Fight Aging! Newsletter, April 3rd 2017

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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  • Fight Aging! Invests in CellAge, Developing New Cellular Senescence Assays
  • Regulatory Processes Relevant to Amyloid Formation in Aging
  • Reassessing Past Evidence for Radiation Hormesis to Extend Life in Dogs
  • A Set of Recent Papers on Aspects of Cellular Quality Control in Aging
  • The Open Longevity Initiative Works Towards Organization of Trials
  • Latest Headlines from Fight Aging!
    • Calico Partners to Obtain Protein Degradation Technology
    • Can a Useful Biomarker of Aging be Built from Very Simple Measures?
    • A Lightning Tour of One Arm of the Longevity Science Community
    • An Examination of Mitochondrial Dysfunction in Senescent Cells
    • A Look at Some Recent Efforts to Push Rapamycin Derivatives to the Clinic
    • The Current State of Senolytic Drug Candidates
    • Proposing that CK2.3 Treatment Can Restore Bone Density in Osteoporosis
    • An Investigation of Declining Autophagy in Aging
    • The Aging of the Extracellular Matrix of the Heart
    • Immune Cell Epigenetics Become More Disarrayed with Age

Fight Aging! Invests in CellAge, Developing New Cellular Senescence Assays

CellAge is one of the new initiatives arisen in recent years from our community of longevity science advocates and researchers. The principals are focused on the biology of senescent cells, and are attempting to apply the new technology of synthetic gene promoters in order to produce a better class of assay for cellular senescence in living tissue. This will test for amounts and types of senescent cell, improving upon the current standard approaches used in research, protocols that have been around for ten to twenty years and are by now showing their age. They are good enough for the sort of lab work that has taken place over that time, but certainly not good enough for the near future in which targeted removal of senescent cells becomes a widespread clinical therapy. This approach to the treatment of aging as a medical condition has great promise, but those therapies will certainly have to be accompanied by low-cost, reliable assays to assess exactly how well they work. I'm very much in favor of efforts to produce the next generation of cellular senescence assays, as this provides an important form of support for the companies that are presently working on senescent cell clearance approaches.

As I'm sure you'll recall, CellAge started out by crowdfunding their initial work via The aim of this first project, now underway, is to produce an improved assay for senescent cells that the company will release for free to the academic community. It was a challenging fundraiser, largely because of the timing, as our community had given a great deal to various other fundraisers over the course of 2016. It was stuck for quite some time half-way to the target. While that was the case, a few of us started to cast around for alternative sources of funding from the for-profit investment community, something always intended by the CellAge founders, just not quite so soon. Putting together a funding round for a very early stage company always takes longer than you think it will to reach a useful conclusion; it is something like herding cats, and a great deal more legally complicated than it needs to be, especially for the UK where CellAge is based. While this process was underway, the CellAge fundraiser came to a much more successful conclusion than hoped, thanks to the hard work of the Life Extension Advocacy Foundation volunteers and the generosity of a number of significant donors. Very gratifying!

Now, on top of that crowdfunding success, I'm pleased to note that the initial CellAge investment round has finally completed assembly, with one of the professional VCs in our community taking the lead and accomplishing the heavy lifting in organizational matters. Fight Aging! and a small group of other angel investors joined in, collectively stretching our available funds in order to give the CellAge founders the fuel they need to reach the next stage following their initial proof of concept work. The hope is that CellAge should have interesting things to demonstrate by the end of the year, and into 2018.

On this topic, it is worth noting that our community has few scientific entrepreneurs. Yet such entrepreneurs play a vital role in the path that leads from concept through research to realized therapy. I think it important that we do our part to assist those researchers who are willing and able to make the leap to successfully starting a company to carry forward their work. In the years ahead they will be the ones picking up new projects and helping to push new rejuvenation therapies from the laboratory to the clinic. They will be the ones employing the next generation of researchers and biotechnologists, inspiring them to make the same leap into medical development. For the SENS vision of human rejuvenation to succeed in the decades ahead, the SENS Research Foundation and its allies must have a diverse community of entrepreneurs to call upon, an important addition to the existing network of researchers and research groups. The CellAge team are first-time founders, but learn quickly, have a great background in the underlying science, and clearly have the right stuff to make a go of it. I'm happy to have been able to do a little to help them build their network and company.

Regulatory Processes Relevant to Amyloid Formation in Aging

The open access paper for today takes a look at amyloid formation and some of the cellular processes that try to hold it back, processes that become increasingly disarrayed with advancing age. Amyloids are one of the distinguishing features of old tissues, absent in the tissues of younger individuals. There are a score or so of different types of amyloid, each corresponding to a particular protein that can become misfolded in a way that makes it precipitate and clump into solid aggregates between cells. Some amyloids are very well associated with specific age-related diseases, as is the case for amyloid-β and Alzheimer's disease, and as is becoming the case for transthyretin amyloid and cardiovascular disease. Others remain more obscure, and it is even possible that some do not contribute meaningfully to aging over a normal human life span.

In those cases where the biochemistry of an amyloid is well explored, as for amyloid-β, it appears that it is not the amyloid per se that is the problem, but the surrounding halo of related compounds. This environment and its interactions with cells has proven to be exceedingly complex, like most areas of interest to modern medicine. Clearing out the amyloid should nonetheless be beneficial, either by removing a source of those errant and damaging molecules, or by damping the reaction of cells to its presence, something that may also be a problem. Not all cellular reactions to the damage and change of aging are beneficial: there are plenty of examples of antagonistic pleiotropy to pick from, in which cellular behavior that helps in the context of a youthful environment is far less benign in the context of aged tissues.

Even before attaining a complete understanding of the biochemistry of any particular amyloid, a task that the Alzheimer's research community has demonstrated to be very challenging, we should be guided towards a strategy of removal. This is on the basis that amyloid is not observed in any significant amount in young tissues. The high level strategy for the development of rejuvenation therapies should be to target and revert known changes, at least in those cases where we can put forward good evidence for the change to occur due to the normal operation of metabolism. In other words that it may be a root cause of aging, not secondary to some other change. Amyloid accumulation appears a good candidate in this model, though given the complexity and still incomplete mapping of the mechanisms involved, the definitive proof will probably arrive from successful clearance rather than successful analysis.

Cellular Regulation of Amyloid Formation in Aging and Disease

As the population is aging, the incidence of age-related neurodegenerative diseases, such as Alzheimer and Parkinson disease, is growing. The pathology of neurodegenerative diseases is characterized by the presence of protein aggregates of disease specific proteins in the brain of patients. Under certain conditions these disease proteins can undergo structural rearrangements resulting in misfolded proteins that can lead to the formation of aggregates with a fibrillar amyloid-like structure. The role of these aggregates in disease is not fully understood: the most prevalent hypothesis is that aggregation intermediates - single or complexes of aggregation-prone proteins - are toxic to cells and that the aggregation process represents a cellular protection mechanism against these toxic intermediates.

Cells have a protein quality control (PQC) system to maintain protein homeostasis. Preserving protein homeostasis involves the coordinated action of several pathways that regulate biogenesis, stabilization, correct folding, trafficking, and degradation of proteins, with the overall goal to prevent the accumulation of misfolded proteins and to maintain the integrity of the proteome.

One of the cellular mechanisms that copes with misfolded proteins is the chaperone machinery. A molecular chaperone is defined as a protein that interacts with, stabilizes or assists another protein to gain its native and functionally active conformation without being present in the final structure. In addition to folding of misfolded proteins, molecular chaperones are also involved in a wide range of biological processes such as the folding of newly synthesized proteins, transport of proteins across membranes, macromolecular-complex assembly or protein degradation and activation of signal transduction routes. Next to their function under normal cellular conditions, chaperones play an important part during neurodegeneration when there is an overload of the PQC system by unfolded proteins. Each neurodegenerative disease is associated with a different subset of chaperones such as heat shock proteins that can positively influence the overload of unfolded proteins

Protein degradation is another key mechanism to deal with misfolded proteins. Three pathways have been described, i.e., the ubiquitin-proteasome system (UPS), chaperone mediated autophagy (CMA), and macroautophagy. Protein aggregates or proteins that escape the first two degradation pathways are directed to macroautophagy, a degradation system where substrates are segregated into autophagosomes which in turn are fused with lysosomes for degradation into amino acids. The proteins involved in neurodegenerative disease can rapidly aggregate and can thereby escape degradation when they are still soluble, the aggregates and intermediate forms are partly resistant to the known degradation pathways.

A further compensatory mechanisms involves the endoplasmic reticulum (ER). The unfolded protein response (UPR), induced during periods of cellular and ER stress, aims to reduce unfolded protein load, and restore protein homeostasis by translational repression. ER stress can be the result of numerous conditions, including amino acid deprivation, viral replication and the presence of unfolded proteins, resulting in activation of the UPR. In addition, misfolded proteins can be sequestered in distinct protein quality control compartments in the cell by chaperones and sorting factors. These compartments function as temporary storage until the protein can be refolded or degraded by the proteasome. Different compartments have been described in the literature that sequester different kind of misfolded proteins at various conditions.

Under normal conditions, the PQC can rapidly sense and correct cellular disturbances by activating stress-induced cellular responses to restore the protein balance. During aging or when stress becomes chronic, the cell is challenged to maintain proper protein homeostasis. Eventually, this can lead to chronic expression of misfolded and damaged proteins in the cell that can result in the formation of protein aggregates. The presence of aggregation-prone proteins contributes to the development of age-related diseases. The decline of protein homeostasis during aging is a complex phenomenon that involves a combination of different factors. In line with the decreased protein homeostasis, there appears to be an impairment of the upregulation of molecular chaperones during aging. Since all major classes of molecular chaperones, with the exception of the small heat shock proteins, are ATPases it has been suggested that the depletion of ATP levels during aging due to mitochondria dysfunction would affect their activity. This is reflected by the repression of ATP-dependent chaperones and the induction of ATP-independent chaperones in the aging human brain. This may contribute to the decline of chaperoning function during aging.

Under the right conditions any protein could form amyloid-like structures. Although amyloids have been traditionally related to diseases, they also have diverse functions in organisms from bacteria to human that may underlie their nature. Nevertheless, the toxicity of amyloid intermediate species associated with disease makes protein aggregation a process that has to be under tight control and regulation. In this context, aging is a key risk factor due to the progressive decline of protein homeostasis, which leads to increased protein misfolding and aggregation. This can eventually result in the onset of age-related diseases characterized by protein aggregation. As the human population becomes older, it is essential to understand the processes underlying age-related diseases that are the result of protein aggregation and its associated toxicity. This is a very broad research field, ranging from biophysics to clinical trials. Every year discoveries are made that involve the identification of factors affecting protein aggregation. It can be concluded that the overall knowledge of the aggregation process is improving, which will allow for the development of new and accurate treatments against aggregation-linked diseases.

Reassessing Past Evidence for Radiation Hormesis to Extend Life in Dogs

It is well known that induction of low or intermittent levels of repairable damage in cells and tissues is a good thing. It triggers more aggressive cellular maintenance for some period of time, and the end result is a net gain in the quality of the cellular environment: fewer damaged proteins and structures left to cause secondary issues. This effect is known as hormesis, and most common forms of molecular damage and stress to cells can trigger it. Exercise and calorie restriction produce hormetic effects, for example, as does exposure to heat and to most toxins at suitably low doses. Of interest for today is the hormesis produced by exposure to low levels of ionizing radiation, a process that has been studied in insects and to a lesser degree in short-lived mammals.

The next step after research involving short-lived mammals is to run studies in longer-lived mammals. The cost of such studies increases dramatically with species life span, which is why the history of any particular subject in the life sciences starts with worms and flies, works up to mice, and only then reaches dogs, pigs, and primates before clinical translation to human medicine. At each stage, compelling results are needed to raise the funding for the next and more expensive set of work. The large amount of data on various methods of modestly slowing aging in this range of species has made it quite clear that a given method becomes dramatically less effective in species of longer life spans. Calorie restriction can add 40% to the life span of mice, but certainly doesn't do that in humans. Life span in our species is much less plastic in response to environmental circumstances and genetic alterations known to impact health and longevity than is the case in flies, worms, and mice.

In the paper noted below, researchers reassess the effects of radiation hormesis in a comparatively short-lived breed of dogs, in both younger and older individuals. The data they use was originally generated in the late 1980s. They claim a gain of remaining life expectancy of 15% or so in older dogs, and 50% or so in younger dogs. The size of the study is not enormous, so I'd certainly like to see that result replicated. The outcome is unexpectedly, even suspiciously large for a hormesis effect in a mammalian species of this life span.

The authors state that the original studies controlled well for confounding variables, but given that they ran in the 1980s, I think it quite plausible that those researchers did not adequately control for calorie restriction effects. This is a major issue with many of the life span studies conducted prior to the turn of the century, and even a sizable fraction of those carried out later. I looked through one of the referenced documents that discussed the experimental protocols, and didn't find any mention of diet there. So I don't think that this paper means we should all be getting low-intensity ionizing radiation sources for our bedrooms - the evidence would have to be far more extensive and bulletproof to start making that sort of suggestion. Taken together with the other animal evidence, however, it does indicate that the present zero tolerance approach to radiation exposure is probably mistaken.

Evidence That Lifelong Low Dose Rates of Ionizing Radiation Increase Lifespan in Long- and Short-Lived Dogs

The overall effects of ionizing radiation on organisms are well known at high doses. At high and low doses, the detailed cell response mechanisms are complicated and may involve all levels of biological organization. About 75% of the human body is water, and a principal effect of radiation is the creation of reactive oxygen species (ROS), including hydrogen peroxide. They are a double-edged sword. Depending on their concentrations, they may cause damage or signaling in terms of stress responses. Studies on experimental living systems and on humans have shown, depending on the individual genome, that low doses of radiation upregulate many biological protective mechanisms, which also operate against nonradiogenic toxins and produce beneficial effects, including a lower risk of cancer.

For more than a century, extensive studies have been carried out on the effects of radiation, which demonstrate that harmful effects, such as radiation illness, may arise after exposures above known threshold dose levels, whereas a range of beneficial effects may be observed following low-dose exposures. Although there appears to be an awareness among the prominent leaders of the radiation protection establishment that current radiation protection policy contradicts this biological evidence; there is a very broad consensus among them that it is impossible to attribute health effects to low radiation exposures, namely to exposures similar to the wide spectrum of background levels. This opinion does not consider the recent progress in biological research on the mechanisms that underlay the fact that living organisms are "complex adaptive systems."

When people increasingly question whether low levels or low doses of radiation are really harmful, protection practitioners argue that "radiation-sensitive individuals" exist who are more vulnerable than average people to potential "health effects" and must be protected. This concern about protecting sensitive individuals and the suggestion that longevity may be the most appropriate measure of the effect of radiation on health led to this examination of the effect of dose rate on the lifespans of dogs. The authors reexamined data on the health effects of long-term irradiations in two large-scale studies on groups of beagle dogs. One exposed the dogs to whole-body cobalt-60 γ-radiation. The other evaluated dogs whose lungs were exposed to α-particle radiation from plutonium. Each group of dogs received a different dose rate.

These studies had been reviewed previously to determine the dependence of the lifespan of 50% mortality dogs on dose rate. The lifespans of dogs at 5%, 10%, and 50% mortality in the control group (background dose rate) were compared with the lifespans of the 5%, 10%, and 50% mortality dogs in each dose rate group. Analysis of the data of the first study suggested an increase in the lifespan of dogs exposed to 50 mGy of γ-radiation per year, compared to the control dogs. Analysis of the data of the second study suggested an increase in longevity for dogs with an initial plutonium lung burden of 0.1 kBq/kg, compared to the control dogs. These are very credible studies, carefully carried out by qualified and experienced scientists who bred the dogs and controlled all confounding factors. Interpolations of the study data suggest that the optimum dose rate for longevity is about 50 mGy per year for all mortality levels. The lifespan increase is about 15% for 50% mortality dogs and much greater for the more radiation-sensitive dogs. The shorter lived control dogs (5% mortality level) have a lifespan of about 3000 days, whereas the dogs in the group with an initial plutonium lung burden of 0.16 kBq/kg have a lifespan of about 4500 days, 50% longer.

If dogs model humans, then one should expect that radiation-sensitive individuals would benefit more from exposures to low-level radiation than average humans. So protecting sensitive people from low-dose γ- or α-radiation would be inappropriate because it would deprive them of the health benefit of a longer life. The results of this review suggest the need to change radiation protection policy. Obviously, maintaining exposures as low as reasonably achievable is very likely detrimental.

A Set of Recent Papers on Aspects of Cellular Quality Control in Aging

Autophagy is a prominent topic in aging research. This is also the case for other forms of cellular maintenance processes, but autophagy is by far the most studied and understood at this time. Here when I say autophagy I mean macroautophagy. There other other, less well cataloged forms, but it is usually the case that when someone refers to autophagy without qualification, then they are talking about macroautophagy. In this type of autophagy, damaged molecules and cell structures are isolated inside a specially constructed membrane, and that then fuses with one of the cellular recycling system known as lysosomes. A lysosome is packed with molecules capable of dismantling near all biological compounds it is likely to encounter, rendering them into raw materials for reuse.

All forms of quality control within cells appear to be quite influential in health and longevity over the long term. Damaged cellular components that linger cause secondary harms, and so the more efficiently they are removed the better the operation of the cell. Then multiply that by all the cells in a tissue. Unfortunately, cellular processes of repair and maintenance appear to succumb to forms of damage as the years pass. In the case of autophagy, one problem is caused by the accumulation of metabolic waste products that the lysosome is not equipped to handle. Lysosomes become bloated and unable to perform their normal tasks efficiently. Cells malfunction or die, and the waste products continue to build up in cells and cellular debris until they are visible as lipofuscin. This is how wear and tear proceeds in a self-repairing system: first the repair mechanisms start to fail, then everything else heads downhill ever more rapidly thereafter.

Beyond the varieties of autophagy, cells boast a panoply of other systems intended to fix problems and clear out unwanted junk, ranging from DNA repair to proteasomes to, as a last resort, encapsulating excess waste material and kicking it out into the space between cells. Not all are well understood. The few open access papers below cover some of this range, and are indicative of the level of attention given to cellular quality control in the medical research community. It isn't a coincidence that these papers focus on the brain and neurodegenerative conditions; that is where much of the academic funding for aging research is directed these days. Alzheimer's research alone accounts for a very large share of the public research funding directed towards aging as a whole, and it is plausible that private funding tends to mirror this distribution.

Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

The ubiquitin-proteasome system (UPS) is one of the major protein degradation pathways, where abnormal UPS function has been observed in cancer and neurological diseases. Many neurodegenerative diseases share a common pathological feature, namely intracellular ubiquitin-positive inclusions formed by aggregate-prone neurotoxic proteins. This suggests that dysfunction of the UPS in neurodegenerative diseases contributes to the accumulation of neurotoxic proteins and to instigate neurodegeneration. Here, we review recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease.

DNA Damage Response and Autophagy: A Meaningful Partnership

Autophagy and the DNA damage response (DDR) are biological processes essential for cellular and organismal homeostasis. Herein, we summarize and discuss emerging evidence linking DDR to autophagy. We highlight published data suggesting that autophagy is activated by DNA damage and is required for several functional outcomes of DDR signaling, including repair of DNA lesions, senescence, cell death, and cytokine secretion. Uncovering the mechanisms by which autophagy and DDR are intertwined provides novel insight into the pathobiology of conditions associated with accumulation of DNA damage, including cancer and aging, and novel concepts for the development of improved therapeutic strategies against these pathologies.

Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

Autophagy is emerging as one of the core orchestrators of healthy aging. This self-degradation process is present in all mammalian cells and tissues, including the central nervous system (CNS), and specializes in directing unnecessary or damaged intracellular material to the lysosome, the major cellular organelle that digests and recycles all types of macromolecules. Autophagy, as a constitutive mechanism, participates in the basal turnover of long-lived proteins and organelles, playing a major role as a checkpoint for quality control. On the other hand, stressful situations such as metabolic starvation or functional damage induce an adaptive autophagic response to restore cellular homeostasis. Thus, adaptive autophagy provides the cell with nutrients and energy during metabolic shortage and relieves it from toxic components during functional damage. Accordingly, a correct completion of the autophagic response is central for optimal CNS physiology and the promotion of neuronal survival. This is evidenced by the elevated number of connections made between the dysregulation of autophagy, aging, and neurodegeneration.

In this review, we will describe the role of autophagy (dys)regulation in the aged and diseased brain. Particularly, we will focus on microglia, the brain's resident macrophages with intrinsic capability to respond to CNS damage, promoting repair and a correct brain function. First, we will briefly outline the process of autophagy and its regulation, and summarize key technical aspects for the correct monitoring of autophagy at the experimental level. Then we will review the role of autophagy in neurons and the impact of autophagy failure in neurodegeneration. Finally, we will detail the current state of the literature on the role of autophagy in peripheral macrophages and microglia, including the regulation of phagocytosis and the inflammatory response.

The Open Longevity Initiative Works Towards Organization of Trials

I noted the existence of the Open Longevity initiative earlier this month. This is an evolution of the core Russian-language longevity science community, involved in the Science for Life Extension Foundation and related advocacy initiatives. The members of that community have been building bridges to the European and US longevity science communities for a decade now, aided by progress in automated translation technologies and the growing prospects for therapies that can meaningful treat the causes of aging. Collectively, we've reached the point at which meaningful treatments are almost at the clinic; it is the time to move beyond talking to helping ensure that these treatments enter trials and become available as soon as possible.

Open Longevity is explicitly structured as an organization of patients, for patients: people who want to treat aging as the medical condition it is, and are willing to organize and participate in medical trials to push forward the state of the art. The present sad situation in medical regulation and the mainstream aging research community is that near all efforts that could be achieved now, this year, if people just went out and did the work, will never happen. No-one will test combinations of the non-chemotherapeutic senolytic drugs; no-one will try building a better polypill for reducing cardiovascular disease; and so on. Within the commercial and regulatory arena, the best that can be hoped for is narrow trials of a single drug candidate for the late stage of age-related disease, which is the goal that UNITY Biotechnology is aiming for with their senolytic treatments.

It is self-evident that better results than this can be achieved by ignoring the FDA and its Western European counterparts, given a bunch of people willing to put in the work and some funding, and who are sufficiently well organized to avoid the pitfalls of self-delusion that tend to beset more amateur citizen science efforts in medicine. Setting up responsible, transparent trials of treatments isn't rocket science, just hard work, and it certainly isn't something that only government organizations can achieve. I'm fairly certain that our broader community is capable of generating such an effort, I hope to see it happen in the years ahead in the matter of senolytic therapies, and indeed, I've written on this topic in past years.

The Open Longevity volunteers look like they are heading in the right sort of direction, for all that they are starting out with potential treatments that I'm not much in favor of spending time on - the standard panoply of calorie restriction mimetics and the like. Taking an incremental approach seems sensible, however, and it is developing the ability to organize and produce unbiased results that is important here, not the particular therapies used as the initial testbeds. Our community and the companies working on therapies have a great need for one or more organizations that can reliably deliver trials and medical tourism outside the present regulatory system as a service, and such an organization would help to greatly speed up progress towards widespread availability of the first rejuvenation therapies. On this note, the following turned up in my in-box earlier this week:

Starting on March 29th in Kotor, Montenegro, the first Longevity School is being held, organized by the patients' organization Open Longevity. The purpose of our organization is to carry out clinical trials of therapies against aging. We are determined to create the best possible therapies based on all achievements of science and considering individual approach. Recently we've started to organize clinical trials of a new type, based on the principles of openness, with a non-commercial approach, and aiming for continuous improvement of the effectiveness of interventions under trial. We believe that by not focusing on opportunities to capitalize the cure for old age, and by immediately publishing the results of clinical experiments, we will achieve a higher level of expertise. The protection of scientific advances by patents and trial data by secrecy leads to a lack of exploration of the potential reuse of existing therapies for new purposes, since it is impossible to ensure sufficient freedom to use the results.

The first task of the Longevity School in Montenegro is to raise the level of knowledge of the participating patients. For this matter, we will conduct 67 lectures on the biology of aging with a final exam. Our goal is to establish cooperation, a dialogue between patients, doctors, and scientists to achieve the common goal of radical life extension. Second, we will start testing a fasting mimicking diet, which aims to reduce the level of insulin-like growth factor 1 in humans. The third step is the preparation of clinical trials protocols for testing combinations of anti-aging interventions. We will have five roundtable discussions to come up with the best strategy. In doing so, our goal is not just to confirm or deny effectiveness of a drug or a combination of drugs. We will not stop at testing of a minor drug candidate like metformin. Our goal is to constantly increase the power of interventions, adapting it to the current situation and health conditions. That is why one of the tasks for Open Longevity project is to implement aging diagnostics into clinical practice.

The first Longevity School will be held from 29 March to 7 April. The Montenegro school is our first one, but we will systematically run Longevity Schools on all continents to engage millions of people into the common cause of life extension. We are moving from simple to complex, from diet to gene therapy, until aging is defeated.

Latest Headlines from Fight Aging!

Calico Partners to Obtain Protein Degradation Technology

For those who like reading the Calico tea leaves, here are a few details on one of their recent partnerships. Calico, the California Life Company, is the aging research venture funded by Google. It launched a few years back, but so far those involved appear to be doing nothing particularly radical, insofar as we know anything about what is going on there. Calico is certainly not supporting the SENS view of damage repair as the best way to treat aging, and may well be turn out to be simply a larger and more secretive version of the Ellison Medical Foundation in the end: an expansion of the largely investigative work already taking place at the NIA, undertaking no projects with the potential to make a large difference to the course of aging in humans. More research is always better than less research, of course, but nonetheless this has grown to have the look of another missed opportunity to add to the recent history of aging research.

Here, Calico is partnering to obtain access to a technology that could be turned to ways to adjust the level of any one or any few of the proteins present in a cell. The approach works by harnessing one of the cell's established recycling mechanisms. This might be intended as an alternative to methods such as RNA interference for use in adjusting cellular operation. The goal is to tinker with the switches and dials of metabolism, all of which are influenced or determined by levels of specific proteins, in order to test approaches that might slightly slow aging by reducing the pace at which damage accumulates. More positively, it might be turned to degrading forms of metabolic waste that cause aging, though beyond amyloid and Alzheimer's disease, there is little sign that Calico researchers are interested in the list of waste compounds outlined in the SENS rejuvenation research proposals, such as cross-links, lipofusin, and so forth.

C4 Therapeutics (C4T) and Calico today announced a five-year collaboration to discover, develop, and commercialize therapies for treating diseases of aging, including cancer. Under the terms of the agreement, the parties will leverage C4T's expertise and capabilities in targeted protein degradation to jointly discover and advance small molecule protein degraders as therapeutic agents to remove certain disease-causing proteins. The partnership will pursue preclinical research and Calico will be responsible for subsequent clinical development and commercialization of resulting products that may emerge from the collaboration.

"We know from decades of translational research that it can be incredibly challenging to find effective pharmacologic inhibitors of many of the biologically well-validated targets, particularly in cancer. Through the alternative strategy of specifically targeting such proteins for degradation, we believe we have the opportunity to identify promising new therapeutics in cancer and in other diseases as well. We're looking forward to collaborating with C4T's scientists and applying their protein degradation technology to the discovery and development of effective new treatments."

C4 Therapeutics is a private biotechnology company developing a new class of drugs based on Targeted Protein Degradation (TPD) to address a broad range of life-threatening and life-impairing diseases. C4T's platform uses small molecule drugs to direct the machinery of the ubiquitin-proteasome system to selectively degrade disease-relevant proteins for therapeutic benefit. This distinctive mechanism provides new opportunities to target traditionally difficult-to-treat diseases and diseases plagued by drug resistance.

Can a Useful Biomarker of Aging be Built from Very Simple Measures?

There is considerable interest in the research community in the construction of a low-cost, reliable biomarker of biological age. The intent is to use such a test immediately before and after the application of a potential rejuvenation therapy to establish how well it worked. It must therefore accurately assess overall health, mortality risk, and remaining life expectancy. Currently DNA methylation assays are a leading approach to the creation of a robust biomarker of aging, as some portions of the changing pattern of DNA methylation are a fairly good reflection of cellular reactions to the damage and decline of aging. Is it possible to produce something far less complicated, however, a biomarker that uses only existing measures of health, but that is nonetheless good enough to evaluate near future rejuvenation therapies? This is an open question, one that can be argued either way.

Mammalian aging is characterized by a gradual decline of numerous health parameters with multiple biochemical, physiological and behavioral manifestations. Several animal models have been successfully used over the last several decades to address mechanistic aspects of aging and development of age-related diseases. In most of these studies the major metric parameter for assessing pro-/anti-aging effect of genetic, nutritional or pharmacological manipulation has been the animals' lifespan. While being informative, longevity by itself however, cannot provide an assessment of the animal's health status, which, like in humans, can significantly decline at older ages and therefore reduce the quality of life. This concern is particularly relevant to research focused on developing the "healthspan"-extending pharmaceuticals, efficacy of which may not be necessarily translated in increased longevity but rather in prolongation of healthy life and require quantitative objective assessment.

Clinical studies in humans measure age-related declines in performance by quantifying the frailty index (FI), which reflects accumulation of health deficits during chronological aging. Since numerous studies have shown that many age-associated changes that occur in humans are also present in aged mice, FI was recently introduced as a measure of mouse aging to pre-clinical models. However, standardized and comprehensive approaches for FI measurements, which will address changes in a broad spectrum of physiological functions, are still missing. Here we describe the development of an alternative scoring system, based on a selected set of non-invasive quantitative and physiological parameters, which could be repetitively used in the same animal over the course of its entire lifespan. We refer to this set of parameters as physiological frailty index (PFI). After measuring 29 diverse parameters including physical (body weight and grip strength), blood cell composition, metabolic, and immune properties, we selected those that show statistically significant change with age. These parameters were used to create PFI of individual mice of different chronological age. The observed gradual increase in mean PFI values with age suggests that our approach can reliably detect the scale of age-dependent health deterioration in a quantitative manner.

We also validated our approach of PFI by testing detrimental (feeding high fat diet, HFD) and beneficial (treatment with mTOR inhibitor rapamycin) factors on animals' longevity. We demonstrated acceleration of growth of PFI in animals placed on a high fat diet, reflecting aging acceleration by obesity. Additionally, we showed that PFI could reveal the anti-aging effect of mTOR inhibitor rapatar (a bioavailable formulation of rapamycin) prior to registration of its effects on longevity. PFI also revealed substantial sex-related differences in normal chronological aging and in the efficacy of detrimental (high fat diet) or beneficial (rapatar) aging modulatory factors.

A Lightning Tour of One Arm of the Longevity Science Community

This popular press article covering one arm of the longevity science research community in the US is better than most, in that it seems moderately accurate when it comes to identifying some of the people who matter and a few of their views on the topic. Of course in any such article you are flying over the terrain at a great height, seeing only the mountaintops, and little of what really makes the place live and breathe. You are also missing the other regions you cannot see. My chief complaint here is unfortunately a typical one, in that the author presents the SENS rejuvenation research program in a fairly disingenuous way. This is no way to treat the class of research and development most likely to turn back aging in the near future.

For decades, the solution to aging has seemed merely decades away. In the early nineties, research on C. elegans, a tiny nematode worm that resembles a fleck of lint, showed that a single gene mutation extended its life, and that another mutation blocked that extension. The idea that age could be manipulated by twiddling a few control knobs ignited a research boom, and soon various clinical indignities had increased the worm's life span by a factor of ten. Death would no longer be a metaphysical problem, merely a technical one. The celebration was premature. Gordon Lithgow, a leading C. elegans researcher, told me, "At the beginning, we thought it would be simple - a clock! - but we've now found about five hundred and fifty genes in the worm that modulate life span. And I suspect that half of the twenty thousand genes in the worm's genome are somehow involved."

For us, aging is the creeping and then catastrophic dysfunction of everything, all at once. Our mitochondria sputter, our endocrine system sags, our DNA snaps. Our sight and hearing and strength diminish, our arteries clog, our brains fog, and we falter, seize, and fail. Every research breakthrough, every announcement of a master key that we can turn to reverse all that, has been followed by setbacks and confusion. A few years ago, there was great excitement about telomeres, DNA buffers that protect the ends of chromosomes just as plastic tips protect the ends of shoelaces. As we age, our telomeres become shorter, and, when these shields go, cells stop dividing. If we could extend the telomeres, the thinking went, we might reverse aging. But it turns out that animals with long telomeres, such as lab mice, don't necessarily have long lives - and that telomerase, the enzyme that promotes telomere growth, is also activated in the vast majority of cancer cells. The more we know about the body, the more we realize how little we know.

In the murk of scientific inquiry, every researcher looks to a ruling metaphor for guidance. Aubrey de Grey likes to compare the body to a car: a mechanic can fix an engine without necessarily understanding the physics of combustion, and assiduously restored antique cars run just fine. De Grey is the chief science officer of Silicon Valley's SENS Research Foundation, which stands for Strategies for Engineered Negligible Senescence - a fancy way of saying "Planning Your Comprehensive Tune-up." De Grey has proposed that if we fix seven types of physical damage we will be on the path to living for more than a thousand years. "Gerontologists have been led massively astray by looking for a root cause to aging, when it's actually that everything falls apart at the same time, because all our systems are interrelated. So we have to divide and conquer." We just need to restore tissue suppleness, replace cells that have stopped dividing and remove those that have grown toxic, avert the consequences of DNA mutations, and mop up the gunky by-products of all of the above. If we can disarm these killers, de Grey suggests, we should gain thirty years of healthy life, and during that period we'll make enough further advances that we'll begin growing biologically younger. We'll achieve "longevity escape velocity."

De Grey vexes many in the life-extension community with his prophetic air of certainty. His 2007 book, "Ending Aging," is replete with both exacting research into the obstacles to living longer and proposed solutions so ambitious that they resemble science fiction. De Grey's fix for mitochondrial mutation, for instance, is to smuggle backup copies of DNA from the mitochondria into the vault of the nucleus, which evolution annoyingly failed to do-probably because the proteins needed in the mitochondria would ball up during their journey through the watery cell body. His fix for that, moving the DNA one way and the proteins that it produces another, amounts to a kind of subcellular hokey pokey. A number of scientists praise de Grey for anatomizing the primary threats, yet they see troubleshooting all seven pathways through such schemes - and you have to troubleshoot them all for his plan to work - as a foredoomed labor. Biogerontologist Matt Kaeberlein said, "It's like saying, 'All we have to do to travel to another solar system is these seven things: first, accelerate your rocket to three-quarters of the speed of light... ' "

Ned David is a biochemist and a co-founder of a Silicon Valley startup called UNITY Biotechnology. UNITY targets senescent cells - cells that, as they age, start producing a colorless, odorless, noxious goo called SASP, which UNITY's researchers call "the zombie toxin," because it makes other cells senescent and spreads chronic inflammation throughout the body. In mice, UNITY's treatments delay cancer, prevent cardiac hypertrophy, and increase median life span by thirty-five per cent. "We think our drugs vaporize a third of human diseases in the developed world." Pharma and biotech companies make money only if they treat a disease, and, because aging affects everything, the FDA doesn't recognize it as an "indication" susceptible to treatment (or to insurance-company reimbursement). So UNITY is taking aim at glaucoma, macular degeneration, and arthritis.

It has to be said that allotopic expression of mitochondrial genes in the cell nucleus is a poor example to pick for something that is alleged to be a doomed labor. The work has been accomplished for three of the thirteen genes needed; this is a capability that exists, and is underway towards completion. The allotopic expression of ND4 is the basis for a therapy that is currently going through clinical trials in Europe. Yes, it takes work, but so does everything else. This is one of the things that frustrates me immensely about many of the critics of SENS - they willfully ignore the progress that has been made, pretending it doesn't exist.

And that isn't even to start in on what is said - and, more importantly, not said - about senescent cell clearance, something that de Grey and other SENS advocates have been promoting as a path to treat aging for the past fifteen years, on the basis of strong evidence. It is right there in the SENS outline; hard to miss. Targeted removal of senescent cells has finally taken off these past few years, the evidence for a significant impact on aging has grown to be nigh irrefutable, and near everyone in the research community is enthused. Yet SENS and many researchers' past rejection of senescent cell clearance as a part of SENS is swept under the rug, never to be mentioned. It is unconscionable behavior, and it happens here: despite covering UNITY Biotechnology, the senolytics company, no mention of senescent cells is made in connection with the SENS vision. It takes some brass to claim SENS to be a doomed effort and then roll right into a discussion with one of the UNITY co-founders on the topic of removing senescent cells to treat aging.

An Examination of Mitochondrial Dysfunction in Senescent Cells

Researchers here review what is known of mitochondrial dysfunction in cellular senescence. Senescent cells accumulate with age, and their growing presence is one of the contributing causes of degenerative aging. Some fraction of the damaging behavior of these cells, particularly their ability to generate chronic inflammation, may be driven by failing mitochondria, but there is the question of the ordering of cause and consequence here: does the state of cellular senescence tend to produce cells populated by damaged mitochondria, or is the sort of mitochondrial DNA damage outlined in the SENS view of aging causing cellular senescence? Both cases seem to occur, but knowing that much doesn't tell us which is more important. Further, mitochondria have important roles to play in the normal progression of cellular senescence: this is a state in which most such cells self-destruct via apoptosis, a process of programmed cell death in which mitochondria play a core role. The situation in which senescent cells start down the path to apoptosis but fail to self-destruct is the interesting one, both for the contribution to aging, and for what the mitochondria might be doing in that pathological situation.

Senescent cells accumulate with age in a wide range of tissues. The rate of accumulation of senescent cells in liver and intestinal crypts predicts median and maximum lifespan of mice in cohorts with widely different aging rates. More importantly, interventions that selectively ablate senescent cells by genetic and/or pharmacologic means may improve healthspan and lifespan in mice. Mechanistically, the age-promoting effects of senescence are associated with the restriction of regenerative capacity of stem and progenitor cells as well as the secretion of bioactive molecules (the so-called senescence-associated secretory phenotype, SASP), specifically pro-inflammatory and matrix-modifying peptides. Pro-aging effects of senescent cells are aggravated by SASP and, possibly, other paracrine mediators which can propagate senescence from cell to cell as a bystander effect. In recent years, evidence has been mounting that senescent cells impact on their environment via yet another principal pathway: mitochondrial dysfunction.

Along with cell senescence, mitochondrial dysfunction is another essential 'hallmark of aging', and the two have been independently identified as important drivers of aging. Importantly, they are closely interlinked: mitochondrial dysfunction drives and maintains cell senescence, while at the same time cell senescence, specifically persistent DNA damage response signalling, directly contributes to Senescence-Associated Mitochondrial Dysfunction (SAMD). Despite the close interdependent relationship between senescence and SAMD, the true complexity of these interactions and their role in aging remains to be elucidated. For example, it is currently unclear how much of the mitochondrial dysfunction that has been observed at tissue level during aging is actually associated with senescence at a cellular level. Furthermore, despite its central contribution to the senescent phenotype, it is not clear how mitochondria become dysfunctional in senescence.

An important question is to what extent aging-associated mitochondrial dysfunction and cell senescence/SAMD are interrelated. Does aging-related mitochondrial dysfunction cause senescence in vivo or vice versa? Is mitochondrial dysfunction in aging actually a mosaic phenomenon, occurring preferentially or exclusively in the senescent cells? Given the high prevalence of senescent cells in many tissues, this appears highly possible. Emerging data suggest that it is SAMD rather more than general loss of mitochondrial function in aging that reduces homeostatic capability, causing compromised responses to peak energy demand and driving metabolic insufficiency in aging. For instance, we have found that SAMD in hepatocytes (and other cell types) includes a compromised capacity to metabolize fatty acids, which causes lipid storage in aging liver and thus contributes to fatty liver (steatosis), a common and pathologically significant complication of liver aging. Adipocyte senescence is an essential driver of adipose tissue dysfunction and obesity, and this link is very probably mediated by SAMD. Analysing mitochondrial dysfunction in aging tissues at single-cell resolution in combination with interventions that selectively ablate senescent cells will enable a better understanding of the importance of SAMD in aging.

A Look at Some Recent Efforts to Push Rapamycin Derivatives to the Clinic

Rapamycin, its derivatives such as everolimus, and the cellular biology directly affected by this class of drug continue to be of interest to that part of the aging research community focused on modestly slowing the progression of aging. The regulatory situation in the US makes it far from straightforward to move matters towards clinic applications for aging, however, even putting aside the usual technical challenges and side-effect issues inherent in this sort of drug development. This is illustrated in the following popular science article:

Can a pill make you younger? One of the few drug studies ever carried out in an attempt to address this question was reported by Novartis on Christmas Eve 2014. The company had sought to see whether giving low doses of a drug called everolimus to people over 65 increased their response to flu vaccines. It did, by about 20 percent. Yet behind the test was a bigger question about whether any drug can slow or reverse the symptoms of old age. Novartis's study on everolimus, which looked at whether the immune system of elderly people could be made to act younger, has been called the "first human aging trial."

Last week a Boston company, PureTech Health, said it was licensing two drug molecules, and the right to use them against aging-related disease, from Novartis and making the research the basis of a startup company, resTORbio. The company says it will further test whether such drugs can rejuvenate aged immune cells. The drug Novartis tested is a derivative of rapamycin, a compound first discovered oozing from a bacterium native to Easter Island, or Rapa Nui, and named after it. Thanks to its broad effects on the immune system, rapamycin has already been used in transplant medicine as an immune suppressant.

What's even more interesting about rapamycin, however, is its reputation as the most consistent way to postpone death, at least in laboratory species. It lengthens the lives of flies, worms, and rodents, too. Feed the compound to mice and they live 25 percent longer, on average. A study is under way in Seattle to see if rapamycin extends the lives of pet dogs. What we don't have yet are formal studies of whether rapamycin or any other drug can lengthen people's life spans. For many reasons, companies haven't been keen to pursue potential anti-aging treatments. Scientifically, longevity pills remain an outré idea, the domain of cranks and quacks. Clinically, it's difficult to prove a drug extends life, as it would take too long. Regulation-wise, there's no clear path forward, as aging hasn't generally been recognized as a disease you can treat. But recently, venture capitalists who used to run from such ideas have begun investing.

Brian Kennedy, who researches aging at the Buck Institute, says the Novartis study was "groundbreaking" because of how it found a way to address the drug's impact on the effects of age. "No one has the stomach to do longevity studies. Or you can do what Novartis did, which is to choose a property of aging and see if you can slow it down." Novartis says it will soon be reporting more results from its studies in the elderly. But the company also decided that the research did not fit its priorities. "We will stop developing it for aging-related disorders. It's outside of our current strategy." The resTORbio startup will try to use the Novartis drugs to reverse what it calls "immunosenescence," or detrimental changes to the immune system that occur with age. In part, that might include trying to restore certain types of T cells, which become exhausted and don't remain vigilant against cancer and infections.

The Current State of Senolytic Drug Candidates

Here, find an examination of the current state of senolytic drug candidates, compounds capable of selectively destroying senescent cells. All of those established by the research community appear to work by provoking lingering senescent cells into taking the final steps into apoptosis and self-destruction. Near all senescent cells in fact undergo apoptosis on their own, or are destroyed by the immune system. The few that remain seem primed for apoptosis, but are held back by a small number of inhibitor mechanisms. Drugs that target those mechanisms have been shown to clear up to 50% of senescent cells from aged tissues, the actual amount varying widely by tissue and drug type - in some tissues, the effect is negligible for the drugs tried to date.

The accumulation of senescent cells with age is one of the root causes of degenerative aging and age-related disease. These cells secrete a harmful mix of signals that promote inflammation, disorder extracellular matrix structures required for correct tissue function, and encourage bad behavior in nearby normal cells. In older individuals, this becomes a significant driver of the damage of aging. The most straightforward approach to this problem is to remove these unwanted cells; they are only a fraction of most tissues, and so can be safely cleared out. Studies in mice have demonstrated an extension of healthy life and reversal of aspects of aging through the use of senolytic therapies; it is an exciting field.

Aging at the cellular level is called "cell senescence", and it contributes profoundly to whole-body aging. The most promising near-term prospects for a leap in human life expectancy come from drugs that eliminate senescent cells. Programs in universities and pharmaceutical labs around the world are racing to develop "senolytic" drugs, defined as agents that can kill senescent cells with minimal harm to normal cells.

By analogy with chemotherapy for cancer, the value of a senolytic treatment is measured by its ability to kill senescent cells without doing harm to normal cells. The index called SI50 (SI for "selectivity index - 50%") is defined by analogy to LD50, the "lethal dose" of a toxin, the dose at which half of all cells die. SI50 is defined as the ratio of LD50 for normal cells and LD50 for senescent cells. It is the concentration of the agent at which half the normal cells die, divided by the concentration at which half the senescent cells die. A recent study in which researchers killed senescent cells by interfering in the crosstalk between FOXO4 and P53 reported an SI50 about 12. My guess is that 12 is an encouraging beginning, but it is not high enough to support a useful therapy.

The encouraging fact is that, at the optimal dose, more than 80% of the senescent cells have succumbed to apoptosis, while the number of eliminated normal cells is still below detection. Unfortunately, senolytic agents studied previously, including dasatinib, quercetin and ATTAC, did not include measurements of SI50 that we might use for comparison. The authors of the FOXO4 study were in a rush to publish. They used a fast-aging strain of mice, and even for these, they did not wait to see survival curves. The indicatators of rejuvenation that they do report look positive: increased activity levels, regrowth of lost fur, and improvement of kidney function lost with age.

I had missed the two papers about senolytic drug candidates ABT-263 and ABT-737. Both ABT-263 and ABT-737 were identifed in screens for agents that block BCL-2. BCL-2 is the founding member of another family of proteins that signal a cell to resist apoptosis. The ABT-263 paper included some in vivo results, indicating enhanced growth of blood stem cells after senescent cells have been removed. In vivo testing of ABT-737 was limited. Neither group reports the selectivity index (SI50), but from graphs that they do present, it is clear that ABT-263 is more selective than ABT-737, and that neither is as selective as the more recent FOXO4 method.

The idea of removing senescent cells has a lot of appeal, and enjoys broad empirical support in mammals. There is now a world-wide effort, making rapid progress toward specificity in senolytic treatments. The FOXO4 approach involves the newest agent, and it shows the best ratio yet for killing senescent cells while avoiding collateral damage to healthy cells. It cannot be taken orally and must be injected, but perhaps this is not such a drawback for a treatment that is needed only intermittently, every few years. How will such promising mouse results translate into human health and life extension? We have as yet no data, not even anecdotes. But perhaps we are near the point where hope and courage will motivate the first self-experimenting volunteers. This is a fast-moving field in which researchers are in a rush to publish and (presumably) pharmaceutical companies are taking pains to keep their results hushed up. Sharing of information and resources could push this research over the top and give us the first full decade of human life extension.

Proposing that CK2.3 Treatment Can Restore Bone Density in Osteoporosis

Two populations of cells work on maintaining bone tissue; osteoclasts break down bone, while osteoblasts build it up. There is a constant dynamic process of remodeling underway in which both cell populations participate. Unfortunately, the balance between creation and destruction runs awry in aging, with an ever greater deficit in the creation of bone tissue. This leads to a progressive loss in bone density and the development of osteoporosis: bones become ever more brittle and fragile. A number of existing and potential treatments attempt to override the activity of osteoclasts or osteoblasts, restoring the balance without addressing the root causes of the change. Here, researchers use modeling to propose that one such treatment could in theory be used to restore the bones of osteoporosis patients to a healthy density. The proof of that remains to be accomplished, however.

They may seem rigid and set in their ways, but your bones are actually under constant construction and deconstruction. They give up their nutrient treasures (calcium) to the body and then rebuild in a constant give-and-take sort of rhythm. When that rhythm shifts with advancing age or the onset of osteoporosis, the rebuilding process decreases. Bones lose density and strength and become more prone to fracture. Now researchers have applied mathematical modeling expertise to biological inquiry in order to point the way to a promising remedy. The biologist has shown that treating a mouse with a peptide known as CK2.3 increases bone mineral density. The mathematician has calculated estimated dosages for human beings. According to their model, injections of CK2.3 can raise bone mineral density of bones badly degraded by osteoporosis back to healthy levels.

Bone mineral density is affected by two processes: bone formation and bone degradation. Current drug treatments, especially bisphosphonates, address the cells involved in bone degradation (osteoclasts). Only the approved drug parathyroid hormone (PTH) addresses the cells involved in bone formation (osteoblasts) but doctors must prescribe bisphosphonates with it to target bone degradation simultaneously. The peptide used in this research - CK2.3 - is the only one that decreases bone degradation while simultaneously increasing bone formation.

One team designed the mimetic peptide CK2.3 and showed that it increased bone mineral density in a mouse model by blocking the CK2 protein's interaction with the BMPR1a protein - an interruption that allows the cells that form new bone (osteoblasts) to increase. Subcutaneous (below the skin) injection increased bone formation in the crown of the skull (known as calvaria), while systemic injection decreased bone degradation and increased bone mineral density. The other team used that information to calculate ideal dosages for healthy humans and those with osteoporosis. A mouse and a human are different in many ways, so calculating a dosage is more complex than just adjusting for differences in weight. Researchers developed part of the model using the concepts in physiology-based pharmacokinetic (PBPK) models. Such models can be used to calculate how a pharmaceutical molecule distributes in different parts of the body. In this case, the researchers needed to know what the local concentration of CK2.3 would be at the site where bone is formed. Once this was determined, another math model was used to calculate bone mineral density.

An Investigation of Declining Autophagy in Aging

Cellular quality control and maintenance processes such as autophagy are important to health and longevity. Unfortunately, like near all systems in our biology, they decline in effectiveness with advancing age, impacted by the accumulation of molecular damage that they cannot effectively deal with. This includes the hardy waste compounds making up lipofuscin, for example, which clutter up the recycling system of the lysosome in long-lived cells and degrade its operation. Researchers here survey some of the noteworthy quality control mechanisms and their failure over time in mice:

Sarcopenia and decreased cardiac function are common features of the decline in physical performance associated with aging. Sarcopenia refers to a loss of skeletal muscle mass that is accompanied by a decrease in muscle strength and increased fatigue. Aging in the heart is associated with pathological hypertrophy and thickening of the ventricle wall, leading to decreased cardiac output. Changes in both metabolism and macroautophagy, a lysosomal-dependent degradation process, have been associated with aging in both these tissues. These, in turn may contribute to the decline in function observed in these tissues during aging.

Macroautophagy, referred as autophagy in the remainder of this manuscript, is the most studied form of autophagic process. It involves the formation of double-membrane vesicles termed "autophagosomes", the sequestration of cytosolic substrate within autophagosomes, and the subsequent fusion of autophagosome and lysosome to form autophagolysosomes, where the engulfed macromolecules are degraded to provide substrates for cellular metabolism as well as damaged proteins and organelles to maintain cellular homeostasis. There is a tight connection between autophagy and life-span, as genetic manipulation to increase expression of specific autophagy genes in lower organisms promotes longevity. Autophagy-deficient mice also mimic several characteristics of age-related diseases, suggesting that autophagy is a key mechanism for protecting against cellular damage during aging. Furthermore, autophagy is a critical process for maintaining muscle and heart function, and tissue-specific impairment of autophagy in muscle and heart leads to sarcopenia and cardiomyopathy, respectively. Although there is evidence suggesting a potential role of autophagy in aging, the specific changes in basal levels of autophagy in skeletal and cardiac muscle during the natural aging process and the underlying mechanisms have not been well characterized.

Chaperone-mediated autophagy (CMA) is another type of autophagic process that specifically targets proteins that have a KFERQ amino acid recognition sequence for degradation. During CMA, target proteins are first recognized and bound by Hsc70. The resulting complex then is targeted to the lysosomes by binding to the lysosomal CMA receptor LAMP-2A, whereupon the target protein is unfolded and translocated into the lysosome for degradation. A decline of CMA during aging has been reported to occur in both the liver and central nervous system that is associated with decreased function; however, little is known about CMA in other tissues during aging.

Mitochondria are the key organelles for oxidative phosphorylation and ATP production. Mitochondria preferentially use fatty acid or glucose as energy sources depending on the availability of the type of fuel. The fuel selectivity by mitochondria also is subjected to hormonal regulation. During aging, cellular and metabolic stresses can increase generation of reactive oxygen species (ROS) that can damage mitochondria and lead to mitochondrial dysfunction, as well as perturb fuel utilization. Thus, mitochondrial quality control is critical for maintaining normal mitochondrial function and metabolism during aging. This quality control can be achieved by mitochondrial fusion, fission, and/or mitochondrial turnover through removal of damaged mitochondria by autophagy (mitophagy) and concomitant biosynthesis of new mitochondria. Currently, little is known about the changes in mitochondrial quality control and relevant metabolites that occur in aged muscle and heart.

In this study, we systematically examined and compared the markers for autophagy, CMA, and mitochondrial quality control in skeletal and cardiac muscle isolated from young and aged mice, as well as performed metabolomics profiling of acylcarnitines, amino acid and ceramides. Our studies confirm that autophagy declines in both the muscle and heart during aging, although the mechanism for the impairment in autophagy appears to be different between these tissues. Furthermore, there are decreased markers for CMA and mitochondrial quality control in the muscle whereas they are unchanged in the heart. The fuel preference and metabolism are differentially altered in these two tissues during aging, with skeletal muscle from aged mice showing a metabolomic signature suggestive of insulin resistance and fatty acid fuel inflexibility whereas the heart exhibited decreased fatty acid β-oxidation. These differential effects in muscle and heart metabolism during aging suggest that different types of metabolic derangements may occur in muscle vs. heart, and thus may require different therapeutic approaches to optimize the function of these two tissues during aging and aging-associated diseases.

The Aging of the Extracellular Matrix of the Heart

Researchers here look at the detailed impact of aging on the extracellular matrix of heart tissue. The extracellular matrix supports cells and its configuration and composition determines the physical properties of tissue. There are many issues that arise with aging in this structure, one of the most important of which is the cross-linking of matrix molecules by metabolic byproducts that are a challenge for the body to remove. Cross-links produce a reduction in tissue elasticity, among other changes, and in cardiovascular tissues this leads to hypertension, remodeling of the heart, and ultimately heart disease and death. Another important age-related issue in the extracellular matrix, one with the same ultimate outcome, is the growth of fibrosis. In this case the structure of the extracellular matrix is disrupted by the formation of scar tissue, something that occurs due to the progressive dysfunction of regenerative processes.

Age-related changes in cardiac homeostasis can be observed at the cellular, extracellular, and tissue levels. Progressive cardiomyocyte hypertrophy, inflammation, and the gradual development of cardiac fibrosis are hallmarks of cardiac aging. In the absence of a secondary insult such as hypertension, these changes are subtle and result in slight to moderate impaired myocardial function, particularly diastolic function. While collagen deposition and cross-linking increase during aging, extracellular matrix (ECM) degradation capacity also increases due to increased expression of matrix metalloproteinases (MMPs).

Of the MMPs elevated with cardiac aging, a number of studies have assessed MMP-9 in cardiac aging. There is strong evidence that MMP-9 is a major mediator for increased stiffness in the aging heart. In addition to proteolytic activity on ECM components, MMPs oversee cell signaling during the aging process by modulating cytokine, chemokine, growth factor, hormone, and angiogenic factor expression and activity. In association with elevated MMP-9, macrophage numbers increase in an age-dependent manner to regulate the ECM and angiogenic responses. Understanding the complexity of the molecular interactions between MMPs and the ECM in the context of aging may provide novel diagnostic indicators for the early detection of age-related fibrosis and cardiac dysfunction. One possible direction is to better understand how MMP activities could be modified to prevent or slow the development of excessive cardiomyocyte hypertrophy and ECM deposition. Aging is a resetting of baseline values to set a new homeostasis, and attempts to delay or prevent this shift may improve the cardiac aging phenotype.

Immune Cell Epigenetics Become More Disarrayed with Age

In this study, researchers note that at least some subsets of immune cells in older animals exhibit greater variability in gene expression (and thus behavior) than is the case in younger animals. At this point in the development of the work we can only speculate as to how this fits in to what is known of aging in general and aging in the immune system specifically. Is it a result of cells reacting to locally different levels of damage, or to secondary changes in cell signaling that vary more widely in older individuals because of molecular damage? Are the immune cells themselves relatively damaged, or does the presence of some damaged immune cells produce problems in communication and coordination across the whole population? These and other questions lack definitive answers at this time.

Researchers have shown that immune cells in older tissues lack coordination and exhibit much more variability in gene expression compared with their younger counterparts. We've all witnessed the progressive decline of function that comes with ageing, but what exactly causes this decline - and why does it happen at different rates for different parts of the body? To find answers, scientists need to unpick all of the mechanisms of ageing at the molecular level, for every tissue. This study focused on immune tissue: specifically, CD4+ T cells.

The immune system is like a symphony orchestra, with many different types and subtypes of cells working together to fight infections. But as the immune system ages, its response to infection weakens for reasons that are not yet clear. One long-standing debate amongst scientists concerns two central hypotheses: either the functional degradation is caused by a loss of cellular performance, or it is down to a loss of coordination among cells. To resolve the debate, scientists have studied many different cell types, analysing 'average' gene expression profiles. This study employed high-resolution single-cell sequencing technology to create new insights into how cell-to-cell variability is linked with ageing. The researchers sequenced the RNA of naïve and memory CD4+ T cells in young and old mice, in both stimulated and unstimulated states. Their findings clearly showed that loss of coordination is a key component of the impaired immune performance caused by T cell ageing.

"Imagine the immune system as a 'cell army', ready to protect the body from infection. Our research revealed that this army is well coordinated in young animals, with all the cells working together and operating like a Greek phalanx to block the infection. This tight coordination makes the immune system stronger, and allows it to fight infection more effectively. We show that as the animal gets older, cell coordination breaks down. Although individual cells might still be strong, the lack of coordination between them makes their collective effectiveness lower." Previous studies have shown that in young animals, immunological activation results in tightly regulated gene expression. This study further reveals that activation results in a decrease in cell-to-cell variability. Ageing increased the heterogeneity of gene expression in populations of two mice species, as well as in different types of immune cells. This suggests that increased cell-to-cell transcriptional variability may be a hallmark of ageing across most mammalian tissues.


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