumor suppression mechanism and also as a contributor to individual aging. Widespread shortening of 3′ untranslated regions (3′ UTRs) in messenger RNAs (mRNAs) by alternative polyadenylation (APA) has recently been discovered in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. Here, we found that hundreds of genes in senescent cells tended to use distal poly(A) (pA) sites, leading to a global lengthening of 3′ UTRs and reduced gene expression. Genes that harbor longer 3′ UTRs in senescent cells were enriched in senescence-related pathways. Rras2, a member of the Ras superfamily that participates in multiple signal transduction pathways, preferred longer 3′ UTR usage and exhibited decreased expression in senescent cells. Depletion of Rras2 promoted senescence, while rescue of Rras2 reversed senescence-associated phenotypes.

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

Oncogenic signals lead to premature senescence in normal human cells causing a proliferation arrest and the elimination of these defective cells by immune cells. Oncogene-induced senescence (OIS) prevents aberrant cell division and tumor initiation. In order to identify new regulators of OIS, we performed a loss-of-function genetic screen and identified that the loss of SCN9A allowed cells to escape from OIS. The expression of this sodium channel increased in senescent cells during OIS. This upregulation was mediated by NF-κB transcription factors, which are well-known regulators of senescence. Importantly, the induction of SCN9A by an oncogenic signal or by p53 activation led to plasma membrane depolarization, which in turn, was able to induce premature senescence. Computational and experimental analyses revealed that SCN9A and plasma membrane depolarization mediated the repression of mitotic genes through a calcium/Rb/E2F pathway to promote senescence.

Mitochondrial (Dys) Function in Inflammaging: Do MitomiRs Influence the Energetic, Oxidative, and Inflammatory Status of Senescent Cells?

A relevant feature of aging is chronic low-grade inflammation, termed inflammaging, a key process promoting the development of all major age-related diseases. Senescent cells can acquire the senescence-associated (SA) secretory phenotype (SASP), characterized by the secretion of proinflammatory factors fuelling inflammaging. Cellular senescence is also accompanied by a deep reshaping of microRNA expression and by the modulation of mitochondrial activity, both master regulators of the SASP. Here, we synthesize novel findings regarding the role of mitochondria in the SASP and in the inflammaging process and propose a network linking nuclear-encoded SA-miRNAs to mitochondrial gene regulation and function in aging cells. In this conceptual structure, SA-miRNAs can translocate to mitochondria (SA-mitomiRs) and may affect the energetic, oxidative, and inflammatory status of senescent cells.

How Would One Go About Building a Company to Bring Cheap Senolytics to the World?
https://www.fightaging.org/archives/2018/02/how-would-one-go-about-building-a-company-to-bring-cheap-senolytics-to-the-world/

Let us for a moment choose to believe that the dasatinib and quercetin combination is a senolytic treatment that does as well in humans as it does in mice. This is to say it kills about 25-50% of senescent cells in the tissues usually most affected by oral medications, meaning the kidney, liver, and cardiovascular system, and some unknown but lower fraction elsewhere. Whether or not this is the case has yet to be determined; the first pilot studies are still running at Betterhumans, and they likely won't tell us the size of the effect in terms of fraction of cells removed. Viable assays for cellular senescence that can be used in human medicine are in short supply - there is only the one that I know of that is ready to go, and even that has just reached the final stage of laboratory proof of concept. If it is the case, however, that treatment with dasatinib and quercetin works in much the same way in humans, then it should have a notably positive effect on the state of health for older individuals, given that the accumulation of senescent cells is one of the causes of aging.

The distinguishing feature of dasatinib and quercetin are that they are cheap. A senolytic therapy would be undergone perhaps once every few years at most; it kills the unwanted cells it can kill, and it is pointless to do it again before there has been enough time for new senescent cells to emerge at their slow pace. Quercetin is a widely used supplement, and enough of it for a single treatment is an insignificant cost. Dasatinib can be purchased from manufacturers for between 20 and 150 for a single dose suitable for senolytic therapy, depending on where the manufacturer is based. The FDA approved packaging of dasatinib, called Sprycel, costs 300-600 for the same amount, assuming you can find someone willing to break down a bottle of tablets to sell you the small amount needed. It is certainly possible to purchase Sprycel for less than this by ordering from outside the US.

If this pharmaceutical does work in humans as imagined above, then at these prices it is a therapy that would be affordable for a sizable portion of the world's population. It isn't the only candidate senolytic drug that is cheap enough to consider in this way. Once the first of these treatments are proven to be at least passably useful in human patients, what is the path to putting these low-cost rejuvenation therapies into the hands of hundreds of millions of people, the majority of which are not wealthy, as soon as possible? We should give this some thought, as it is a opportunity that will likely arrive much sooner than most of us expected it to. This is a big deal: early senolytics could provide a gain in health for much of humanity if the opportunity is managed correctly. That makes it worth consideration even prior to proof arriving in human studies.

There are always roadblocks. Like all such matters, the use of dasatinib is tied up by patents and regulation. No-one can build a large-scale business selling a pharmaceutical where the intellectual property and regulatory approval are owned by a large and influential concern - in this case Bristol-Myers Squibb (BMS). It is certainly the case that there is a healthy marketplace of scofflaws outside the US who sell directly from manufacturers, but they are not a single target, and it is hardly worth BMS's time to try to squash them while dasatinib is generating only the level of revenue possible for a cancer drug. That economic calculus may well change if it suddenly becomes a viable treatment for every older individual, and physicians show interest in off-label use - that is a vastly larger potential market. Certainly, BMS exerted their influence to block attempts to produce a cheaper generic version in India. That was associated with the Indian government and thus had a convenient single point of attack, unlike the manufacturer marketplace.

Dasatinib is still patent protected, at least until 2020, which means that any earnest effort to make dasatinib a household term in the near future would have to engage with BMS and gain at last tacit approval in order to grow. After 2020, no permission is needed. BMS will continue to tinker with their formula to extend patent protection on the versions of Sprycel that they sell, but they will no longer be able to directly make life difficult for those who wish to manufacture and sell dasatinib per the original formulation. The price will likely drop considerably at that point. So how could a group proceed if willing to found a company to work on distribution of low-cost senolytics?

The Non-Profit Approach

The most obvious option is to build a non-profit that focuses on education and partnership. The goal would be to deliver low-cost dasatinib and the understanding needed for widespread use to less wealthy regions of the world. The non-profit would focus on building relationships with physicians, medical organizations, manufacturers, and the product owner, BMS. There is considerable precedent for this sort of endeavor, and many larger pharmaceutical companies carry out in-house programs of this nature. It can benefit the pharmaceutical company considerably even if they make little to no revenue from the use of their product in those markets. It is usually the case that they wouldn't have been able to sell at profitable prices there anyway, and the program can be very good for their public image - something that Big Pharma entities are always in need of, for some strange reason.

The For-Profit Scofflaw Approach

Prior to 2020, one would require deep pockets and to be based outside the US, preferably in a country that doesn't regard the US with any great favor, in order to build something large that undercuts BMS, or even simply to sell into markets that BMS chooses not to serve. Being a small company that ships dasatinib at low cost from China to other parts of the world is probably viable, but growth to any significant size would bring a quick end to the endeavor. As mentioned, an attempt was made in India, where there is a history of threatening to break international intellectual property agreements in order to bring low-cost medications to that part of the world. That failed, and I'd say that India is probably the most likely region to successfully host a defensible patent breaking exercise.

The For-Profit BMS Enabler Approach

The enabler approach runs something like this: establish a path to obtain Sprycel in bulk at a workably low cost, and in an approved manner for the regulatory framework, and then build a revenue stream based on selling wrapped packages of services and Sprycel to physicians, nursing home operators, and other interested groups. Businesses and other organizations are better customers to start with in less wealthy regions, as there is a greater chance of being able to gain sufficient revenue to expand. Optionally, partner with BMS, though this is typically hard to do without connections.

The packages sold might include: educational materials and classes; professional services to assist with insurance and other regulatory concerns for prescribing off-label usage; membership of a network that helps bring in patients interested in the treatment and thus contributes to a physician's bottom line; tests and organization of testing services to evaluation results; and so forth. Everything is carried out in a such a way that it benefits BMS, such that the company has incentives to allow the business to grow. There are many possible variations on this theme, some of which are similar to the promotional activities carried out by the pharmaceutical companies themselves, while others look more like patient or physician associations or service organizations.

The Wait Until 2020 Approach

In either non-profit or for-profit models by which dasatinib might be distributed to the less wealthy regions of the world in volume, the prospects look a lot better once BMS is no longer the gatekeeper. The price of manufacture will fall precipitously, and an enterprising group with a good approach and competent execution might be able to do quite well in markets traditionally neglected by large pharmaceutical concerns. "Quite well" in this case would mean - under the assumptions at the top of this post - a significant number of people living incrementally longer in better health at a cost that is reasonable for them, considering the benefits achieved. That seems a worthwhile goal to aim for.

TET2 Overexpression Enhances Neurogenesis and Cognitive Function in Old Mice
https://www.fightaging.org/archives/2018/02/tet2-overexpression-enhances-neurogenesis-and-cognitive-function-in-old-mice/

Heterochronic parabiosis is the process of linking the circulatory systems of an old and young animal. It improves measures of aging in the older individual, and worsens measures of aging in the younger individual. Researchers use this technique to try to pinpoint the important signaling and other cell behavior changes that take place with advancing age. This isn't just a matter of looking at signals in the bloodstream, however. Researchers can analyze any of the changing gene expression patterns and biochemical relationships inside cells, as they respond to the altered environment. That is the case in the open access paper I'll point out here; a research team experimenting with heterochronic parabiosis found that it increased expression of TET2 in old mice, and they present evidence to implicate reduced levels of TET2 in age-related cognitive decline.

Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain

During aging, the number of neural stem/progenitor cells (NPCs), and subsequently neurogenesis, precipitously declines in the subgranular zone of the dentate gyrus (DG) in the hippocampus. Mounting evidence in animal models indicates the potential for rejuvenation of regenerative and cognitive functions in the aging brain through interventions, such as heterochronic parabiosis (which exposes aged animals to young blood). However, the ability to utilize this neurogenic potential is predicated on identifying molecular targets that reverse the effects of aging in the brain.

Recent studies have begun to link changes in the functions of epigenetic mediators to age-related regenerative decline. Interestingly ten eleven translocation methylcytosine dioxygenase 2 (Tet2) is emerging as a potential epigenetic regulator of aging. Human genetic studies identified an increased frequency of somatic TET2 mutations with age that are associated with elevated risk for aging-associated disorders, such as cancer, cardiovascular disease, and stroke. Notwithstanding, the involvement of Tet2 in mediating the aging process in the adult brain has yet to be investigated.

Here we demonstrate that Tet2 offsets age-related neurogenic decline and enhances cognition in the hippocampus of adult mice. We detect an age-dependent decrease in the levels of Tet2 in the aging hippocampus coincident with decreased adult neurogenesis. Mimicking an age-related loss of Tet2 in the adult neurogenic niche of the hippocampus, or adult NPCs, impairs regenerative capacity and associated hippocampal-dependent learning and memory processes. Conversely, increasing Tet2 in the hippocampus of mature animals increases restores adult neurogenesis to youthful levels and enhances cognitive function.

Recently, it has been demonstrated that constitutive whole-body loss of Tet2 yields opposing effects on neurogenic processes, resulting in increased adult NPC proliferation but decreased neuronal differentiation. In contrast, our data indicate that decreasing Tet2 expression acutely in the adult neurogenic niche impairs all stages of hippocampal neurogenesis, while loss of Tet2 in adult NPCs impairs neuronal differentiation processes. These data point to differential regulation of distinct stages of neurogenesis by Tet2 that arise from the loss of Tet2 at the level of the whole organism, neurogenic niche, and adult NSC during development versus adult ages. In the context of aging, our data implicate decreased Tet2 in the aging hippocampus with age-related regenerative decline.

Aging is a process of layers. At the bottom of it, the root causes are forms of molecular damage: an accumulation of broken, misbehaving cells; growing deposits of metabolic waste; mutated mitochondrial DNA; and so on. Above this is a very complicated and poorly mapped middle layer in which cells react to damage, changing countless signals and behaviors in response. Some of this is compensation, with varying degrees of success, and some of it wild flailing that makes everything worse. Then at the upper layer we find the familiar age-related diseases and classes of organ dysfunction, the sort of thing that is described in terms of the capacity that is failing or lost rather than how that failure or loss happened: kidney failure; dementia; heart disease; and so on.

Most research into aging starts at the top layer, with the evident symptoms of age-related disease, and then works just a little way back down into the upper part of the middle layer, trying to make sense of the final part of the chain of cause and effect. Then the researchers usually try to build therapies rather than carry on deeper. The work here is an excellent example of the way in which this proceeds. Having identified reduced levels of TET2 as a proximate cause of loss of neurogenesis and cognitive function, the next step is not to ask why levels of TET2 are lower, but to try to override that change. When this strategy is repeated over and again across the research community, is it any wonder that we have very little detailed knowledge of how the known root causes of aging - those summarized in the SENS rejuvenation research portfolio - interact and progress to give rise to all the various measures of aging.

Not that I think it is necessarily the right thing to do to work further downwards through the middle layer to the bottom. Quite the opposite, in fact. I think the most economical way forward is to build repair therapies capable of addressing the damage that causes aging, changing the bottom layer, and then see what happens next as those repairs propagate their effects. In the case of senescent cells and aging, this approach is ongoing, and generating new knowledge at a much, much faster pace than was the case in the years prior to the emergence of the first senolytic therapies capable of selectively destroying these cells. In a better world, the research community would have enough funding to energetically pursue all options: compensatory treatments as well as those that address root causes. As it is, it is largely the former that take place, while the latter remain neglected. Given that repairing the root causes should be far more effective than compensating for a small slice of their downstream effects, this is a real problem.

Quantifying Nuclear DNA Mutation Rates in Stem Cells Doesn't Tell Us the Degree to which those Mutations Contribute to Aging
https://www.fightaging.org/archives/2018/02/quantifying-nuclear-dna-mutation-rates-in-stem-cells-doesnt-tell-us-the-degree-to-which-those-mutations-contributes-to-aging/

The study noted here provides numbers for the mutation rates in muscle stem cells, the stochastic damage that occurs over time as small numbers of errors slip past the highly efficient molecular machinery of cellular replication and DNA repair. The researchers used single cell genomic sequencing, a very useful and still comparatively new capability. It produces a much more detailed view of the state of nuclear DNA inside a cell population, showing the enormous variations in stochastic mutational damage that takes place over the years. Every cell has thousands of different areas of damage in their DNA, and it is becoming apparent that the damage in stem cell populations is cloned out into tissues. Stem cells maintain tissues by providing a supply of somatic cells, and those somatic cells divide many times before they reach the Hayflick limit. So the mutations present in a stem cell will over time propagate into a fraction of the supported tissue.

Is this important? Mutation in nuclear DNA is certainly a contributing cause of cancer, though it can be argued that the decline of the immune system - responsible for killing cancers before it gets underway - is actually more significant than mutations when it comes to the age-related nature of cancer risk. One can look at the numbers for mutational damage in old cells and it sounds fairly horrific out of context, but everything irelated cells and cellular biochemistry involves huge numbers. We know that nuclear DNA becomes more mutated over time, and we know that many of the methods of slowing aging, such as calorie restriction, produce reduced levels of mutation at a given age in comparison to normally aging individuals. However: at present there is no compelling causal evidence to show that nuclear DNA damage alone has a significant effect over the present human life span in comparison to other contributions to degenerative aging. If anything, the slight tilt in the present indirect evidence is in the opposite direction, towards skepticism for a significant role over the present human life span.

Nonetheless, it is the present consensus that nuclear DNA damage does cause meaningful metabolic dysfunction; a lot of research proceeds upon this assumption. The authors of the open access paper here are quite ready to theorize a connection between stem cell mutation level and age-related declines in muscle mass and strength, but their data only shows a correlation. A great many things happen over the course of aging, and not all are directly connected to one another: aging is a tree, a spreading set of damage and issues stemming from a few root causes. The far branches will appear correlated even if they have little to do with one another.

I'm in the camp of those who would like to see more work directed towards the production of a compelling demonstration to show that nuclear DNA damage either is or is not a major factor in aging beyond cancer risk. The best way to do that is to repair a significant amount of the damaged DNA, but that is exceptionally challenging, beyond present capabilities. It might be possible in the near future to use one of the new forms of genetic technology to tackle the clonal expansions of specific mutations, provided there are only a few of them and they are present in large numbers of cells. Once we start talking about scores or hundreds of mutations, however, then that is just not a near term prospect. So a less direct approach is called for, something clever yet to be assembled, that will be obvious in hindsight to the rest of us.

Stem cell study may result in stronger muscles in old age

It has already been established that natural ageing impairs the function of our skeletal muscles. We also know that the number and the activity of the muscles' stem cells decline with age. However, the reasons for this has not been fully understood. In a new study, researchers have investigated the number of mutations that accumulate in the muscle's stem cells (satellite cells). "What is most surprising is the high number of mutations. We have seen how a healthy 70-year-old has accumulated more than 1,000 mutations in each stem cell in the muscle, and that these mutations are not random but there are certain regions that are better protected."

The researchers have benefited from new methods to complete the study. The study was performed using single stem cells cultivated to provide sufficient DNA for whole genome sequencing. The mutations occur during natural cell division, and the regions that are protected are those that are important for the function or survival of the cells. Nonetheless, the researchers were able to identify that this protection declines with age. "We can demonstrate that this protection diminishes the older you become, indicating an impairment in the cell's capacity to repair their DNA. And this is something we should be able to influence with new drugs."

"We achieved this in the skeletal muscle tissue, which is absolutely unique. We have also found that there is very little overlap of mutations, despite the cells being located close to each other, representing an extremely complex mutational burden." The researchers will now continue their work to investigate whether physical exercise can affect the number of accumulated mutations. Is it true that physical exercise from a young age clears out cells with many mutations, or does it result in the generation of a higher number of such cells?

Somatic mutagenesis in satellite cells associates with human skeletal muscle aging

Satellite cells (SCs) are a heterogeneous population of stem and progenitor cells that have been demonstrated to play a pivotal role in skeletal muscle (SkM) regeneration. The SCs are normally kept in a quiescent state and activated upon exposure to stimuli, such as exercise or SkM injury. When committed to myogenic differentiation, SCs proliferate further, fuse to existing SkM fibers, and contribute new nuclei to the growing and regenerating fibers. Aged human SkMs show a decline in the number and proliferative potential of the SCs. As a consequence, a dysfunctional SC compartment is envisaged as a major contributor to age-related defects, including reduced capacity to respond to hypertrophic stimuli such as exercise and impaired recovery from muscle disuse and injury.

A well-known factor in the decline of stem cell function is the loss of genome integrity, for example, caused by the appearance of somatic mutations. These modifications of the genome range from single-base changes (single-nucleotide variants) to insertions or deletions of a few bases (indels) to chromosomal rearrangements and occur during the whole life, starting from the first division of the embryo. In contrast to germline variants, somatic variants are not propagated to the whole individual but to a subpopulation of cells in the body, with the final consequence that adult human tissues are a mosaic of genetically different cells. Moreover, somatic mutation burden increases during a lifetime as a result of accumulating errors occurring either during cell division or because of environment-induced DNA damage. At present, nothing is known about somatic mutation burden in human SCs or SkM.

Here, we investigate the genetic changes that occur with aging in the genome of human adult SCs and use the results to elucidate mutational processes and SC replication rate occurring in vivo in adult human muscles. We assess the functional effects of somatic mutations on SC proliferation and differentiation and predict the global consequence on muscle aging and sarcopenia. Our analyses reveal an accumulation of 13 mutations per genome per year that results in a 2-3-fold higher mutation load in active genes and promoters in aged SCs. High mutation burden correlates with defective SC function. Overall, our work points to the accumulation of somatic mutations as an intrinsic factor contributing to impaired muscle function with aging.

Towards Lasting Therapeutic Manufactories that Operate Inside the Body
https://www.fightaging.org/archives/2018/02/towards-lasting-therapeutic-manufactories-that-operate-inside-the-body/

Gene therapies involve delivering instructions into cells to ensure that specific proteins are manufactured, either temporarily or permanently. This is effectively a hijacking or programming of cellular mechanisms. There is another approach, which is to deliver suitable DNA machinery into the body, capable of manufacturing the desired proteins outside cells. This isn't helpful for all types of protein, but in many cases it is. That machinery needs protection, however: naked, it would be quickly removed by the immune system or otherwise broken down. One possibility is to employ engineered bacteria, which removes the need to introduce changes into a patient's cells, but adds a sizable set of other complications. Another approach is to build a suitable structure from scratch, such as a membrane that will not alert the immune system, containing a carefully limited set of DNA machinery that will turn out the desired proteins for a lengthy period of time, but is incapable of any other activity. These constructs would in many ways resemble extracellular vesicles more than cells, and the research community has been capable of building such things for a few years now.

Researchers have successfully treated a cancerous tumor using a "nanofactory" - a synthetic cell that produces anti-cancer proteins within the tumor tissue. The research combines synthetic biology, to artificially produce proteins, and targeted drug delivery, to direct the synthetic cell to abnormal tissues. The synthetic cells are artificial systems with capacities similar to, and, at times, superior to those of natural cells. Just as human cells can generate a variety of biological molecules, the synthetic cell can produce a wide range of proteins. Such systems bear vast potential in the tissue engineering discipline, in production of artificial organs and in studying the origins of life. Design of artificial cells is a considerably complex engineering challenge being pursued by many research groups across the globe.

The researchers integrated molecular machines within lipid-based particles resembling the natural membrane of biological cells. They engineered the particles such that when they "sense" the biological tissue, they are activated and produce therapeutic proteins, dictated by an integrated synthetic DNA template. The particles recruit the energy sources and building blocks necessary for their continued activity, from the external microenvironment (e.g., the tumor tissue).

After experiments in cell cultures in the lab, the novel technology was also tested in mice. When the engineered particles reached the tumor, they produced a protein that eradicated the cancer cells. The particles and their activity were monitored using a green fluorescent protein (GFP), generated by the particles. This protein can be viewed in real-time, using a fluorescence microscope. "By coding the integrated DNA template, the particles we developed can produce a variety of protein medicines. They are modular, meaning they allow for activation of protein production in accordance with the environmental conditions. Therefore, the artificial cells we've developed may take an important part in the personalized medicine trend - adjustment of treatment to the genetic and medical profile of a specific patient."

How Does Age Affect Induced Pluripotency for Regenerative Medicine?
https://www.fightaging.org/archives/2018/02/how-does-age-affect-induced-pluripotency-for-regenerative-medicine/

One of the more intriguing discoveries relating to the cell reprogramming used to produce induced pluripotent stem cells is that this process appears to reverse some aspects of cell aging. It perhaps triggers some fraction of the mechanisms at work in early embryonic development, those that ensure that children are born young, with nowhere near the load of persistent damage present in the adult parents. This is not a well-explored topic, unfortunately - it is still too recent for much to be said in certainty, and a sizable fraction of the evidence is conflicting. Related to all of this is the question of how exactly the age of the donor affects the reprogramming of donated cells. Near all potential uses of regenerative medicine based on reprogrammed cells involve age-related disease and older individuals. It is important to understand whether it is safe to proceed, how effective approaches might be in practice, and where the problems lie, so that they can be addressed.

Induced pluripotent stem cells (iPSCs) avoid many of the restrictions that hamper the application of human embryonic stem cells, and the donor's clinical phenotype is often known when working with iPSCs. Therefore, iPSCs seem ideal to tackle the two biggest tasks of regenerative medicine: degenerative diseases with genetic cause (e.g., Duchenne's muscular dystrophy) and organ replacement in age-related diseases (e.g., end-stage heart or renal failure), especially in combination with recently developed gene-editing tools.

In the setting of autologous transplantation in elderly patients, donor age becomes a potentially relevant factor that needs to be assessed. Here, we review and critically discuss available data pertinent to the questions: How does donor age influence the reprogramming process and iPSC functionality? Would it even be possible to reprogram senescent somatic cells? How does donor age affect iPSC differentiation into specialised cells and their functionality? We also identify research needs, which might help resolve current unknowns.

Until recently, most hallmarks of ageing were attributed to an accumulation of DNA damage over time, and it was thus expected that DNA damage from a somatic cell would accumulate in iPSCs and the cells derived from them. In line with this, a decreased lifespan of cloned organisms compared with the donor was also observed in early cloning experiments. Therefore, it was questioned for a time whether iPSC derived from an old individual's somatic cells would suffer from early senescence and, thus, may not be a viable option either for disease modelling nor future clinical applications. Instead, typical signs of cellular ageing are reverted in the process of iPSC reprogramming, and iPSCs from older donors do not show diminished differentiation potential nor do iPSC-derived cells from older donors suffer early senescence or show functional impairments when compared with those from younger donors.

Thus, the data would suggest that donor age does not limit iPSC application for modelling genetic diseases nor regenerative therapies. However, open questions remain, e.g., regarding the potential tumourigenicity of iPSC-derived cells and the impact of epigenetic pattern retention.

Astrocytes Become Inflammatory in the Aging Brain
https://www.fightaging.org/archives/2018/02/astrocytes-become-inflammatory-in-the-aging-brain/

Astrocytes are one of the common types of support cell in the brain, performing a wide variety of tasks that range from repair to maintaining the balance of various signal and electrolyte molecules. Researchers find evidence to suggest that astrocytes shift into an inflammatory mode in large numbers with advancing age. Chronic inflammation is a feature of most neurodegenerative conditions, and of aging in the broader sense. It disrupts the complex relationships between cell types that are needed for most sophisticated behavior in tissues, such as regeneration, or any number of cell communication processes required for correct function of the brain.

This is particularly interesting in the context of recent findings regarding cellular senescence in astrocytes. A large fraction of these cells show some signs of senescence in older individuals, and one of the characteristic bad behaviors of senescent cells is the generation of chronic inflammation through the senescence-associated secretory phenotype. Researchers have pinned down astrocyte senescence as a contributing factor in Parkinson's disease, for example. It is also worth noting that this business of cells shifting into an inflammatory mode in greater numbers with advancing age is also observed in macrophages, where it disrupts regenerative processes, and in microglia, another of the support cells of the brain. They also generate chronic inflammation in brain tissue, which contributes to the complicated breakdown of the normal operation of the brain.

The decline of cognitive function occurs with aging, but the mechanisms responsible are unknown. Astrocytes instruct the formation, maturation, and elimination of synapses, and impairment of these functions has been implicated in many diseases. These findings raise the question of whether astrocyte dysfunction could contribute to cognitive decline in aging. We performed RNA sequencing of astrocytes from different brain regions across the lifespan of the mouse. We found that astrocytes have region-specific transcriptional identities that change with age in a region-dependent manner.

Detailed analysis of the differentially expressed genes in aging revealed that aged astrocytes take on a reactive phenotype of neuroinflammatory A1-like reactive astrocytes. Hippocampal and striatal astrocytes up-regulated a greater number of reactive astrocyte genes compared with cortical astrocytes. Moreover, aged brains formed many more A1 reactive astrocytes in response to the neuroinflammation inducer lipopolysaccharide.

We found that the aging-induced up-regulation of reactive astrocyte genes was significantly reduced in mice lacking the microglial-secreted cytokines (IL-1α, TNF, and C1q) known to induce A1 reactive astrocyte formation, indicating that microglia promote astrocyte activation in aging. Since A1 reactive astrocytes lose the ability to carry out their normal functions, produce complement components, and release a toxic factor which kills neurons and oligodendrocytes, the aging-induced up-regulation of reactive genes by astrocytes could contribute to the cognitive decline in vulnerable brain regions in normal aging and contribute to the greater vulnerability of the aged brain to injury.

Assembling Cells and Scaffolds into a Suitable Trachea Replacement
https://www.fightaging.org/archives/2018/02/assembling-cells-and-scaffolds-into-a-suitable-trachea-replacement/

Researchers here report on their efforts to build a suitable structure to replace a trachea, starting with patient cells and artificial scaffolds. Since the trachea is a thin-walled pipe, engineered tissue can be constructed in this way without the need for complex blood vessel networks, as at no point is the tissue so thick as to prevent direct perfusion of nutrients and oxygen to the inner cells. Unfortunately, it remains the case that decellularized donor tissue is the only reliable solution for the production of capillaries to support thicker tissues, scores of such vessels passing through every square millimeter. This is why most of the more ambitious work, closer to clinical application, involves thin tissues and tubular structures - larger blood vessels, skin, and so forth - while everyone else is working with the tiny sections of engineered tissue known as organoids.

Biomedical engineers are growing tracheas by coaxing cells to form three distinct tissue types after assembling them into a tube structure - without relying on scaffolding strategies currently being investigated by other groups. "The unique approach we are taking to this problem of trachea damage or loss is forming tissue modules using a patient's cells and assembling them into a more complex tissue." Recent tissue engineering approaches using synthetic or natural materials as scaffolding for cells have met with challenges. Difficulties have included uniformly seeding cells on the scaffolding, recreating the multiple different tissue types found in the native trachea, tailoring the scaffolding degradation rate to equal the rate of new tissue formation, and recreating important contacts between cells because of the intervening scaffold.

The trachea engineering strategy now being pursued, however, wouldn't have those problems because it doesn't rely on a separate scaffold structure. A new trachea replacement must do three critical things to function properly: (1) maintain rigidity to prevent airway collapse when the patient breathes; (2) contain immunoprotective respiratory epithelium, the tissue lining the respiratory tract, which moistens and protects the airway and functions as a barrier to potential pathogens and foreign particles; and (3) integrate with the host vasculature, or system of blood vessels, to support epithelium viability.

The self-assembling rings developed by researchers meet all three of those requirements because they can fuse together to form tubes of both cartilage and "prevascular" tissue types. Prevascular refers to tissues potentially ready to participate in the formation of blood vessels, though not yet functional in that way. The cartilage rings are formed by aggregating marrow-derived-stem cells in ring-shaped wells. Polymer microspheres containing a protein that induces the stem cells to become "chondrocytes," or cells that form cartilage, are also incorporated into the cell aggregates. These prevascular rings are comprised of both these marrow-derived stem cells and endothelial cells, the thin layer of cells that line the interior of blood vessels.

The researchers then coat the tubes with epithelial cells to form multi-tissue constructs that satisfy all of those requirements: cartilage provides rigidity, epithelium serves the role of immunoprotection and the vascular network would ultimately permit blood flow to feed and integrate the new trachea tissue. Using this method, the team has been able to engineer highly elastic "neo-tracheas" of various sizes, including tissues similar to human trachea. When these tracheas were implanted under the skin in mice, there was evidence the prevascular structures could join up with the host vascular supply.

Arguing for Tau to be More Important than Amyloid-β in Alzheimer's Disease
https://www.fightaging.org/archives/2018/02/arguing-for-tau-to-be-more-important-than-amyloid-%ce%b2-in-alzheimers-disease/

This isn't the first paper I've seen to argue the point that there should be a greater focus on tau aggregation in Alzheimer's disease, and that tau may be more important to the progression of the condition. As I'm sure the readers here are aware, Alzheimer's is characterized by the buildup of both amyloid-β and tau in the brain. Forms of these normally soluble proteins precipitate into solid deposits that are accompanied by a complex halo of biochemistry that degrades the function of neurons and ultimately kills these cells. The primary focus for development of therapies has long been the removal of amyloid-β, but despite enormous effort there is no light at the end of the tunnel yet. The history of clinical trials for amyloid-β clearance is one of unremitting failure, even recently in trials that produced evidence for amyloid-β to be removed to some degree in patients.

It is much debated as to whether trials are failing because amyloid-β is the wrong target, despite being harmful in and of itself, or because Alzheimer's is a hard problem. Alzheimer's research has proceeded in parallel with mapping the brain at the necessary level to talk about how exactly it is damaged by protein aggregates, and also in parallel with the development of immunotherapy technologies, both of which are challenging areas of research and development. The biochemistry of the brain, its operation, and its failure modes are all enormously complex. We seem to be reaching a tipping point, however, in which discontent with the focus on amyloid-β is spilling over into greater emphasis and funding for alternatives. Rightly or wrongly in this specific case, I think that diversity in approaches is almost always better in the long term.

The hallmarks of Alzheimer's disease (AD) pathology are marked by accumulation of extracellular amyloid-β (Aβ) plaques in the brain followed by intracellular neurofibrillary tangle (NFT) growth. Aβ upregulates the generation of NFTs by increasing glycogen synthase kinase-3 (GSK-3) activity, leading to the phosphorylation of tau. Phosphorylated tau (pTau) begins to self-assemble to form NFTs. Aβ plaques, soluble Aβ oligomers, and NFTs interfere with normal neuronal cell function by disrupting synaptic signaling. Each protein's accumulation leads to neuron damage, eliciting diminished brain mass and cognitive function.

The removal of Aβ plaques does not influence elimination of NFTs after NFTs have been established in the brain, but early intervention can prevent pTau development. Therefore, targeted late stage treatments may specifically eliminate Aβ without impacting pTau levels that have already accumulated, which enables NFTs to continue amplifying cognitive deficits. Comparison of differences in pTau and Aβ levels in treated mice illuminate differences between the proteins' impact on cognitive function. For example, pTau levels were reduced by chemical treatment as Aβ levels continued to increase, yet cognitive function improved. This result implies that there is a quantitative difference between how the two proteins effect cognitive deterioration, and moreover, that decreasing pTau may ultimately be more important than reducing Aβ in the quest to successfully treat AD.

The Amyloid Cascade Hypothesis states that Aβ is the center piece in AD pathology leading to hyperphosphorylation of tau and numerous neurotoxic pathways causing cell death. Treatments targeting Aβ and Aβ precursors have failed to pass clinical trials to improve patient outcomes. The presence of Aβ is associated with a decrease in cognitive performance; however, the quantitative level of Aβ inconsistently predicts the amount of cognitive decline. Instead, it is suggested that other contributors, such as the hyperphosphorylation of tau, are the functional cause of degeneration after the initial onset of AD.

The present study compares the effects of Aβ and pTau levels on cognitive performance in the Morris water maze (MWM) and Novel Object Recognition (NOR) through a large-scale meta-analysis of 3xTg-AD mouse model experiments. The triple-transgenic mouse model (3xTg-AD) of AD expresses tangle and plaque pathology as well as synaptic dysfunction. Multiple linear regression confirmed pTau is a stronger predictor of MWM performance than Aβ. Despite pTau's lower physical concentration than Aβ, pTau levels more directly and quantitatively correlate with 3xTg-AD cognitive decline.

A Measure of Cerebrospinal Fluid Flow Suggests that Brain Aging Commences Early
https://www.fightaging.org/archives/2018/02/a-measure-of-cerebrospinal-fluid-flow-suggests-that-brain-aging-commences-early/

There is a growing faction in the neurodegenerative research community whose members think it likely that rising levels of metabolic waste in brain, such as tau and amyloid aggregates, are due to failing drainage of cerebrospinal fluid. That drainage is a primary method of removal, and as it declines the wastes build up. The Methuselah Foundation is somewhat ahead of the game here, having incubated Leucadia Therapeutics to develop a possible solution. A number of other groups have turned their attention to this topic, and it has been interesting to see a flurry of papers in the last year or so. The work noted here is related, though the researchers are looking at circulation of cerebrospinal fluid within the brain, driven by cardiovascular activity, rather than drainage. The open access paper - worth looking at, but very dry - describes a low-cost way of assessing this flow and some exploration of the findings. Their measurements start to show changes at a comparatively early age, much earlier than one would expect for a process linked to cardiovascular function. This is quite interesting, though it is far too early to do more than speculate on why this might be the case.

Physicists have devised a new method of investigating brain function. This new non-invasive technique could potentially be used for any diagnosis based on cardiovascular and metabolic-related diseases of the brain. The researchers deciphered oscillations in the cerebrospinal fluid which lies between the scalp and skull; a device for non-invasive recordings of this translucent fluid was developed and recordings on healthy subjects were made.

It has been shown that the circulation throughout the brain of this fluid is highly fluctuating, and that these fluctuations are slow but interconnected by the rhythms of breathing and the heart rate. Researchers found that some of these oscillations are linked with blood pressure, but are generally slower, occurring at lower frequencies, which have been shown in previous studies to be related to oscillations in vascular motion and blood oxygenation.

Preliminary results showed evidence of a decline in the coherence between these oscillations in participants over the age of 25, indicating that brain ageing may begin earlier than expected. "Combining the technique to noninvasively record the fluctuation corresponding to cerebrospinal fluid and our sophisticated methods to analyse oscillations which are not clock-like but rather vary in time around their natural values, we have come to an interesting and non-invasive method that can be used to study ageing."

Present Medical Practice is Not Configured to Manage a Future of Ever-Improving Rejuvenation Therapies
https://www.fightaging.org/archives/2018/02/present-medical-practice-is-not-configured-to-manage-a-future-of-ever-improving-rejuvenation-therapies/

The present day organization of medical practice and its regulation is built atop the infectious disease model, even where it engages with age-related diseases. Prevention is a comparatively thin thread in an industry largely focused on the strategy of waiting until there is a problem, then attacking the symptoms of that problem with every available tool, as aggressively as possible. This isn't all that useful for age-related disease to start with, but it simply doesn't work for a world in which rejuvenation therapies that can repair the damage that causes aging initially arrive in a prototype form and then grow more capable over time. In that world - our world! - prevention quickly becomes enormously important and effective, and should be prioritized accordingly. This will require major change in a large number of conservative, hidebound organizations and communities, and will no doubt proceed only slowly and reluctantly.

A mainstay of preventive medicine innovators and medical futurists has been the concept of longevity escape velocity (LEV). LEV represents the time at which someone is gaining greater than 1 year of predicted healthy life expectancy per year, essentially making his or her healthy life expectancy unlimited. But practically, what are the likely requirements to reach such a "longevity escape velocity"? Around 95% of medical service budgets today are spent on acute medicine, with only around 5% on preventive care. How can today's medicine adapt to bring around a care system that provides LEV on a population scale?

To help patients achieve and maintain LEV, medical knowledge is required from diverse medical specialties and from outside specialties typically practiced by doctors. General practice (also known as primary care or family medicine) is the current specialty with the most similarity to LEV medicine; however it lacks in knowledge in many key areas, as well as in availability of time. An LEV medical specialty could be a subspecialty training of general practice, internal medicine, geriatrics, or clinical research. Core elements of an LEV medical specialty training would include education in prioritization of clinical problems according to magnitude and probability of clinical outcome or surrogate marker impact to a specific person's budget; understanding clinical biogerontology frameworks, including pathology based frameworks (such as the Strategies for Engineered Negligible Senescence [SENS] framework) and process based frameworks (such as the Hallmarks of Aging framework) and the associated markers and current state of therapies and clinical or research access to these.

How can LEV be measured accurately? Initial models are needed that take into account a minimum number of quality measurements across broad clinical outcomes and frameworks of aging (such as SENS and Hallmarks of Aging). Optimal ranges for clinical outcomes can be established for diverse markers and used to create an effective "biological age" for individual organs or systemic aging pathologies. Combined with current best risk prediction calculators for broad sets of diseases as well as a current annual "coefficient of baseline gain in life expectancy" due to current innovation rates, and taking into account a qualitative measure of a person's financial budget, motivation, and "LEV-related education," a client's LEV might be be determined to fall within a certain range.

Research is paramount to accelerate the generation of evidence of efficacy and safety of new measurements, therapies, and clinical pathways that are relevant to LEV. A core element of LEV medicine should be that any novel practice across any aspect of LEV medicine, be it a new annual screening panel, an off label pharmaceutical, an experimental stem cell or gene therapy, should be part of a formal registry, with all data captured and published open access, and ideally collated to a central LEV society or organization for analysis, methodological and ethical critique, and distribution to parties that may benefit. For example, what proportion of potentially useful surrogate marker or clinical outcomes data is captured, collated, and distributed from the proportion of people globally experimenting with novel therapies? It is likely under 0.01%; global standards to capture such data usefully - such as via guidelines for basic experimental protocol that doctors and patients may follow for each novel intervention, as well as systems to capture, collate, analyze, and disseminate such data - could have ensured perhaps 1000 or 10,000 times more data on all novel practices to date, providing benefits for everyone.

DAMPs May Link Age-Related Mitochondrial Dysfunction and Chronic Inflammation
https://www.fightaging.org/archives/2018/02/damps-may-link-age-related-mitochondrial-dysfunction-and-chronic-inflammation/

Mitochondria-derived damage-associated molecular patterns (DAMPs) are a range of DNA and protein fragments that are thought to be generated as a result of mitochondrial damage, insufficient mitochondrial quality control, or some combination of the two. Mitochondria are the power plants of the cell, each cell having its own small herd of these descendants of ancient symbiotic bacteria. They have long since evolved into integrated cellular components, but retain a little of their original DNA. There is copious evidence to point to a sizable role for mitochondria in the harms caused by aging. In the SENS view, the most important problem is that mitochondrial DNA (mtDNA), less protected than the DNA in the cell nucleus, becomes damaged in ways that both cause dysfunction and make the broken mitochondria more resistant to removal by the machinery responsible for quality control.

The focus of this open access paper is on understanding how mitochondrial dysfunction can be linked to the characteristic chronic inflammation that occurs with age. There are many contributions to inflammation among the processes of aging. Obviously, issues internal to the immune system account for much of the problem, but any cell is, in principle, given the right circumstances, capable of generating signals that will induce local immune cells to adopt an inflammatory state. This is one of the ways in which senescent cells cause significant harm, for example, forcing the immune system into consistent overactivation, a state that disrupts the usual beneficial activities of immune cells. Do cells that are not senescent, but are suffering significant mitochondrial damage produce similar outcomes? Do they also rouse the immune system into constant activation, via different mechanisms? Possible so.

Due to the relevance of mitochondria to cell physiology and whole-body metabolism, a comprehensive set of adaptive quality control mechanisms is in place to ensure the preservation of mitochondrial structural and functional integrity. Mitochondrial quality control (MQC) mechanisms also allow for the dynamic modulation of organelle function and number to meet the heterogeneous energy demands of the various tissues. MQC is accomplished through a set of interrelated processes (i.e., protein folding and degradation, mitochondrial autophagy, mitochondrial fission and fusion, and mitochondrial biogenesis).

The regulation of mitochondrial content is achieved through the dynamic balance between mitochondrial biogenesis and degradation. Mitochondrial biogenesis is a multistage process finalized to producing new mitochondria upon the coordinated expression of nuclear and mtDNA-encoded genes. Mitochondrial fusion allows for mtDNA mixing within the network, thereby preventing focal accumulation of mutant mtDNA and preserving mtDNA integrity. Mitochondrial fission, instead, segregates defective or unnecessary organelles for their subsequent removal through mitophagy. The integration of mitochondrial dynamics with the selective removal of dysfunctional mitochondria, referred to as mitophagy, ensures an efficient MQC process and preserves metabolic cellular "fitness."

Derangements of the MQC axis have been described during aging and in the context of a number of disease conditions, including cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. Along with mitochondrial dysfunction, chronic inflammation is a hallmark of both aging and degenerative diseases. The two phenomena may be linked to one another. Indeed, emerging evidence indicates that circulating cell-free mtDNA, one of the damage-associated molecular patterns (DAMPs), may establish a functional relationship between mitochondrial damage and systemic inflammation. mtDNA can be released into the circulation in response to cell insults. Here, it is able to induce an inflammatory response through hypomethylated CpG motifs resembling those of bacterial DNA. These regions, indeed, bind and activate membrane or cytoplasmic pattern recognition receptors (PRRs), such as the Toll-like receptor (TLR), the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR), and cytosolic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) DNA sensing system-mediated pathways.

The possible contribution of mitochondrial DAMPs to the inflammatory milieu that characterizes muscle wasting disorders has not yet been explored. However, this hypothesis is worth being pursued as it could help identify novel biological targets for the management of muscle loss. Here, we summarize the current evidence on circulating mtDNA as a trigger for age-related systemic inflammation. We first describe two candidate mechanisms generating and releasing cell-free mtDNA: (1) dysregulation of TFAM binding to mtDNA, and (2) impairment of mitophagy. Subsequently, we illustrate the pathways linking mitochondrial dysfunction with systemic inflammation during aging. Finally, we propose a role for the triad "MQC failure/cell-free mtDNA/inflammation" in two major muscle wasting disorders, sarcopenia and cachexia.

Calorie Restriction Boosts Intestinal Stem Cell Numbers and Improves Regeneration
https://www.fightaging.org/archives/2018/02/calorie-restriction-boosts-intestinal-stem-cell-numbers-and-improves-regeneration/

Researchers here look at the effects of calorie restriction on the stem cell populations that support intestinal tissue. There is plenty of evidence for calorie restriction to improve stem cell activity in other tissues, not to mention aiding many other mechanisms relevant to health. The practice of calorie restriction is very broadly beneficial. It slows aging over the long term, and in the short term improves near all measures of health. Despite the similarities in short term effects between mice and humans, however, it is the case that human life spans are not extended by anywhere near as much as those of mice. The evolutionary argument for this outcome involves the length of seasonal famine in comparison to length of life: the degree to which life spans are plastic in response to circumstances depends on the usual length of adverse circumstances. A mouse requires a much greater proportional extension of life to pass through a seasonal famine into a time of plenty again, and so that greater extension is selected for.

Years of research have demonstrated that existing on a calorie restricted diet can boost healthy lifespan, reducing the risk of heart attack, diabetes, and other age-related conditions. Other, more recent work has shown that calorie-restricted animals regenerate tissue more effectively following injury. "The beneficial effects of calorie restriction are at this point not really up for debate; it's quite clear. But there are all sorts of questions about the cellular and molecular basis to these benefits."

One theory has been that calorie restriction slows age-related degeneration and enables more efficient tissue function by influencing the integrity and activity of adult stem cells, the precursor cells that dwell within specific tissues and give rise to the diversity of cell types that compose that tissue. Recent studies focused on the effects of calorie restriction on the active intestinal stem cells. While these active stem cells bear the burden of daily tissue turnover and act as the workhorses of intestinal function, they are also known to be highly susceptible to DNA damage, such as that induced by radiation exposure, and thus are unlikely to be the cells mediating the enhanced regeneration seen under calorie restriction. Instead of looking at these active stem cells, researchers examined a second population of intestinal stem cells known as reserve stem cells. The team had previously shown that these reserve stem cells normally reside in a dormant state and are protected from chemotherapy and radiation. Upon a strong injury that kills the active cells, these reserve stem cells "wake up" to regenerate the tissue.

To investigate this hypothesis, the scientists focused on how a subpopulation of mouse intestinal stem cells responded under calorie restriction and then when the animals were exposed to radiation. When mice were fed a diet reduced in calories by 40 percent from normal, the researchers observed that reserve intestinal stem cells expanded five-fold. Paradoxically, these cells also seemed to divide less frequently, a mystery the researchers hope to follow up on in later work. When the research team selectively deleted the reserve stem cells in calorie-restricted mice, their intestinal tissue's regeneration capabilities were cut in half, implicating these cells as having an important role in carrying out the benefits of calorie restriction.

"These reserve stem cells are rare cells. In a normal animal they may make up less than half a percentage of the intestinal epithelium and in calorie restricted animals maybe slightly more. Normally, in the absence of injury, the tissue can tolerate the loss, due to the presence of the active stem cells, but, when you injure the animal, the regeneration is compromised and the enhanced regeneration after calorie restriction was compromised in the absence of the reserve stem cell pool. These reserve stem cells that we had shown were important for the beneficial effects of calorie restriction, were repressing many pathways that are all known to be regulated by the protein complex mTOR, which is most well known as being a nutrient-sensing complex. Curiously, we see that, when they're injured, the calorie-restricted mice were actually better able to activate mTOR than their counterparts. So somehow, even though mTOR is being suppressed initially, it's also better poised to become activated after injury. That's something we don't fully understand.

The researchers conducted experiments using leucine, an amino acid that activates mTOR, and rapamycin, a drug which inhibits mTOR, to confirm that mTOR acted within these reserve stem cells to regulate their activity. Reserve stem cells exposed to leucine proliferated, while those exposed to rapamycin were blocked. Pretreating the animals with leucine make the reserve stem cells more sensitive to radiation and less able to regenerate tissue following radiation injury, while rapamycin protected the reserve stem cells as they were more likely to remain dormant. The researchers caution, however, that rapamycin cannot be used as a stand-in for calorie restriction, as it would linger and continue to block mTOR activation even following injury, hindering the ability of the reserve stem cells to spring into action and regenerate intestinal tissue.

The Latest Rejuvenation Research Commentary on Relevant Papers
https://www.fightaging.org/archives/2018/02/the-latest-rejuvenation-research-commentary-on-relevant-papers/

The "commentary on some recent theses" section is a regular feature of the Rejuvenation Research journal, penned by Aubrey de Grey and collaborators. Historically it has been behind a journal paywall, but it is presently open access - and in this day and age of organized copyright heretics who assemble online databases of papers normally locked away, it is ceasing to much matter whether or not journals maintain a paywall when it comes to access. The most recent commentary touches on a range of different topics; reading it all is recommended. The quoted material here relates to an interesting discovery regarding the senescence of astrocytes in the aging brain, which, as noted, offers the promise of effective near future treatments for a range of neurodegenerative conditions.

Of the seven strands of the SENS platform, the ablation of senescent cells (ApoptoSENS) has thus far made the most progress towards the clinic; drugs that selectively eliminate these toxic and superfluous cells are referred to as senolytics, and several are now undergoing or are soon to enter clinical trials. Recent evidence from preclinical work has indicated that the role of senescent cells in the aging process is remarkably significant, such that resolving this single form of damage yields dramatic benefits across the spectrum of age-related decline - simultaneously extending both lifespan and healthspan in mouse models.

Although the existence of a true senescent phenotype in postmitotic cells such as neurons is still unproven, its existence in their crucial support cells, the astrocytes, has been recognized since the beginning of this decade. A recent dissertation makes vital progress towards proving the clinical relevance of the phenomenon - laying the groundwork for the translational application of senolytics to major neurodegenerative diseases. Glutamate (together with aspartate) is the major excitatory neurotransmitter in the human brain, and dysfunctions of its handling are clearly associated with both acute and chronic neurological conditions. That such dysfunction is here shown to be an intrinsic consequence of physiologically realistic levels of astrocyte senescence leaves little doubt that a mechanistic connection must exist. In Alzheimer's disease specifically, it is notable that the loss of glutamate receptors in postmortem samples tracks both the brain's major excitatory pathways and also the very well-established progressive staging of the disease. These results are good news indeed!

Replacing intrinsically aged neurons without disrupting synaptic connectivity has always been accepted to be a daunting task, but astrocyte turnover - while low in healthy tissue - is a routine process following injury (albeit one that has side effects of its own when driven to excess in the context of chronic inflammation, although these appear somewhat treatable). Thus, depleting senescent astrocytes and so neutralizing their inflammatory effects may well automatically induce their replacement by healthy new cells; and even if not, stimulating that process is not an insurmountable challenge. At the very least, such a therapy should prevent further degeneration - and perhaps even create the conditions for the repair of pre-existing neuronal decline as well, especially since a subset of those astrocytes may be able to function as neural stem cells.

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