Improving Natural Mitochondrial DNA Repair Mechanisms as a Potential Way to Slow the Progression of Aging

Our cells each contain hundreds of mitochondria, the descendants of symbiotic bacteria that are responsible for generating the chemical energy store molecule adenosine triphosphate (ATP) used to power cellular activity, as well as being deeply integrated with many other important cellular processes. Mitochondria have their own DNA, structured somewhat differently from the DNA of the cell nucleus. It is more vulnerable to damage, being right next door to energetic mitochondrial processes that generate reactive oxygen species, as well as being called upon to replicate a lot more frequently, leading to an increased incidence of replication errors. Further, its repair processes are different and less effective than those of the nucleus. This is all unfortunate, as the random occurrence of deletion mutations that remove access to critical proteins in the machinery that generates ATP is one of the root causes of aging.

Most damaged mitochondria are removed by quality control processes, just like any other structure in the cell. The culled mitochondria are replaced by replication of the survivors. Not all damage is equal, however. Damage that disables the primary method of generating ATP, the process known as oxidative phosphorylation, produces malfunctioning mitochondria that are broken and harmful to the cell, but also either resistant to quality control or capable of replicating more efficiently than their correctly functioning peers. The clones of any one mitochondrion that suffers this sort of damage take over the mitochondrial population of its host cell quite quickly, and the cell becomes dysfunctional as a result. The harm isn't limited to the cell itself, as it begins to export damaging reactive molecules into the surrounding tissues. This is thought to be one of the mechanisms leading to oxidatively damaged lipids entering the bloodstream, spurring development of atherosclerosis wherever they interact with blood vessel walls.

If we had better DNA repair processes active in the mitochondria, could we avoid this fate, or would it only modestly reduce this contribution to aging? That, as ever, depends on the details, and for any given specific approach to enhanced in situ mitochondrial DNA repair it is hard to say without trying it. Modeling and simulation can only go so far at the moment. The SENS Research Foundation approach to mitochondrial DNA damage is arguably based on improved DNA repair: it involves copying the vulnerable mitochondrial genes into the cell nucleus, altered suitably to enable the proteins produced to find their way back to the mitochondria where they are needed. Nuclear DNA is far more resilient than mitochondrial DNA, and this should minimize the problem to the point at which it is insignificant in comparison to other causes of aging. Is it practical at this time to aim for a similar degree of increased efficiency in existing mitochondrial DNA repair processes as a viable alternative? My suspicion is that the answer will turn out to be no, and that these processes have inherent limits, but it can't hurt to check.

Unravelling the mystery of DNA attacks in cells' powerhouse could pave way for new cancer treatments

The five-year study reveals how the enzyme TDP1 - which is already known to have a role in repairing damaged DNA in the cell's nucleus - is also responsible for repairing damage to mitochondrial DNA (mtDNA). Mitochondria are the powerhouses of cells, they generate the energy required for all cellular activity and have their own DNA - the genetic material which they rely upon to produce important proteins for their function. During the process of energy production and making proteins, a large amount of rogue reactive oxygen species are produced which constantly attack the DNA in the mitochondria. These attacks break their DNA, however the new findings show mitochondria have their very own repair toolkits which are constantly active to maintain their own DNA integrity.

"Each mitochondria repair toolkit has unique components - enzymes - which can cut, hammer and seal the breaks. The presence of these enzymes is important for energy production. Defects in repairing DNA breaks in the mitochondria affect vital organs that rely heavily on energy such as the brain." Although much research has focused on how free radicals damage the DNA in the cell's nucleus, their effect on mitochondrial DNA is less well understood despite this damage to mtDNA being responsible for many different types of disease such as neurological disorders.

The team further identified a mechanism through which mtDNA can be damaged and then fixed, via a protein called TOP1, which is responsible for untangling coils of mtDNA. When the long strands become tangled, TOP1 breaks and quickly repairs the strands to unravel the knots. If free radicals are also attacking the mitochondrial DNA, then TOP1 proteins can become trapped on the mitochondrial DNA strands, making repair even more difficult. Researchers believe the findings could pave the way for the development of new therapies for mitochondrial disease that boost their DNA repair capacity, or for cancer treatments which could use TDP1 inhibitors to prevent mtDNA repair selectively in cancer cells.

Mitochondrial protein-linked DNA breaks perturb mitochondrial gene transcription and trigger free radical-induced DNA damage

Breakage of one strand of DNA is the most common form of DNA damage. Most damaged DNA termini require end-processing in preparation for ligation. The importance of this step is highlighted by the association of defects in the 3′-end processing enzyme tyrosyl DNA phosphodiesterase 1 (TDP1) and neurodegeneration and by the cytotoxic induction of protein-linked DNA breaks (PDBs) and oxidized nucleic acid intermediates during chemotherapy and radiotherapy. Although much is known about the repair of PDBs in the nucleus, little is known about this process in the mitochondria.

We reveal that TDP1 resolves mitochondrial PDBs (mtPDBs), thereby promoting mitochondrial gene transcription. Overexpression of a toxic form of mitochondrial topoisomerase I (TOP1), which generates excessive mtPDBs, results in a TDP1-dependent compensatory up-regulation of mitochondrial gene transcription. In the absence of TDP1, the imbalance in transcription of mitochondrial- and nuclear-encoded electron transport chain (ETC) subunits results in misassembly of ETC complex III. Bioenergetics profiling further reveals that TDP1 promotes oxidative phosphorylation under both basal and high energy demands. Together, our data show that TDP1 resolves mtPDBs, thereby regulating mitochondrial gene transcription and oxygen consumption by oxidative phosphorylation, thus conferring cellular protection against reactive oxygen species-induced damage.

Towards Manufactured Blood

One of the near future goals in the tissue engineering field is the low-cost mass-manufacture of blood, removing the need for donations and blood banks. Development leading towards mass produced blood has proven a slower process than hoped, however. Here researchers report on a step forward in the generation of the necessary infrastructure technologies:

Researchers have generated the first immortalised cell lines which allow more efficient manufacture of red blood cells. The team were able to manufacture red blood cells in a more efficient scale than was previously possible. The results, could, if successfully tested in clinical trials, eventually lead to a safe source of transfusions for people with rare blood types, and in areas of the world where blood supplies are inadequate or unsafe. Previously, research in this field focused on growing donated stem cells straight into mature red blood cells. However that method presently produces small numbers of mature cells and requires repeat donations. The researchers have now developed a robust and reproducible technique which allows the production of immortalised erythroid cell lines from adult stem cells. These premature red cells can be cultured indefinitely, allowing larger-scale production, before being differentiated into mature red blood cells.

"Previous approaches to producing red blood cells have relied on various sources of stem cells which can only presently produce very limited quantities. By taking an alternative approach we have generated the first human immortalised adult erythroid line (Bristol Erythroid Line Adult or BEL-A), and in doing so, have demonstrated a feasible way to sustainably manufacture red cells for clinical use from in vitro culture. Globally, there is a need for an alternative red cell product. Cultured red blood cells have advantages over donor blood, such as reduced risk of infectious disease transmission. Scientists have been working for years on how to manufacture red blood cells to offer an alternative to donated blood to treat patients. The first therapeutic use of a cultured red cell product is likely to be for patients with rare blood groups because suitable conventional red blood cell donations can be difficult to source. The patients who stand to potentially benefit most are those with complex and life-limiting conditions like sickle cell disease and thalassemia, which can require multiple transfusions of well-matched blood."


Investigating the Normal Regulation of Insulin Receptors in Aging

Genetically altered organisms lacking an insulin receptor live longer. The related processes of insulin and growth hormone signaling are one of the better-studied areas of biochemistry in the context of aging as a result, largely focused on loss of function mutants and why they are long-lived. Here, however, researchers investigate the normal function of insulin receptors, attempting to expand our understanding of the way in which natural variations in longevity are determined by the operation of cellular metabolism.

Early in evolution, sugar intake and the regulation of life span were linked with each other. The hormone insulin is crucial here. It reduces blood sugar levels by binding to its receptor on the cell surface. However, many processes for stress management and survival are shut down at the same time. When there is a good supply of food, they appear unnecessary to the organism, although this reduces life expectancy over the long term. The insulin receptor thus acts like a brake on life expectancy. Genetically altered laboratory animals in which the insulin receptor no longer functions actually live much longer than normal. But how is the insulin receptor normally kept in check in our cells and tissue? A recent study answers this fundamental question.

The team of researchers shows that the protein CHIP plays a crucial role here. It acts like a disposal helper, in that it supplies the insulin receptor to the cellular breakdown and recycling systems by affixing the molecule ubiquitin onto the receptor. The life expectancy brake is thus released and CHIP unfurls anti-aging activity. CHIP fulfils this function in nematodes, as well as in fruit flies and in humans. The findings were initially very surprising, as CHIP had so far been associated with completely different breakdown processes. Specifically, CHIP also disposes of faulty and damaged proteins, which increasingly occur at an older age and the accumulation of which leads to dementia and muscle weakness. The researchers actually recreated such degenerative illnesses in the nematode and in human cells and observed that there was no longer enough CHIP available to break down the insulin receptor. Premature aging is the result.

Can the dream of a fountain of youth be made a reality and life extended in that researchers encourage cells to form more CHIP? Unfortunately, it's not that easy. When there is too much CHIP, undamaged proteins are also recycled and the organism is weakened. However, the researchers are already looking for mechanisms that control CHIP when breaking down the insulin receptor and that could one day also be used for new treatments.


The California Life Company is Secretive, but Sadly Also Probably Irrelevant

It will not be news to this audience that the California Life Company, or Calico for short, Google's venture into aging research, is secretive. Outside of the staff, few people can do more than read the tea leaves regarding what exactly they are up to. The high level summary is that Google is channeling a large amount of funding into some sort of long-term development plan for therapeutics to treat aging as a medical condition. Over the past few years Calico has made sizable development deals with pharmaceutical and biotechnology companies, and hired some of the most noteworthy names in the aging research community. It is usual for biotechnology and drug development companies to be fairly secretive in their early stages, for reasons that largely relate to investment regulations. At some point they have to talk about what they are doing, however, given that the goal is clinical trials, customers, and revenue.

Google is super secretive about its anti-aging research. No one knows why.

In 2013, Time magazine ran a cover story titled Google vs. Death about Calico, a then-new Google-run health venture focused on understanding aging - and how to beat it. "We should shoot for the things that are really, really important, so 10 or 20 years from now we have those things done," Google CEO Larry Page told Time. But how exactly would Calico help humans live longer, healthier lives? How would it invest its vast $1.5 billion pool of money? Beyond sharing the company's ambitious mission - to better understand the biology of aging and treat aging as a disease - Page was vague. I recently started poking around in Silicon Valley and talking to researchers who study aging and mortality, and discovered that four years after its launch, we still don't know what Calico is doing.

I asked everyone I could about Calico and what it's up to - and quickly learned that it's an impenetrable fortress. Among the little more than a dozen press releases Calico has put out, there were only broad descriptions of collaborations with outside labs and pharmaceutical companies - most of them focused on that overwhelmingly vague mission of researching aging and associated diseases. The media contacts there didn't so much as respond to multiple requests for interviews. People who work at Calico, Calico's outside collaborators, and even folks who were no longer with the company, stonewalled me. There were no clinical trials or patents filed publicly under the Calico brand that I could find and only a few aging-related scientific papers.

It may be the case that Calico is simply following the standard biotechnology startup game plan over a longer time frame and with more funding than is usually the case, including the secrecy portion of that plan, but by now most of those interested in faster progress and beneficial upheaval in the research community have written off Calico as a venture unlikely to make any meaningful difference. Given who has been hired to lead it, and given the deals made, the most likely scenario is that Calico is the second coming of the Ellison Medical Foundation. By that I mean an organization that is essentially running more of the same research funded at the National Institute on Aging, with a poor or absent focus on clinical translation, and constrained in goals to the paradigm of drug development to slightly slow the progression of aging. In this area you will find things like calorie restriction mimetics, pharmaceutical enhancement of autophagy, and so forth. The past twenty years of research have made it clear that it is very hard and very expensive to produce even marginally effective and reliable drugs capable of slowing aging. Yet this is exactly what most research groups continue to try.

There is an alternative approach. Instead of altering the poorly understood intersection between metabolism and aging in an attempt to slow the damage of aging, instead periodically repair the quite well cataloged list of fundamental cell and tissue damage that causes aging. This approach is exemplified by senescent cell clearance - a way to extend healthy life and turn back symptoms of aging and age-related disease that is already showing itself more robust and useful than any of the present drug candidates aimed at altering the operation of metabolism to slow aging. Senescent cell clearance as a way to reverse aging has been pushed by the SENS rejuvenation research advocates for more than 15 years, with good evidence as support. Yet over that span of time the majority of the research community rejected damage repair in favor of focusing on efforts to slow aging, efforts that have not succeeded in producing useful therapeutics with sizable results on human health.

That rejection was clearly not sound. Once efforts started in earnest on development of methods of senescent cell clearance, it required only the past few years to robustly demonstrate its effectiveness as a rejuvenation therapy. It is gathering ever more attention now - but not from Calico, so far as we know, and not from the majority of the research community that continues to work on slowing aging through adjustment of metabolism, an approach to aging as a medical condition that is demonstrably marginal and expensive. The funding used to bring senescent cell clearance up to its present point of proven success is a tiny fraction of what has been spent on so far futile efforts to produce calorie restriction mimetic drugs that would, even if realized, be far less effective and far less useful to patients. On the whole I think Calico is most likely a larger than usual example of the primary problem in aging research: the dominance of initiatives that put their funds towards complex, lengthy, and uncertain projects that even in the best of circumstances are only capable of producing poor outcomes for patients. In short, the problem is an unwillingness to pursue the repair and rejuvenation approach that is demonstrably more effective than the adjusting metabolism to slow aging approach. Excessive secrecy is a minor quibble in comparison.

Using CRISPR to Suppress Cytokine Receptors and Reduce Inflammation

Researchers believe they have established a method of reducing inflammation via epigenetic alterations that can in principle be broadly applied to a range of conditions in which inflammation is important. Inflammation is significant in aging, as the immune system falls into a malfunctioning state in which inflammatory mechanisms are inappropriately and consistently overactive. Unfortunately many age-related conditions are caused or accelerated by processes related to inflammation, and are age-related precisely because of this increase in inflammation over time. Dialing down inflammation thus has the potential to be broadly useful, if it can be accomplished in a suitably narrow and targeted way that minimizes any further negative impact on immune function.

Researchers have discovered a way to curb chronic pain by modulating genes that reduce tissue- and cell-damaging inflammation. The team's discovery was published in a new paper this month. "In this study we demonstrate the use of clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing to alter cell response to inflammatory environments by repressing inflammatory cytokine cell receptors, specifically TNFR1 and IL1R1. This has applications for many inflammatory-driven diseases. It could be applied for arthritis or to therapeutic cells that are being delivered to inflammatory environments that need to be protected from inflammation."

In chronic back pain, for example, slipped or herniated discs are a result of damaged tissue when inflammation causes cells to create molecules that break down tissue. Typically, inflammation is nature's way of alerting the immune system to repair tissue or tackle infection. But chronic inflammation can instead lead to tissue degeneration and pain. The team is using the CRISPR system - new technology of modifying human genetics - to stop cell death and keep the cells from producing molecules that damage tissue and result in chronic pain. But it doesn't do this by editing or replacing genes, which is what CRISPR tools are typically used for. Instead, it modulates the way genes turn on and off in order to protect cells from inflammation and thus breaking down tissue. "So they won't respond to inflammation. It disrupts this chronic inflammation pattern that leads to tissue degeneration and pain. We're not changing what is in your genetic code. We're altering what is expressed. Normally, cells do this themselves, but we are taking engineering control over these cells to tell them what to turn on and turn off."

Now that researchers know they can do this, doctors will be able to modify the genes via an injection directly to the affected area and delay the degeneration of tissue. In the case of back pain, a patient may get a discectomy to remove part of a herniated disc to relieve the pain, but tissue near the spinal cord may continue to breakdown, leading to future pain. This method could stave off additional surgeries by stopping the tissue damage.


Relations Between the Endoplasmic Reticulum and Mitochondria in Aging

This open access paper serves as a reminder that there is an enormous amount of complexity yet to be mapped and understood in cellular biochemistry, let alone in the way that this biochemistry changes over the course of aging. For example, there is still lot of room for discovery in, separately, the operation of mitochondria and the operation of the endoplasmic reticulum, both of which are of interest in the context of aging. Nothing in the cell is either static or stands alone, however, and so in addition to the internal operation of a specific type of cellular component, one has to also consider its relationships with other components, and how they interact in detail. It matters. This is one of the reasons why I am less optimistic about attempts to adjust the operation of metabolism in order to slow aging: the scope of work is enormous, given both the extent of the blank spaces still left on the map, and that filling in those blanks is necessary for meaningful progress along this road. One of the big advantages of the alternative course of action, of repairing the known root causes of aging, is that this attempts to revert metabolism back to the youthful configuration that we know works, even if we do not yet have a precise map to tell us exactly how and why it works.

Cellular organelles are no longer conceived as isolated entities with defined and unique functions, but as dynamic signaling nodes, where a single organelle may engage and influence the functioning of several cellular compartments and processes. Interorganelle interactions are facilitated by specialized structures that tie them together structurally and functionally. Mitochondria-associated membranes (MAMs) are subdomains that bring the endoplasmic reticulum (ER) and mitochondria into close proximity, enabling a complex cross talk. This physical association shapes mitochondrial morphology and dynamics, in addition to participate in the response to various stress stimuli, modulating metabolism, redox control, and apoptosis.

The ER is the primary site where transmembrane and secretory proteins are folded; in addition to operate as the main intracellular calcium reservoir and a site of lipid biosynthesis. Abnormal accumulation of misfolded proteins within the ER lumen may result in the loss of proteostasis, a condition referred to as ER stress. ER stress is triggered by physiological demands including high secretory activity, in addition to pathological conditions that may perturb protein folding and maturation, calcium homeostasis, redox balance, among other events. Under ER stress the unfolded protein response (UPR) is engaged, operating as a dynamic signaling network that enforces adaptive programs to restore proteostasis by reducing the load of unfolded proteins through the upregulation of genes involved in almost every aspect of the secretory pathway. However, if ER homeostasis cannot be restored, the UPR switches its signaling toward a proapoptotic mode to eliminate irreversibly damaged cells. Thus, the UPR is a central adjustor to control cell fate under ER stress, contributing to diverse pathological conditions including cancer, neurodegeneration, and diabetes, among others.

Interorganelle communication is emerging as a homeostatic network determining the switch from adaptive programs to cell death under stress conditions, where specialized sentinels are localized at organelle membranes to induce the core apoptosis pathway. Mitochondria represent an ancestral integrator of stress signals, modulating metabolic demands on a constantly fluctuating environment. Although the literature is still poor in relating the activity of the UPR to mitochondrial function, a new model is emerging where proteostasis and metabolic control are tightly interconnected at the structural and functional levels. This integration might be particularly relevant in pathological conditions such as diabetes and cancer, where the ER and mitochondria undergo high metabolic demands. The physical and functional relation between the ER and mitochondria has pleiotropic consequences to the cell by regulating autophagy, ROS production, metabolism, and protein synthesis.

At the intersection of all these processes, calcium mobilization is considered a key player in the dynamic cross talk between the ER and mitochondria. Importantly, different core members of the UPR are highly mutated in cancer, suggesting a direct contribution to disease initiation. Several pharmacological agents are available to target the UPR with interesting protective effects in cancer. It remains to be determined whether these therapeutic agents influence mitochondrial function through MAMs. Overall, the relevance of the intersection between ER and mitochondria is gaining increasing attention in recent years, and thus the specific activities of the UPR at MAMs needs to be systematically studied. Strategies to dissect and manipulate compartmentalized UPR responses may generate novel therapeutic insights, expanding the avenues in the area of drug discovery.


Further Investigations of Cellular Senescence in Muscle Aging and Frailty

As a topic for aging research, cellular senescence passed its tipping point a few years ago. Prior to that growth of interest and attention it was a struggle to raise funding for this area of work, and thus it didn't matter how compelling the evidence was for its involvement in the processes of aging. Researchers follow the course that ensures funding, not the course that ensures progress. Sometimes we are fortunate and those two streams overlap, but it is more often the case that great efforts of persuasion and philanthropy are required to shift the scientific mainstream onto the right track, such as that undertaken by the Methuselah Foundation and SENS Research Foundation over the past fifteen years.

Never for one moment think that scientific research at the large scale progresses rationally towards optimal outcomes: it is just as prone to human whim and fallibility as all other fields of research; those involved are just as likely to ignore the high road in favor of the low road simply because the low road is easier. Fortunately for all of us, when it comes to senescent cells and their role as a root cause of aging, the fight to make this a major topic of research is done and finished, the point made, the funding in full flow, and now everyone is working to incorporate cellular senescence into their portfolio - doing what could have been accomplished ten to fifteen years ago, had there been the will and the interest at that time.

A great deal of attention of late has been directed towards the role of cellular senescence in the age-related decline of muscle regeneration. The stem cells responsible for maintaining muscle tissue are one of the most studied stem cell populations, and thus a sizable fraction of new discoveries in regeneration and aging take place in this context. Do growing numbers of senescent cells produce signaling that causes stem cell populations to become less active, or do the stem cell and related populations involved in muscle regeneration fall into a senescent state themselves? These and many other questions remain to be firmly answered, but now that senescent cells can be selectively destroyed, those answers should be arriving more rapidly than would otherwise be the case.

New Insights on Triggering Muscle Formation

Researchers have identified a previously unrecognized step in stem cell-mediated muscle regeneration. The study provides new insights on the molecular mechanisms that impair muscle stem cells (MuSCs) during the age-associated decline in muscle function that typically occurs in geriatric individuals. It also provides further insight into the connection between accelerated MuSC aging and muscular dystrophies. "In adult skeletal muscle, the process of generating muscle - myogenesis - depends on activating MuSCs that are in a resting, or quiescent, state. As we age, our MuSCs transition to a permanently inactive state called senescence, from which they can't be 'woken up' to form new muscle fibers. If we could encourage senescent MuSCs to start replicating and advance through myogenesis - perhaps through pharmacological interventions - we may have a way to help build muscle in patients that need it."

The goal of the study was to define the molecular determinants that lead to irreversible MuSC senescence. Using a combination of a mouse model and human fibroblasts, the team found that the reason old MuSCs can't be activated to generate muscle cells is that they spontaneously activate a DNA damage response (DDR) even in the absence of exposure to exogenous genotoxic agents. This senescence-associated DDR chronically turns on the machinery needed to repair breaks and errors in DNA, and activate cell cycle checkpoints, which inhibit cells from dividing. "In our study, we found that the senescence-associated DDR prevents MuSCs from differentiating by disabling MyoD-mediated activation of the muscle gene program. We also learned that a prerequisite for activating the muscle gene program is progression into the cell cycle, a process that is irreversibly inhibited in senescent cells. We did identify experimental strategies to get senescent cells to move through the cell cycle and activate myogenesis, which is a promising result. However, we also discovered that enforcing old MuSCs to form new muscles might lead to the formation of myofibers with nuclear abnormalities resulting from genomic alterations generated during aging."

"Given the tremendous impact that decline in muscle function has on aging and lifespan, research that elucidates pathways and networks that contribute to the progressive impairment of MuSCs - such as that reported here - may lead to targeted pharmacological interventions that improve human health. However, the findings from this study should warn against overenthusiasm for strategies aimed at rejuvenating muscle of elderly individuals by enforcing the regeneration process, as they might carry a sort of trade-off at the expense of the genomic and possibly functional integrity of the newly formed muscles."

DNA damage signaling mediates the functional antagonism between replicative senescence and terminal muscle differentiation

The molecular determinants of muscle progenitor impairment to regenerate aged muscles are currently unclear. We show that, in a mouse model of replicative senescence, decline in muscle satellite cell-mediated regeneration coincides with activation of DNA damage response (DDR) and impaired ability to differentiate into myotubes. Inhibition of DDR restored satellite cell differentiation ability. Moreover, in replicative human senescent fibroblasts, DDR precluded MYOD-mediated activation of the myogenic program.

A DDR-resistant MYOD mutant could overcome this barrier by resuming cell cycle progression. Likewise, DDR inhibition could also restore MYOD's ability to activate the myogenic program in human senescent fibroblasts. Of note, we found that cell cycle progression is necessary for the DDR-resistant MYOD mutant to reverse senescence-mediated inhibition of the myogenic program. These data provide the first evidence of DDR-mediated functional antagonism between senescence and MYOD-activated gene expression and indicate a previously unrecognized requirement of cell cycle progression for the activation of the myogenic program.

A Nanoparticle Cancer Vaccine Effective Against Multiple Varieties of Cancer

The most important projects in cancer research are those that might produce therapies effective against many different types of cancer. There are too many varieties of cancer and individual tumors can evolve too rapidly for the research community to achieve its goals by working on highly specific therapies. To defeat cancer within the next few decades, the aim must be to produce broadly effective therapies, targeting common mechanisms and vulnerabilities shared by many or all cancers. There projects cost the same as more narrowly applicable approaches, but are much more cost-effective for the results they might produce. The research noted here is among a number of lines of work that, collectively, are a step in the right direction, even if there is a way to go yet to reach proof of effectiveness in humans and widespread clinical availability:

Researchers have developed a first-of-its-kind nanoparticle vaccine immunotherapy that targets several different cancer types. The nanovaccine consists of tumor antigens - tumor proteins that can be recognized by the immune system - inside a synthetic polymer nanoparticle. Nanoparticle vaccines deliver minuscule particulates that stimulate the immune system to mount an immune response. The goal is to help people's own bodies fight cancer. "What is unique about our design is the simplicity of the single-polymer composition that can precisely deliver tumor antigens to immune cells while stimulating innate immunity. These actions result in safe and robust production of tumor-specific T cells that kill cancer cells."

Typical vaccines require immune cells to pick up tumor antigens in a "depot system" and then travel to the lymphoid organs for T cell activation. Instead, nanoparticle vaccines can travel directly to the body's lymph nodes to activate tumor-specific immune responses. "For nanoparticle vaccines to work, they must deliver antigens to proper cellular compartments within specialized immune cells called antigen-presenting cells and stimulate innate immunity. Our nanovaccine did all of those things." In this case, the experimental nanovaccine works by activating an adaptor protein called STING, which in turn stimulates the body's immune defense system to ward off cancer. The scientists examined a variety of tumor models in mice: melanoma, colorectal cancer, and HPV-related cancers of the cervix, head, neck, and anogenital regions. In most cases, the nanovaccine slowed tumor growth and extended the animals' lives. The investigative team is now working with physicians to explore clinical testing of the STING-activating nanovaccines for a variety of cancer indications.


A Mechanism to Link Air Pollution and Cardiovascular Disease

Air pollution is associated with increased mortality and risk of a variety of age-related diseases, but as is often the case in human epidemiological data it isn't all that clear as how much of this is due to direct versus indirect effects. Lesser degrees of air pollution are associated with wealthier regions of the world, for example, and wealth in turn correlates with lower mortality and less age-related disease. That said, there are range of direct mechanisms for air pollution to impact long-term health, some with better accompanying evidence than others, such as the one explored here:

Tiny particles in air pollution have been associated with cardiovascular disease, which can lead to premature death. But how particles inhaled into the lungs can affect blood vessels and the heart has remained a mystery. Now, scientists have found evidence in human and animal studies that inhaled nanoparticles can travel from the lungs into the bloodstream, potentially explaining the link between air pollution and cardiovascular disease.

The World Health Organization estimates that in 2012, about 72 percent of premature deaths related to outdoor air pollution were due to ischemic heart disease and strokes. Pulmonary disease, respiratory infections and lung cancer were linked to the other 28 percent. Many scientists have suspected that fine particles travel from the lungs into the bloodstream, but evidence supporting this assumption in humans has been challenging to collect. So researchers used a selection of specialized techniques to track the fate of inhaled gold nanoparticles.

In the new study, 14 healthy volunteers, 12 surgical patients and several mouse models inhaled gold nanoparticles, which have been safely used in medical imaging and drug delivery. Soon after exposure, the nanoparticles were detected in blood and urine. Importantly, the nanoparticles appeared to preferentially accumulate at inflamed vascular sites, including carotid plaques in patients at risk of a stroke. The findings suggest that nanoparticles can travel from the lungs into the bloodstream and reach susceptible areas of the cardiovascular system where they could possibly increase the likelihood of a heart attack or stroke.


More Evidence for Senescent Cells as a Significant Cause of Osteoarthritis

UNITY Biotechnology has obtained a large amount of venture funding in order to work on senolytic therapies, treatments capable of removing significant numbers of the senescent cells that accumulate with advancing age. Cellular senescence is one of the root cases of aging, as these cells cause inflammation and disruption of tissue structure and function. Enough of them can and will kill you, though the usual mechanism of producing ultimately fatal age-related diseases, assuming that none of the other causes of aging get there first. The UNITY Biotechnology principals initially aim to push senolytics through the regulatory process as a treatment for degenerative joint conditions such as osteoarthritis, though in reality removal of senescent cells is a general purpose rejuvenation therapy that everyone should undergo every few years, and as such should be expected to impact most age-related conditions. Regulators are not in favor of treatments for aging, however, so efforts become channeled into becoming narrowly approved, late stage interventions. The true and most beneficial use will happen unofficially, or via medical tourism.

Since there is now a great deal of money and interest in this field, and since osteoathritis is an early target for UNITY Biotechnology, a fair number of interesting papers on this topic have emerged in recent months, providing ever more evidence for senescent cells in joint tissues to be a direct cause of degeneration. The latest paper quoted below is more of the same, and I think the point has been well made by now. The next thing to look for is proof of principle in early human tests. If they follow the pattern established in animal models, determination of effectiveness and reliability should follow on fairly rapidly from the treatment, perhaps a matter of a few weeks or months at the outside. This, of course, is a good reason to start with joint diseases, if you have to focus on any one class of conditions. Results are more easily assessed.

UNITY Biotechnology is expected to kick off human trials at some point this year, and it appears that at least at the outset they are working with navitoclax, or ABT-263. Confusingly, they use their own company code for the compound here, UBX0101; you'd have to read the full paper to see that it refers to navitoclax. Unfortunately it isn't open access. I have to think, and have said as much recently, that UNITY Biotechnology is not going to follow all the way through with navitoclax, though they may well use it for their first trials. It has the advantage of being well characterized as a drug, but beyond that it is somewhat worse than many of the other approaches to clearing senescent cells. For one, it is a chemotherapeutic with significant side-effects, and to pick two examples, both the Oisin Biotechnologies gene therapy and the new FOXO4-p53 therapy are not expected to produce notable side-effects while clearing senescent cells. So I believe that the UNITY Biotechnology researchers will switch horses at some point.

Nature Medicine Study Describes a Novel Senolytic Molecule that Slows the Progression of Osteoarthritis

UNITY Biotechnology, Inc. announced today the publication of new research demonstrating that the selective elimination of senescent cells with a drug may delay, prevent, or even reverse the progression of osteoarthritis (OA), the age-associated inflammatory condition causing chronic joint pain in 80% of people over 65. Researchers found that senescent cells accumulate in the knees of mice, and that the selective elimination of these senescent cells using UBX0101 - UNITY's first-in-class senolytic molecule - slowed the progression of disease, reduced pain, and induced cartilage production in human knee tissue grown in culture.

"For decades, OA has been thought of as a chronic inflammatory disease. The big mystery in OA was where the inflammatory molecules were coming from. Our new work answers this question, at least in part. It appears that the inflammatory factors that drive OA are made by senescent cells. You eliminate senescent cells, and you stop OA. This is a unique approach to the treatment of osteoarthritis and if it can be translated into a therapeutic approach for human OA, it could result in a major change in the way we treat the disease."

Osteoarthritis was induced in both young and old mice by using a standard ACL transection (ACLT) model. The resulting mechanical instability of the joint drives the accumulation of senescent cells in the articular cartilage and synovial membranes of the knees. The senescent cells appear within weeks of ACL transection and symptoms of OA are evident at 30 days. A similar accumulation of senescent cells occurs naturally over time as mice age, resulting in cartilage destruction without any surgical intervention. In mice, elimination of senescent cells from 12 months onwards maintains youthful cartilage, even in animals as old as 28 months (equivalent to approximately 80 years old for people). Following clearance of senescent cells with UBX0101 in the ACLT model, both OA-related pain and cartilage erosion were reduced, and cartilage began to regenerate. In cartilage grown from human knees with advanced OA, UBX0101 selectively eliminated senescent cells, increased proliferation of healthy chondrocytes, and induced new cartilage growth.

Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment

Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown.

To test the idea that SnCs might play a causative role in OA, we used a transgenic mouse model that allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.

An Approach to Deliver Chimeric Antigen Receptor T Cells to Solid Tumors

The approaches to cancer therapies that we should pay attention to are those capable of targeting many different types of cancer. The only practical way to meaningfully accelerate progress towards robust control of cancer as a whole is for the research community to prioritize treatments that have a much broader impact for a given investment in development. Chimeric antigen receptor (CAR) methods, in which T cells are engineered to direct their attention towards markers that identify cancer cells, can plausibly be adapted to many different cancers with minimal cost. Given that, they are a step in the right direction towards making cancer research cost-effective. So far CAR T cells have proven effective against various leukemias, but adapting this form of immunotherapy to the much larger range of cancers that form solid tumors has been a challenge. Here, researchers outline one possible way forward:

Cellular immunotherapy is beginning to bring new hope to patients with certain blood cancers. Tumors that form solid masses, such as breast and pancreatic cancer, are the next frontier for the strategy - but scientists are still grappling with how to overcome the unique challenges large clusters of tumor cells present to engineered immune cells. Researchers have now shown that a dissolving biopolymer sponge packed with therapeutic ingredients can shrink tumors and extend survival in laboratory models of cancer. Loaded with engineered immune cells, molecules that help stimulate those cells' ability to eliminate cancer, and a special ingredient that recruits a patient's own immune cells for a second round of anti-cancer attacks, the spongey, lattice-like scaffold offers a new strategy for tackling genetically variable and crowded masses of tumor cells.

Cellular immunotherapies currently being tested - and showing promise - in clinical trials are delivered intravenously. This can work well in some patients with blood cancers like leukemia, as the engineered cells fan out to hunt down cancer cells circulating in the blood (or residing in the bone marrow). But because solid tumors like breast cancer present millions upon millions of diseased cells all packed together, they require a concentrated effort. Merely injecting a solution of T cells onto a tumor would result in most of them seeping away without a chance to get a toehold in the tumor. The new approach is to concentrate engineered immune cells known as CAR T cells directly at the site of the tumor using the scaffold. A T cell is a specialized type of immune cell capable of recognizing and eliminating diseased cells. Researchers genetically engineer T cells with a scientist-designed chimeric antigen receptor, or CAR, that gives them the ability to "see" cancer cells with specific targets on their surface.

The biopolymer sponge, which lasts for about a week before dissolving harmlessly in the body, gives the CAR T cells a comfortable home base and retains them right where they're needed. The synthetic T-cell headquarters is well-stocked with molecules that help energize the T cells. Because tumors release a number of molecules that switch T cells to a lethargic state, the immune boosters are necessary to ensure that the scaffold-delivered T cells are on high alert for cancer cells and ready to pounce as they exit the implant. When the researchers tested their strategy in a mouse model of pancreatic cancer, they found that CAR T cells delivered with immune-boosting nourishment via the scaffold multiplied their numbers and responded robustly to the cancer: The animals' tumors shrank. In contrast, CAR T cells that were injected into tumors (without activating molecules to support their attack) didn't expand their numbers and reacted anemically in the face of millions of tumor cells.


Exercise Improves Cognitive Function in Older Individuals

Researchers here analyze the results from dozens of papers in which exercise was shown to have a beneficial effect on cognitive function in older adults. The broad consensus is that the mechanisms for this effect primarily involve vascular health. There are numerous ways in which the cardiovascular system is linked to the function of the brain, ranging from the pace at which small blood vessels suffer structural failures and damage brain tissue to the capability to deliver sufficient nutrients to brain cells. Vascular dementia is the name given to the end stages of blood vessel failure and loss of sufficient blood supply to the brain, and it is quite common in patients found to be suffering any form of cognitive decline.

A combination of aerobic and resistance exercises can significantly boost the brain power of the over 50s, finds the most comprehensive review of the available evidence to date. The effects were evident irrespective of the current state of an individual's brain health, the analysis shows. Physical exercise for older adults is seen as a promising means of warding off or halting a decline in brain health and cognitive abilities. Yet the evidence for its benefits is inconclusive, largely because of overly restrictive inclusion criteria in the reviews published to date, say the researchers. In a bid to try and plug some of these gaps, they systematically reviewed 39 relevant studies published up to the end of 2016 to assess the potential impact of varying types, intensities, and durations of exercise on the brain health of the over 50s. They included aerobic exercise; resistance training (such as weights); multi-component exercise, which contains elements of both aerobic and resistance training; tai chi; and yoga in their analysis.

They analysed the potential impact of these activities on overall brain capacity (global cognition); attention (sustained alertness, including the ability to process information rapidly); executive function (processes responsible for goal oriented behaviours); memory (storage and retrieval); and working memory (short term application of found information). Pooled analysis of the data showed that exercise improves the brain power of the over 50s, irrespective of the current state of their brain health. Aerobic exercise significantly enhanced cognitive abilities while resistance training had a pronounced effect on executive function, memory, and working memory. The evidence is strong enough to recommend prescribing both types of exercise to improve brain health in the over 50s, say the researchers.


SENS Research Foundation Expands Collaboration with the Buck Institute to Work on Senescent Cells and Immune Aging

The SENS Research Foundation and the Buck Institute for Research on Aging are both based in the Bay Area, California, and collaborate on a small variety of projects relevant to the development of rejuvenation therapies. This includes clearance of the neurofibrillary tangles that appear in age-related tauopathies, to pick an example announced earlier this year. There is also some cross-pollination of researchers; the aging research field is still a comparatively small community, and people who are or have been involved in SENS rejuvenation research programs can be found scattered throughout. SENS research has been going on for long enough now to produce a fair number of alumni who have gone on to run their own labs or work in other parts of the field. Today the SENS Research Foundation announced an expansion of the Buck Institute collaboration, to include work on the intersection of cellular senescence and immune aging:

SRF and Buck Institute to Collaborate on Senescent Cells

SENS Research Foundation (SRF) has launched a new research program focused on dysfunctional white blood cells in collaboration with the Buck Institute for Research on Aging. Judith Campisi, a leading global expert on aging and age-related diseases, will be running the project in her lab at the Buck. Various types of unwanted cells accumulate during aging and affect the function of many systems, including the immune system. Some of these cells are cleared by the immune system, but some are not, possibly leading to a vicious cycle of decline. It is therefore a priority to explore techniques for eliminating these cells and rejuvenating the body, by forcing the unwanted cells to "commit suicide", and/or by augmenting the cell-killing function of healthy immune cells.

"One of our major goals is to find treatments to augment the aging immune system's defenses against senescent cells. This collaboration with SRF will enable us to explore a range of hitherto neglected ways to do that. We are extremely proud to be partnering once again with Judith Campisi's lab and the Buck on this critical project." This research has been made possible through the generous support of the Forever Healthy Foundation and its founder Michael Greve, as well as the support of our other donors.

Aging is not a linear process; it accelerates as it progresses. As might be expected, this also appears to be more or less the case for the forms of cell and tissue damage that cause aging. When it comes to the state of health and tissues, the difference between 30 and 40 is not the same as the difference between 40 and 50 or the difference between 50 and 60. The downward pace picks up over time. This is characteristic of a self-repairing system, in that there are two primary determinants of the pace of functional decline. The first is the rate at which damage accrues, and the second is the efficiency with which that damage is repaired. The accumulation of lingering senescent cells is a good illustration of the point. Senescent cells are created constantly in our tissues, every time a somatic cell reaches the Hayflick limit on replication, or most of the time when a cell becomes damaged and potentially cancerous. Near all such cells are destroyed quite quickly, either by their own programmed cell death processes, or by the immune system. Unfortunately the immune system - just like all other agents of repair - becomes damaged with age, and its effectiveness declines. As this happens, the rate at which senescent cells accumulate increases.

Of interest in this picture is that at least some of the age-related malfunctioning of the immune system is caused by immune cells becoming senescent and lingering to cause harmful side-effects. While some researchers suggest that this might, at least at first, act as a beneficial adaptation in the face of failing resources, the same can be said of other senescent cells. They help to suppress cancer, at least at the outset when their numbers are small. But by the time they are plentiful, the harms done by their presence far outweigh any help they provide - and in the end, they produce a high degree of chronic inflammation that in fact encourages cancer development. At the present time, it is starting to look like there are multiple classes of senescent cell lingering in the body, sharing a similar set of characteristics, all harmful to health, but possibly different enough to require some tailoring of the therapies presently under development to deal with them.

Since senescent cells attack the effectiveness of the repair system set to watch over them, they encapsulate a cause of death by aging in and of themselves. Even if cellular senescence was the only form of damage that lies at the root of aging, and it is not, it would be able to kill us by crippling the immune system and then going on to produce the failure of organs and other systems as ever more cells in every tissue become senescent. Fortunately the approach of destroying these cells indiscriminately, without caring much about subtypes, seems likely to produce significant benefits based on results in mice to date. Numerous variants of this approach are presently in commercial development. Given that the first of these therapies destroy between a quarter and a half of senescent cells, and only in some tissues, the second generation yet to be developed has considerable room for improvement. That improvement will come alongside the development of better and more discriminating assays for cellular senescence, and this is likely where research into the potential varieties of cellular senescence will prove helpful.

It is also worth considering entirely unrelated efforts to restore immune function in older patients. These are likely to produce sizable benefits to health, as the failure of the immune system is one of the primary causes of frailty in the old. No-one knows whether such a restoration would sweep out a fair portion of senescent cells as well, or how this would compare with targeted therapies for destruction of senescent cells. The only real way to find out is to try it, perhaps initially through the creation and infusion of large numbers of immune cells cultured from a patient sample. Other approaches worth chasing for immune restoration in the old include regeneration of the thymus, the organ that determines the pace at which new immune cells are created, or complete destruction and recreation of the immune system in order to clear out all of the misconfigured and misbehaving cells. In the latter case, the approaches presently used to effect a cure of autoimmune disorders by clearing all immune cells are probably not safe for use in very old people, being essentially chemotherapeutics with harsh side-effects. But it should be possible to produce better methods of targeted cell killing with minimal side-effects, such as via adaptation of the programmable gene therapy approach used by Oisin Biotechnologies to attack senescent cells.

Osteoarthritis as an Inflammatory Condition

This open access paper discusses current views on the degree to which osteoarthritis is driven by inflammation, as is the case for many other age-related diseases. With aging the immune system declines into a malfunctioning state of chronic inflammation, ever more active while also ever less effective at the tasks of destroying pathogens and errant cells. In young people, inflammation in short bursts is a necessary part of the immune response, but in the old it becomes a consistent destructive process, gnawing away at the proper function of organs and systems in the body and brain. Addressing this in some way, perhaps through an adaptation of the immune destruction and recreation approach taken for some autoimmune diseases, should be broadly beneficial.

Affecting approximately 3.8% of the global population, osteoarthritis (OA) is regarded as a prevalent cause of morbidity and disability worldwide. OA shows many disease characteristics, such as cartilage degradation, moderate synovial inflammation, pain, alteration of bony structure, and impaired mobility. However, despite the severity of the disease, relatively little is known about its exact etiology. Recent compelling investigations have attributed the onset of OA to various person-level factors such as age, sex, obesity, and diet and joint-level factors such as injury, malalignment, and abnormal joint loading. Although more and more researchers have recently presented hypotheses concerning the involvement of these factors in OA, especially for person-level factors, few of their hypotheses have been demonstrated experimentally, and some have even been challenged by the latest observational studies and clinical trials.

Of the several factors potentially involved in the pathogenesis of OA, T cell-mediated immune responses and their influence on the biology of OA are the focus of this review. The scientific community once understood OA to be induced by mechanical stress in the form of cartilage destruction, with minimal if any involvement of immune responses. Thus, OA was regarded as a non-inflammatory disease, in contrast with rheumatoid arthritis (RA), an inflammatory disease. However, recent studies suggest that at least in certain patients, OA is an inflammatory disease; patients have frequently been found to exhibit inflammatory infiltration of synovial membranes. Most recent studies have shown that the number of inflammatory cells in the synovial tissue is lower in patients with OA than in patients with RA, but higher than that in healthy subjects. Indeed, little difference has been found in the percentages of T cells, B cells, and natural killer cells in the peripheral blood between patients with OA and RA. The similarity of the immune cell profiles of RA and OA and suggested that abnormalities in T cells may also contribute to the pathogenesis of OA.

Further experiments indicated that inflammation in OA is anatomically restricted and varies in intensity. The synovial membranes in regions rimming the cartilage of OA patients, which contain T cells bordered by B lymphocytes and plasma cells, showed a pronounced inflammatory response. In contrast, only a few infiltrating lymphocytes were observed in the synovial membranes taken from macroscopically non-inflamed areas in OA patients. This may explain the suggestion made by some researchers that immune responses are not involved in the pathogenesis of OA. When synovial samples from patients with knee OA were analyzed, the synovial lining cells showed strong immunoreactivity and phagocytic potential with cluster of differentiation (CD) 68 antibodies. These findings suggested that macrophages may be associated with the pathogenesis of knee OA. Of 20 osteoarthritic synovial membranes, 5 showed lymphoid follicles containing T cells, B cells, and macrophages, and 10 (including the latter five) displayed a diffuse cellular infiltrate containing T and B cells, macrophages, and granulocytes. These results suggested that B cells and granulocytes may also be involved in the pathogenesis of knee OA.


Evidence for Fat-Triggered Immune Dysfunction in the Liver to Contribute to the Symptoms of Type 2 Diabetes

In this research, scientists explore a link between the presence of excess fat and the dysfunctional blood sugar regulation that is characteristic of type 2 diabetes. The vast majority of type 2 diabetes patients suffer the condition because they are overweight, and could turn back its progression even in late stages through sustained low-calorie diets and losing that weight. Type 2 diabetes is a prevalent age-related disease because we live in an age of cheap calories and little exercise, older people have more time and opportunity to gain the necessary excess fat tissue to trigger the condition, and other mechanisms cause a decline in the aging pancreas and its beta cells, making it more likely that a given gain in weight will push metabolic syndrome over the line into full blown diabetes.

Using cells from mice and human livers, researchers demonstrated for the first time how under specific conditions, such as obesity, liver CD8+ T cells, white blood cells which play an important role in the control of viral infections, become highly activated and inflammatory, reprogramming themselves into disease-driving cells. Scientists have been trying for many years to discover why the liver continues to pump out too much glucose in people with diabetes. This paper sheds light on the markers of activation and inflammation in CD8+ T cells and the Interferon-1 pathway which helps stimulate their function. In fact, the normal function of the immune cells becomes misdirected. The pathways they would typically use to fight infection create inflammation, unleashing a chemical cascade which impacts insulin and glucose metabolism.

In the study, researchers fed mice a high-fat diet, 60 per cent of which was saturated fat, for 16 weeks. Compared with normal chow diet-fed mice, the high-fat diet mice showed worsened blood sugar, increased triglycerides, a type of fat (lipid) in the blood, and a substantial increase in the numbers of CD8+ T cells in the liver. Instead of responding to viruses or other foreign invaders in the body, the activated CD8+ T cells launch an inflammatory response to fat, and to bacterial components that migrate to the liver from the gut through the blood. The activated T-cells divide rapidly, pumping out increased numbers of cytokines, proteins that assist them in an active and excessive immune response. This pro-inflammatory response in turn interferes with normal metabolism in the liver, specifically jamming up or blocking insulin signaling to the liver cells.

Since the liver stores and manufactures glucose or sugar depending upon the body's need, the hormone insulin signals whether the liver should store or release glucose. This system keeps circulating blood sugar levels in check. If that signal is disrupted or blocked, the liver continues to make more sugar, pouring it into the bloodstream. If the liver is over-producing glucose, it becomes difficult to regulate blood sugar. "We're moving from studying diabetes as a metabolic syndrome - a combination of nutritional and hormonal imbalances - to include the role of the immune system and inflammation. That's the developing link. Inflammation is emerging to be a major mediator of insulin resistance."

The researchers found that in genetically-modified mice lacking Interferon-1, who were also fed a high-fat diet, the CD8+ T cells did not produce an inflammatory response, and the mice had near normal blood sugar levels. In further investigations of human liver cells from nearly 50 donor tissues of humans with varying degrees of body mass index (BMI) and liver fat, higher levels of CD8+ T cells were linked with higher levels of blood sugar or more advanced fatty liver disease.


If Much Older than 30, Save More Aggressively Over the Next Decade or Two

Five years from now, it will be possible to fly to an overseas clinic and undergo a treatment that will clear out between a quarter and half of the senescent cells in your body. That will to some degree damp down fibrosis, restore tissue elasticity, reduce inflammation, reduce calcification of blood vessels, and in addition improve many other measures of health that are impacted by the normal progression of aging. In short you will walk away a little rejuvenated, literally: one of the root causes of aging will be turned back for some years, perhaps decades, however long it takes for the removed senescent cells to emerge once again. Given the present cost of senolytic drug candidates, varying from a few dozen to a few thousand dollars per dose depending on whether or not they are at present mass manufactured, I think that the likely initial cost of treatment five years from now will be somewhere in the $5,000 to $25,000 range. Higher would seem unlikely, given that this is a competitive area of development already, and lower will probably have to wait for bigger players to enter the game in regulated markets. That cost will then fall as availability spreads.

Senolytics are just the start. Five years to a decade after the first candidate therapy for breaking glucosepane cross-links in humans, that treatment will also be available to anyone with the necessary funds put aside. It will also turn back the clock, removing some portion of one of the root causes of aging. Tissue elasticity will be restored, hypertension controlled as arteries become more flexible, and scores of other consequences of cross-linking reduced in their impact. That first therapy could emerge in the laboratories this year or at any time thereafter; a number of groups are working on it. There are a range of other rejuvenation treatments and compensatory therapies at similar points, on the verge in one way or another. Gene therapies to boost muscle generation, or dramatically reduce blood cholesterol. Approaches to clear harmful amyloids from old tissue. The next twenty years will bring numerous opportunities to benefit for anyone willing organize their own treatments via medical tourism, and who happens to know enough about the field to pick out the metal from the dross.

Therapies are not free, however. Funds are needed. Thus anyone much over the age of 30 who has an interest in this field should be saving more aggressively than he or she is at present. Live more frugally. Put more aside. On one chart is the ascending curve of savings and safe investments, on another chart the descending curve of cost of therapies. The objective for most of us is to make those lines cross sooner rather than later. If you dent your savings in a way that pushes out the achievement of traditional retirement goals by a few years in order to undergo an effective rejuvenation therapy, I think that puts you ahead of the game. Besides, traditional retirement isn't going to look very traditional any more by the time most of the younger folk in the audience get there. The aging of the population ensures that more people will simply remain working because there will be more work to accomplish than young people available to accomplish it. The advent of rejuvenation therapies will mean that older people can in fact continue working. And not just working: living a life that is worth it; interesting and active. Rejuvenation means additional health and vigor, not just extra years.

The rest of this century will be a grand adventure. The course of a human life is no longer planned and plotted and set in stone as it was for your grandparents. Medical technology, the development of rejuvenation therapies, will break us from tradition and the limits that aging places on the human condition. The traditional ways and means, the passing of generations, the declining trajectory of old age, are on the way out, fast or slow, sooner or later. We'll all be making it up as we go, exploring entirely new territory when it comes to the manners and organization of society. In the early days, however, only the prepared will find it easy to hitch a ride. So don't be unprepared. Everyone in the younger half of life has years ahead in which to save funds while keeping a weather eye on the state of research and medical tourism. Having a nest egg put aside will make all the difference when it comes time to strike out, repair the damage that aging has inflicted upon your health, and stride forth into a far better future than was offered to our ancestors.

How Does Tau Cause Neurodegeneration?

As research progresses, it is becoming clear that the situation for amyloid-β and tau in the aging brain is quite similar at the high level. As amounts increase with advancing age, perhaps due to the progressive failure of clearance mechanisms, both produce distinct solid aggregates, neurofibrillary tangles in the case of tau, but the aggregrates themselves do not appear to be the primary harmful mechanism that damages neural function and kills cells. This open access paper takes a look at what is known of tau and its involvement in age-related neurodegeneration:

Aging has long been considered as the main risk factor for several neurodegenerative disorders including a large group of diseases known as tauopathies. Even though neurofibrillary tangles (NFTs) have been examined as the main histopathological hallmark, they do not seem to play a role as the toxic entities leading to disease. Recent studies suggest that an intermediate form of tau, prior to NFT formation, the tau oligomer, is the true toxic species. However, the mechanisms by which tau oligomers trigger neurodegeneration remain unknown.

NFTs do not appear to be the main toxic entities leading to disease. In Alzheimer's disease, tau pathology and neuronal cell loss coincide in the same brain regions, and as brain dysfunction progresses, NFTs are found in greater anatomical distributions. However, the role of NFTs in the progression of the disease is poorly understood. Compared to non-demented controls, Alzheimer's brains exhibit up to 50% of neuronal loss in the cortex, exceeding the number of NFTs. In addition, neurons containing NFTs are functionally intact in vivo and have been found in brains of cognitively normal individuals. Further, intra-neuronal NFTs do not affect post-synaptic function and signaling cascades responsible for long-term synaptic plasticity, suggesting that synaptic deficits cannot be attributed to NFTs.

While evidence indicates that these deposits are not toxic, many studies suggest that the tau oligomer, an intermediate entity, is likely responsible for disease onset. Hyper-phosphorylated tau assembles into small aggregates known as tau oligomers in route of NFT formation. As hyper-phosphorylated tau dislodges from microtubules, its affinity for other tau monomers leads individual tau to bind each other, forming oligomeric tau, an aggregate. These tau oligomers potentiate neuronal damage, leading to neurodegeneration and traumatic brain injury. As these granular tau oligomers fuse together, they form tau fibrils, which ultimately form NFTs. These steps hint that tau oligomers may be involved in neuronal dysfunction prior to NFT formation.

When tau oligomers, rather than tau monomers or fibrils, are injected into the brain of wild-type mice, cognitive, synaptic, and mitochondrial abnormalities follow. Additionally, studies have discovered that aggregated tau inhibits fast axonal transport in the anterograde direction at all physiological tau levels, whereas tau monomers have had no effect in either direction. This suggests that monomers are not the toxic entity either. Most noteworthy, tau oligomers induce endogenous tau to misfold and propagate from affected to unaffected brain regions in mice, whereas fibrils do not. This indicates that tauopathies progress via a prion-like mechanism dependent upon tau oligomers. With this concept, tau may be able to translocate between neurons and augment toxic tau components; in fact, evidence suggests probability of tau oligomer propagation between synaptically connected neurons. If true, then pathology begins in a small area and becomes symptomatic as it spreads to other areas of the brain.

Discovering the pathological role of tau oligomers within the brain along with related mechanisms of cellular tau oligomer secretion, propagation, and uptake will allow for a better understanding of tauopathies. Further, mitochondrial dysfunction caused by internalized tau oligomers may play an important role in pathogenesis. Admittedly, little is known regarding cellular tau oligomer release. Yet with greater knowledge regarding disease pathogenesis, better therapeutic approaches can be generated. We hypothesize that preventing tau oligomers from cellular release and uptake will relieve some toxic effects induced by tau oligomers in tauopathies.


Increased Cardiac Troponin T Associated with Neuromuscular Junction Aging

Decline in the neuromuscular junctions that connect nerve tissue to muscle tissue is one of the ways in which muscles age and lose strength. Researchers here examine changing levels of proteins in neuromuscular junctions, and identify increased amounts of cardiac troponin T as one of the proximate causes of decline. Reducing the amount of this protein improves the function of aged neuromuscular junctions in mice:

Ageing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast-twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow-twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre-type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia. Cardiac troponin T (cTnT), the heart muscle-specific isoform of TnT, is a key component of the mechanisms of muscle contraction. It is expressed in skeletal muscle during early development, after acute sciatic nerve denervation, in various neuromuscular diseases and possibly in ageing muscle. Yet the subcellular localization and function of cTnT in skeletal muscle is largely unknown.

Studies were carried out on isolated skeletal muscles from mice, vervet monkeys, and humans. Immunoblotting, immunoprecipitation, and mass spectrometry were used to analyse protein expression, real-time reverse transcription polymerase chain reaction was used to measure gene expression, immunofluorescence staining was performed for subcellular distribution assay of proteins, and electromyographic recording was used to analyse neurotransmission at the NMJ.

Levels of cTnT expression in skeletal muscle increased with ageing in mice. In addition, cTnT was highly enriched at the NMJ region - but mainly in the fast-twitch, not the slow-twitch, muscle of old mice. We further found that the protein kinase A (PKA) RIα subunit was largely removed from, while PKA RIIα and RIIβ are enriched at, the NMJ - again, preferentially in fast-twitch but not slow-twitch muscle in old mice. Knocking down cTnT in fast skeletal muscle of old mice: (i) increased PKA RIα and reduced PKA RIIα at the NMJ; (ii) decreased the levels of gene expression of muscle denervation markers; and (iii) enhanced neurotransmission efficiency at NMJ. This knowledge could inform useful targets for prevention and therapy of age-related decline in muscle function.


Calorie Restriction Slows Progression of the Earliest Stages of Cancer

The practice of calorie restriction has been shown to extend both healthy and overall life span in near every species tested to date - though of course the human life span data is still too sparse to do more than make educated guesses. Calorie restriction also provides considerable short term benefits to measures of heath, larger than anything that medical science can presently provide for basically healthy individuals, and the short term human data matches that obtained from other mammals. Eating less while maintaining optimal levels of micronutrients is a healthy practice, with a weight of evidence backing that claim, even if there is considerable uncertainty over the degree to which it will lengthen human life. It certainly doesn't produce the same 40% extension of life observed in mice, as that outcome would have been noted centuries past. As a general rule the life spans of short-lived species are far more plastic in response to circumstances than those of long-lived species. The consensus in the research community is that calorie restriction, while being very good for your health, and significantly reducing incidence of age-related disease, probably doesn't add more than five years of life at the outside.

Almost every measure of aging is slowed and almost every aspect of cellular metabolism is altered in calorie restricted individuals. Nutrient sensing mechanisms touch on all of the low-level, important cellular behaviors, such as replication and maintenance processes, and this has made it very difficult to understand how exactly the calorie restriction response works. Understanding calorie restriction cannot easily be separated from the vast undertaking of building a complete understanding of cellular biochemistry and the way in which it changes over the course of aging - and why. Some major areas of interest in cellular biology have been blocked out by the aging research community, such as insulin signaling, sirtuins, mTOR, and so forth. Over the past twenty years a great deal of time and funding has gone towards mapping more of these mechanisms, in search of ways to reproduce calorie restriction without the dieting, but for all that effort there are few signs that an end is in sight. Human biochemistry is enormously complex.

The paper here is an example of one of the many ways in which calorie restriction slows the progression of aging. The researchers provide evidence to show that the earliest stages of cancer advance more slowly and are in general suppressed in calorie restricted animals. Cancer is a manifestation of aging in the sense that it is a numbers game: firstly, the more damage to DNA that an individual suffers, the more likely that a cancerous cell arises. Secondly the mechanisms responsible for assassinating cancerous cells falter with age due to their own burden of damage and dysfunction. Lastly the inflamed environment of old tissues makes it easier for cancers to thrive once they get underway. Calorie restriction has a positive impact on all of these points, and hence calorie restricted individuals have a lower incidence of cancer. Understanding exactly why this is the case at a deep enough level to produce therapies that replicate its effects is whole different story, of course, and something than may not happen for decades yet.

Caloric restriction delays early phases of carcinogenesis via effects on the tissue microenvironment

Neoplastic disease is inextricably associated with aging. Five out of six cancer-related deaths occur in patients aged 60 years and older. However, the intimate nature of this association is yet to be fully clarified. An important concept emerging from the literature is that aging and cancer do not merely represent two chronologically parallel processes, but they share relevant pathogenetic mechanisms. Along these lines, in a recent study we have provided evidence to indicate that aging promotes the growth of pre-neoplastic cells through alterations imposed on the tissue microenvironment, i.e. by generating an age-associated, neoplastic-prone tissue landscape. Similarly, it has been reported that aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors; it was proposed that cell competition may in fact drive the emergence of oncogenically altered cells in a background of age-induced decline in tissue fitness, in a process that has been referred to as "adaptive oncogenesis".

The notion that age-associated tissue changes may play a direct role in the origin of neoplasia has far-reaching implications. It suggests that strategies aimed at modulating the rate of aging may have a direct impact on early and/or late steps of neoplastic disease, i.e. the quest for a longer lifespan may coincide, at least in part, with the goal to defer the occurrence of cancer.

A most effective and consistent means to delay aging is by reducing caloric intake compared to ad libitum (AL) feeding. Caloric restriction (CR) is the most studied and reproducible non-genetic intervention known to extend lifespan in organisms ranging from unicellular yeast to mammals, including non-human primates, although the latter observation is disputed. On the other hand, it is also well documented that CR exerts a beneficial effect on the incidence of chronic diseases related to old age, including cancer, consistent with the notion that changes occurring during the aging process may bear direct relevance to the pathogenesis of neoplasia. However, the precise mechanisms responsible for the CR-induced delay on carcinogenic process are yet to be identified.

Based on the above, in the present studies we tested the hypothesis that the modulatory effect of CR on age-associated neoplastic disease might be related, at least in part, to a CR-induced delay in the emergence of age-related tissue alterations promoting the growth of pre-neoplastic cells. Using a well characterized cell transplantation system in the rat, we report that when pre-neoplastic hepatocytes were infused in aged animals exposed to either AL or CR diet, their growth was significantly reduced in the latter group. Analysis of donor-derived cell clusters performed at 10 weeks post-transplant revealed a significant shift towards smaller class sizes in the group receiving CR diet. Clusters comprising more than 50 cells, including large hepatic nodules, were thrice more frequent in AL vs. CR animals. Incidence of spontaneous endogenous nodules was also decreased by CR. These results are interpreted to indicate that CR delays the emergence of age-associated neoplastic disease through effects exerted, at least in part, on the tissue microenvironment.

Show Your Appreciation for the Fundraising Work of

The and Life Extension Advocacy Foundation (LEAF) volunteers have over the past few years put together and maintained a crowdfunding infrastructure used to successfully raise hundreds of thousands of dollars for rejuvenation research projects. They have carried the message that aging can be effectively treated as a medical condition out to new audiences, expanded our community of supporters, and helped to connect researchers and entrepreneurs to new patrons. The LEAF volunteers are presently running a small fundraiser in search of monthly donors to help expand their present advocacy for the cause of rejuvenation research. If you have been following their efforts for the past few years, I encourage you show your appreciation for all they have done by signing up for a modest monthly donation.

Here at we are funding research to help extend healthy human lifespan, and thanks to our community here we've done amazing work already: raising over $200,000 for companies and nonprofits working to overcome age-related disease, decrease the period of ill-health during life, and address key societal issues being faced by our aging population. All we've done thus far has been primarily volunteer effort, and we believe we can go so much further with even a modest budget of our own. So we're turning to you, and asking you to stand with us, to #BeTheLifespan, and help us overcome age-related diseases for good. What this means is that we're asking you to be a Lifespan Hero by supporting us with monthly contributions, which will allow us to not only fund more research but also offer amazing community rewards.

In addition to improving our features on this site, we'll create a private networking group for patrons and researches. We'll also begin running a live-streamed journal review, led by our own Dr. Oliver Medvedik, where we'll go through the latest papers with researchers and you, so we all learn together. We'll be able to make awesome collaboration videos with popular creators on services like YouTube to engage the world. This has the power to inform millions of people about the feasibility and desirability of longevity research, and can be a game changer in terms of raising societal awareness. If we can get to $10,000 a month, we'll even start running an annual full-scale longevity conference in New York City, to help make this research truly mainstream. In addition to driving the field forward with increased sharing of information, a stronger presence in NYC will attract private capital, and help build a thriving longevity biotech industry.

Every day over 100,000 people die of age related diseases: Alzheimer's, heart disease, cancer. Together we can fight this; together we can be Heroes.


A Perspective on Clinical Translation of Senolytic Drugs

Researchers here discuss the path to the clinic for the first batch of senolytic drugs, compounds that nudge senescent cells into self-destruction. Senescent cells accumulate with age, and secrete signals that disrupt tissue function and produce chronic inflammation. Their growing presence is one of the root causes of aging, and their effects on surrounding cells contribute to many age-related diseases. Researchers have demonstrated extended life and reversal of measures of aging in rodents through the targeted removal of senescent cells; the sooner this class of treatment makes it to the clinic the better.

Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric syndromes, and loss of resilience. Delaying senescent cell accumulation or reducing senescent cell burden is associated with delay, prevention, or alleviation of multiple senescence-associated conditions.

The first senolytic drugs, compounds that selectively eliminate senescent cells by causing apoptosis, were discovered using a hypothesis-driven approach. This approach was based on the observation that senescent cells are resistant to apoptosis, suggesting senescent cells have up-regulated pro-survival pathways that protect them from their own pro-apoptotic SASP. Up-regulation of these Senescent Cell Anti-apoptotic Pathways (SCAPs) might be related to senescence-associated mitochondrial dysfunction (SAMD). An essential part of SAMD appears to be a decrease in mitochondrial membrane potential related to mitochondrial membrane permeabilization. SAMD could explain why senescent cells depend on upregulated pro-survival pathways and why they are more sensitive to drugs that interfere with these SCAP pathways than non-senescent cells.

The first SCAPs were identified through expression profiling of senescent vs. non-senescent human cells and confirmed in RNA interference studies. Drugs that target these SCAPs were tested for senolytic activity. The tyrosine kinase inhibitor, dasatinib (D) and the flavonoid, quercetin (Q), were shown to induce apoptosis in senescent cells. Ten months later, two groups simultaneously reported that navitoclax (N; ABT-263), which targets components of the Bcl 2 pathway, is senolytic. Recently, the specific BCL-XL inhibitors A1331852 and A1155463, were found to be senolytic. Fisetin, related to Q, was discovered to be senolytic. Fisetin is an especially promising candidate because of its favorable side-effect profile. Piperlongumine, which is also related to Q, was noted to be senolytic in vitro in some senescent cell types. None of the individual agents reported so far selectively induces apoptosis of all senescent cell types. N, A1155463, and possibly A1331852 appear to be more toxic than D, Q, piperlongumine, or fisetin. A number of additional senolytic drugs are currently being developed. Some of the most promising senolytic agents are already being moved through preclinical studies towards clinical application.

To conduct clinical trials with senolytics, it will be important to have ways to track changes in senescent cell burden. It might be feasible to do so using biopsies, blood assays, other body fluids, and imaging, but more research on developing and optimizing assays needs to be done and reported. Complicating matters, the definition of cellular senescence is somewhat vague, particularly since several potentially pro-inflammatory cell types, such as macrophages or osteoclasts as well as pre-cancerous or cancer cells share many characteristics of senescent cells and could arguably be the same as what are currently regarded as being senescent cells. Few tissue assays are very sensitive or specific for senescent cells. Work needs to be done to establish, optimize, and validate these assays. Novel assays, such as of the microvesicles shed into blood or urine by senescent cells, need to be developed and optimized for use in clinical trials of senolytic drugs.

Healthspan, lifespan, or other very long-term potential endpoints for clinical trials of interventions that target basic aging processes, including SASP-inhibitors or senolytics, would be difficult or next to impossible to study for reasons that are obvious, as would endpoints occurring in old age as a consequence of beginning to administer a drug in adulthood or middle-age. Initial trials of senolytics or other agents that target fundamental aging processes will need to test effects on endpoints that can be measured weeks to a couple of years after initiating treatment. Furthermore, because the risk:benefit ratio must favor benefits for the ethical conduct of clinical trials, new interventions would have to be tested in situations in which side-effects would be considered to be acceptable. In diseases for which no effective treatment is available, some side effects may be acceptable in individuals who are already symptomatic or who are almost certain to become symptomatic within a short time. If any consequential side effects are anticipated, the treatment would also need to address a problem that would cause serious harm if left untreated.

There is a possibility that senolytics and SASP inhibitors could be transformative, substantially benefiting the large numbers on patients with chronic diseases and enhancing healthspan. That said, as this is a very new treatment paradigm, there are many obstacles to overcome. Treatments that appear to be highly promising in mice frequently fail once clinical trials start, with lack of effectiveness in humans compared to mice related to the unique aspects of human biology, unforeseen side-effects, and a host of other issues. At least one reassuring advantage of targeting cellular senescence is the conservation of fundamental aging mechanisms such as senescence across mammalian species. In diseases like Alzheimer's dementia, atherosclerosis, or non-injury-related osteoarthritis, which do not occur naturally in mice, translation from genetically- or surgically-induced mouse models of these conditions to humans is more likely to fail than conditions that are more evolutionarily conserved, such as aging. Furthermore, unlike the situation for developing drugs to eliminate infectious agents or cancer cells, not every senescent cell needs to be eliminated to have beneficial effects. Unlike microbes or cancer cells, senescent cells do not divide, decreasing risk of developing drug resistance and, possibly, speed of recurrence. With respect to risk of side-effects, single or intermittent doses of senolytics appear to alleviate at least some age- or senescence-related conditions in mice. This suggests that intermittent treatment may eventually be feasible in humans.